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Long non-coding RNA signature in gastric cancer
Journal Pre-proof Long non-coding RNA signature in gastric cancer
Soudeh Ghafouri-Fard, Mohammad Taheri PII:
S0014-4800(19)30823-8
DOI:
https://doi.org/10.1016/j.yexmp.2019.104365
Reference:
YEXMP 104365
To appear in:
Experimental and Molecular Pathology
Received date:
28 October 2019
Revised date:
18 December 2019
Accepted date:
28 December 2019
Please cite this article as: S. Ghafouri-Fard and M. Taheri, Long non-coding RNA signature in gastric cancer, Experimental and Molecular Pathology(2019), https://doi.org/ 10.1016/j.yexmp.2019.104365
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© 2019 Published by Elsevier.
Journal Pre-proof Long non-coding RNA signature in gastric cancer Soudeh Ghafouri-Fard1, Mohammad Taheri 2* 1. Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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2. Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Corresponding author: Mahammad Taheri Tel & Fax: 00982323872572 Email: [email protected]
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Journal Pre-proof Abstract Gastric cancer as a common human malignancy has been associated with aberrant expressions of several coding and non-coding genes. Long non-coding RNAs (lncRNAs) as regulators of gene expressions at different genomic, transcriptomic and post-
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transcriptomic levels are among putative biomarkers and therapeutic targets in gastric cancer. In the present study, we have searched available literature and listed lncRNAs that are involved in the pathogenesis of gastric cancer. In addition, we discuss associations
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between expressions of these lncRNAs and tumoral features or risk factors for gastric cancer. Based on the established role of
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lncRNAs in regulation of genomic stability, cell cycle, apoptosis, angiogenesis and other aspects of cell physiology, the potential of
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these transcripts as therapeutic targets in gastric cancer should be evaluated in future studies.
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Key words: lncRNA, gastric cancer, expression
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Journal Pre-proof Introduction Long non-coding RNAs (lncRNAs) are a group of transcripts that modulate many cellular functions (Soudyab et al., 2016, Taheri et al., 2018). With a total length of more than 200 nucleotides, they regulate expression of genes through chromatin remodeling as well
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as transcriptional and post-transcriptional alterations (Dykes and Emanueli, 2017, Kaikkonen et al., 2011). Aberrant expression of lncRNAs in a variety of human malignancies has implied their role in the pathogenesis of cancer(Ghafouri-Fard et al., 2019).
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Moreover, a number of recent studies have shown associations between lncRNA genomic variants and risk of common cancers
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(Taheri et al., 2017a, Taheri et al., 2017b). Taken together, lncRNAs are putative culprits in the pathogenesis of cancer and potential biomarkers and therapeutic targets in this regard.
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Globally, gastric cancer (GC) is the fourth most prevalent malignancy and has ranked the second position in cancer-related mortality
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(Sitarz et al., 2018). Both environmental and genetic factors are involved in the pathogenesis of this cancer (Sitarz et al., 2018). Diet,
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infection with Helicobacter pylori (H. pylori) or Epstein–Barr virus (EBV), obesity, pernicious anemia, blood type A and germline mutations in some genes including CDH1 are among the recognized risk factors for GC (Sitarz et al., 2018). A recent study has shown associations between some single nucleotide polymorphisms (SNPs) within lncRNAs and reduced risk of GC through in silico screening of differentially expressed lncRNAs and confirmation of the results in a population of GC patients and normal subjects (Duan et al., 2018). Others have assessed expression profile of selected lncRNAs in GC tissues/ cell line compared with normal tissues/ cell lines (Chen et al., 2017c). Several studies have reported associations between expression levels of lncRNAs in GC tissues
Journal Pre-proof and tumor features such as depth, distant metastasis, lymph node involvement and clinical stage (Zhu et al., 2017a, Esfandi et al., 2019b, Esfandi et al., 2019a, Esfandi et al., 2019d, Esfandi et al., 2019c). Based on the results of previous studies regarding aberrant expression of lncRNAs in GC, we conducted the current study to systematically search for lncRNAs with putative roles in the pathogenesis of GC.
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Search method
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PubMed, Google scholar, Web of Science and Scopus databases were searched with the key words "gastric cancer" or "gastric
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malignancy" AND "long non-coding RNA" or "lncRNA". We included only English original articles for subsequent assessments.
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Next, we screened them based on the number of specimens used for expression analysis and report of the clinical data of patients. We
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also included in vitro studies with adequate mechanistic evaluations. Based on their expression levels in tumoral tissues compared
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with non-tumoral tissues and functional experiments they can be divided to oncogenic lncRNAs and tumor suppressor lncRNAs.
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Tables 1 and 2 summarize information of these two subsets of lncRNAs respectively. Table 1. Up-regulated lncRNAs in GC (OS: overall survival, DFS: disease free survival). LncRNA
Chromosomal location
Number of cases
Signaling pathway
Correlation with patients' outcome
Function
Reference
Journal Pre-proof TP73-AS1
1p36.32
58 pairs of GC tissues and adjacent nontumor tissues
HMGB1signaling, RAGE signaling , NF-κB
Shorter OS
cell proliferation, cell cycle and apoptosis
76 paired GC samples and matched nontumor tissues
Bcl-2/caspase-3 pathway
Shorter OS
cell proliferation, metastatic properties, EMT, (Zhang et al., tumor growth 2018f)
-
Shorter OS
cell proliferation
SNHG1
11q12.3
50 GC tissues and pair-matched adjacent normal
SNHG6
8q13.1; 8q13
data mining from Oncomine database (69 MAPK pathways, JNK tissue samples) + serum of 114 GC pathway patients and 99 healthy subjects
-
78 GC tissues with matched adjacent normal tissues
EMT
Shorter OS
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(Peng, 2018)
(Hu et al., 2017b)
cell proliferation and senescence , tumor growth
(Li et al., 2018d)
cell growth, cell migration, EMT
(Yan et al., 2017b)
Proliferation
(Wang et al., 2017a)
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SNHG8 lncRNA was found to affect several gastric cancer-specific pathways and target genes of EBV
(Huang et al., 2016b)
Shorter OS
cell growth, colony formation, proliferation and invasion
(Zhang and Lu, 2018)
miR-145/SOX9 axis and PI3 K/AKT/mTOR
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cell viability, migration, invasion, and cell apoptosis
(Liu et al., 2018g)
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SNHG7
9q34.3
68 GC tissues with matched adjacent normal tissues
-
SNHG8
4q26
88 paired GC and adjacent tissues
-
SNHG12
1p35.3
SNHG14
15q11.2
20 GC patients
SNHG13 (DANCR)
4q12
65 pairs of GC tissues and adjacent normal tissues+ 55 serum samples of GC patients and 39 healthy controls
EMT
-
proliferation, apoptosis, migration and invasion
(Pan et al., 2018)
60 pairs of GC and corresponding nontumor gastric tissues
DANCR–lncRNA-LET axis
-
migration and invasion
(Mao et al., 2017)
GC tissues of the 118-patient cohort
-
Shorter OS
proliferation, cell metabolism
(Hao et al., 2017)
106 paired GC samples and adjacent histologically normal tissues
-
Shorter OS
cell proliferation
(Chen et al., 2016c)
SNHG15
7p13
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-
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Journal Pre-proof SNHG16
17q25.1
122 tumor tissue and the corresponding adjacent tissues
-
-
proliferation, apoptosis, invasion, migration, tumor growth
(Lian et al., 2017)
SNHG20
17q25.2
Cell line study
EMT, GSK-3β/β-catenin signaling pathway
-
proliferation and invasion, EMT
(Liu et al., 2017a)
UCA1
19p13.12
Cell Line study
UCA1-miR-7-5p-EGFR axis -
cell migration
(Liu et al., 2018d)
82 GC tissues and adjacent non-tumor tissues
-
GC tissues and matched normal tissues were collected from 39 patients
AKT/GSK-3B/cyclin D1 axis -
102 paired GC tissues and adjacent noncancerous
PI3K-Akt-mTOR signaling pathway
-
49 primary cancer tissues and the paired adjacent non-tumor tissue
-
-
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28 GC tissues and adjacent normal tissues UCA1
19p13.12
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associated with lymph node metastasis, TNM stage, tumor size
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Metastasis, Proliferation
(Wang et al., 2017b)
cell migration and invasion, metastasis
(Wang et al., 2017b) (Ke et al., 2017)
regulation of chemosensitivity
(Fang et al., 2016)
UCA1/miR-590-3p/ CREB1 associated with lymph axis node metastasis, TNM stage , worse survival
cell proliferation and cell invasion
(Gu et al., 2018)
GC tissues and matched non-tumour tissues were collected from 48 patients
ERK-MMP9 signalling pathway, ubiquitinproteasome pathway
-
migration and invasiveness, metastasis, ubiquitination
(Wang et al., 2017c)
Cell line Study
PI3K/AKT/GSK3β and NFκB signal pathways
-
Apoptosis, cell viability, migration, invasion
(Qin et al., 2018a)
37 paired GC tissues and the corresponding adjacent normal tissues
TGFb1/UCA1-EMT
Poor clinicopathological Cell proliferation, and invasion and migration, (Zuo et al., 2017) parameters and shorter EMT OS
77 GC and adjacent normal tissues
PI3K/AKT pathway
Shorter OS
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62 GC tissue samples and matched adjacent normal tissues
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(Li et al., 2018a)
Proliferation, Apoptosis, chemotherapy resistance
(Shang et al., 2016)
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GHET1
7q36.1
112 tumor tissue samples and matched normal adjacent tissue
-
shorter 5-year OS and DFS
42 GC tissues and pair-matched adjacent normal gastric tissues
-
Shorter OS
Proliferation
GC tissues and paired adjacent tissues (>5 cm from the tumor) from 42 GC patients
-
cell proliferation, cell migration and invasion, (Xia et al., 2018) metastasis
20 pairs of gastric cancer tissues and Numb/Cyclin D1 and adjacent tumor tissues from gastric cancer Numb/MMP2/9. patients
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40 gastric carcinoma tissues that 20 samples from cisplatin sensitive patients and another 20 from drug-resistant patients were obtain
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2p16.1
21 paired GC tissues and adjacent normal MAPK, JAK-STAT and tissues ERBB signaling pathway
CCAT1 (CARLO5)
8q24.21
57 GC tissue samples than in 57 paired adjacent normal tissue
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51 paired GC and adjacent non-tumor gastic tissues
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ERK/MAPK pathway.
(Huang et al., 2017c)
apoptosis
(Huang et al., 2017c)
Shorter OS
cell cycle, apoptosis, invasion, metastasis
(Huang and Chen, 2018)
-
cell proliferation, apoptosis, invasion
(Huang et al., 2017c)
-
Proliferation, apoptosis
(Zhang et al., 2014c)
cell migration
(Zhou et al., 2016a)
30 paired GC/nontumor specimens
CCAT1/miR-490/hnRNPA1 axis
240 GC tissue samples and matched normal tissues
-
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(Yang et al., 2014)
cell cycle, invasion and migration
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LINC01793
(Zheng et al., 2015a)
Shorter OS
(Liu and Shangguan, 2017)
19 paired gastric carcinoma Tissue samples +19 Normal gastric tissues from obese patients, undergoing laparoscopic sleeve gastrectomy.
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Within the normal gastric tissue samples, no significant difference in CCAT1 expression was observed in helicobacter pylori negative and positive patients.
(Mizrahi et al., 2015)
20 gastric carcinoma tissues and their pair-matched adjacent normal gastric tissues
-
proliferation and migration
(Yang et al., 2013)
-
Journal Pre-proof CCAT2
8q24.21
85 gastric cancer and adjacent non-tumor tissues
Shorter OS
108 gastric cancer tissue and adjacent normal tissue
EMT
Shorter DFS and OS
cell proliferation, migration and invasion, EMT
(Wang et al., 2016c)
208 paired normal and cancerous gastric tissues
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unfavorable prognostic factor
cell proliferation and invasion
(Wu et al., 2017b)
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167 blood samples of GC patients and 110 blood samples from healthy controls + 20 paired GC tissues with matched adjacent normal tissues
-
associated with tumor size, TNM stage and shorter OS
cell proliferation, apoptosis
(Xie et al., 2015b)
Shorter OS
cell growth
(Xu et al., 2018c)
tumor promoter via PTENAKT-slug pathway
Shorter OS
proliferation, migration and invasion
(Luo et al., 2018d)
NF-κB1
-
GC cell growth, Apoptosis
(Zhou et al., 2015b)
HOXA-AS2
7p15.2
55 paired GC and corresponding adjacent HOXA-AS2non-tumorous gastric samples P21/PLK3/DDIT3- EZH2
FOXD2-AS1
1p33
106 The tumor/adjacent non-tumor tissue -
linc-GPR65-1 14q31.3 (LINC01146-202) (ENST00000553929.5)
50 gastric cancer tissues and paired normal tissues
BANCR
30 paired gastric adenocarcinoma tissues and adjacent tissues,
9q21.11-q21.12
(Liu et al., 2015b)
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(Zhang et al., 2017a)
167 blood samples of GC patients and 110 blood samples from healthy controls + 20 paired GC tissues with matched adjacent normal tissues
-
(Zhang et al., 2017a)
-
(Zhang et al., 2017a)
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AOC4P
17q21.31
167 blood samples of GC patients and 110 blood samples from healthy controls + 20 paired GC tissues with matched adjacent normal tissues
LINC01606
8q12
75 human GC tissues and respective ANTs
Wnt/β-catenin signaling, contributes to poor working as a ceRNA of miR- nutritional status in 423-5p in GC cells patients with GC
invasion and metastasis
(Luo et al., 2018d)
Journal Pre-proof EGFR-AS1
7p11.2
58 GC tissues and pair adjacent normal gastric tissues
-
-
LINC00324
17p13.1
66 paired GC and corresponding normal adjacent tissues
“LINC00324-HuRFAM83B” axis
Shorter DFS (P < 0.001) Proliferation, Apoptosis, migration and OS (P < 0.001).
MACC1-AS1
7p21.1
123 pairs of GC tissues and matched adjacent normal gastric mucosa tissues (FFPE)
promotes MACC1 mRNA Shorter OS stability via the AMPK/Lin28 pathway
EGOT (EGO)
3p26.1
39 GC patients
Hedgehog Pathway
ETS1-AS1 (pancEts-1)
11q24.3
30 Normal gastric tissues from biopsies + pancEts-1/ NONO/ERG/Ets- Shorter OS Fresh cancer and precancerous specimens 1 axis from 81 primary cases of gastric cancer
MALAT1
11q13.1
cell line study
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25 Gastric adenocarcinoma tissues and matched normal adjacent tissues 11q13.1
cell viability, metabolic plasticity, cell proliferation, metastasis
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150 pairs of GC tissues and corresponding non-cancerous gastric mucosa
MALAT1
cell proliferation
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the cell proliferation, cell differentiation
-
(Zou et al., 2018)
(Zhao et al., 2018c)
(Peng et al., 2017)
(Luo et al., 2018a)
(Wang et al., 2014a) (Okugawa et al., 2014)
-
migration and invasion, metastasis
(Deng et al., 2016a)
plasma samples from 72 GC patients and miR-122-IGF-1R axis 36 healthy controls+ 25 pairs gastric cancer tissue
Shorter OS
proliferation, cell cycle progression and apoptosis, migration and invasion
(Xia et al., 2016)
60 cases fresh-frozen gastric cancer tissues and adjacent normal tissues
MALAT1/miR-202/Gli2 pathway
-
proliferation and cell apoptosis
(Zhang et al., 2017c)
50 fresh gastric cancer tissue and paired adjacent
β-catenin signaling
-
cell proliferation and apoptosis, invasiveness and migration
(Lee et al., 2017)
150 GC and 15 peritumoral paraffinembedded tissues
VE-cadherin/β-catenin, Shorter OS ERK/MMP and FAK/paxillin
migration and invasion, angiogenesis
(Li et al., 2017a)
20 GC and 20 adjacent normal
EMT
migration and invasion, metastasis, EMT
(Chen et al., 2017a)
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(Hu et al., 2018)
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Journal Pre-proof
TRERNA1
20q13.13
78 GC tissues and adjacent non-cancerous MALAT1/miRtissues 1297/HMGB2
Shorter OS
38 pairs of gastric tumor and adjacent normal paraffin-embedded tissue
EMT
-
cell proliferation, cell cycle progression and cell apoptosis, EMT
(Li et al., 2017b)
Cell line study
-
-
autophagy
(YiRen et al., 2017)
48 paired fresh gastric cancer tissues and adjacent non tumorous
TFAP4-TRERNA1 axis
-
48 fresh GC tissues and paired adjacent non-tumor tissues
EMT
-
DLEU2
13q14.2
12 paired GC tissues, compared with adjacent normal tissues
-
DDX11-AS1 (SCAT4)
12p11.21
12 paired GC tissues, compared with adjacent normal tissues
-
MIAT
22q12.1
120 Paired gastric cancer and normal gastric tissue
HOTAIR
6p24.3
12q13.13
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(Liu et al., 2018a)
cell invasion and migration, metastasis, EMT (Wu et al., 2017a)
Cell Proliferation, cell proliferation
-
(Liu et al., 2018a)
(Liu et al., 2018a)
MIAT/miR-141/DDX5
-
cell proliferation, apoptosis, migration, invasion, metastasis
(Sha et al., 2018)
miR-29a-3p/HDAC4 axis
-
proliferation, migration and invasion
(Du et al., 2017)
GC tissue samples from 42 GC + Plasma samples from 42 GC patients and 25 volunteers
EMT
Shorter OS
Apoptosis, chemoresistance
(Zhang et al., 2016c)
Serum samples from 173 GC, 30 gastric polyps, 30 high atypical hyperplasia or intestinal metaplasia, patients and 110 age-matched healthy controls
-
Shorter OS
serum HULC expression was significantly correlated with H. pylori infection
(Jin et al., 2016a)
58 of GC tissues and adjacent non-cancer EMT tissues
-
Proliferation, Apoptosis, Autophagy
(Zhao et al., 2014)
30 of GC samples and paired non-tumor tissues
-
drug resistance, cell proliferation, cell cycle, and migration
(Wang et al., 2018b)
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HULC
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migration and invasion
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(Li et al., 2017a)
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Journal Pre-proof 150 pairs of GC tissues and noncancerous gastric mucosa
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associated with cell proliferation, tumorigenicity, migration peritoneal metastasis and and invasion poor outcome
(Okugawa et al., 2014)
Plasma from 50 patients with newly diagnosed gastric cancer and 50 age- and sex-matched healthy controls
-
metastasis
(Elsayed et al., 2018)
32 pairs of GC tumor tissues
-
Shorter OS
cell proliferation, chemosensitivity, invasion, (Feng and Huang, metastasis 2017)
27 GC and adjacent normal tissues
PI3K/Akt Wnt/β-catenin
-
65 primary GC patients
EMT
Shorter OS
30 paired primary gastric cancer and adjacent noncancerous tissues
PI3K/AKT/MRP1
-
Gastric cancer tissues were obtained from 40 patients
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GA tissues from 168 patients
HOTAIR
12q13.13
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-
migration and invasion
(Wu et al., 2017a)
cell resistance to cisplatin
(Yan et al., 2016)
cell proliferation
(Ma et al., 2016c)
-
(Zhang et al., 2015b)
60 GC tissues and matched adjacent tissue -
-
(Song et al., 2015)
61 matched tumor tissues and adjacent non-tumor tissues
Shorter OS
invasion and metastasis, EMT
(Liu et al., 2015b)
50 FFPE gastric cancer and adjacent non- tumors gastric tissues
Shorter OS
cell motility and invasion, metastasis, tumor growth
(Zhang et al., 2015b)
83 pairs of human GC and adjacent noncancerous tissues.
EMT
Shorter OS
Metastasis, EMT, Invasiveness
(Xu et al., 2013)
31 pairs of specimens, tumor tissues and their adjacent normal ones,
-
-
(Hajjari et al., 2013)
68 gastric cancer tissues
-
-
(Endo et al., 2013)
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Apoptosis, multidrug-resistance tumor growth (Cheng et al., 2018)
HGF/C-Met/Snail pathway, EMT
Journal Pre-proof 78 paired gastric cancer and adjacent samples
CYTOR (C2orf59) or (LINC00152) or (ENSG00000222041)
2p11.2
-
Shorter OS
cell proliferation and apoptosis, migration and (Liu et al., 2014c) invasion
60 specimens of gastric cancer tissues and adjacent benign tissues
-
metastasis
50 gastric cancer tissue and paired adjacent tissue
EMT
-
cell proliferation and apoptosis, cell motility, (Lee et al., 2014b) EMT, invasion and migration
60 paired GC samples
EMT
-
20 GC tissues and adjacent normal tissue LINC00152/miR-193asamples 3p/MCL1 pathway -
Cell line study
Wnt/beta-Catenin Pathway
Shorter OS
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72 cases of patients who underwent gastric cancer radical resection
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cell viability and colony formation, apoptosis, (Zhao et al., 2015) cell proliferation, EMT, migration and invasion cells proliferation, tumor growth
(Huang et al., 2018)
cell glycolysis
(Sun et al., 2018a)
Cell Proliferation and Metastasis
(Shan et al., 2017b) (Pang et al., 2014)
PI3K/AKT
-
cell proliferation, tumor growth
(Zhou et al., 2015a)
-
Shorter OS
cell proliferation
(Chen et al., 2016d)
-
-
-
(Yang et al., 2016a)
Paired plasma samples (preoperative and postoperative) from 79 GC patients + 31 plasma samples from patients with GED + Control samples from 81 healthy volunteers
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97 primary GC patients
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serum samples from 285 subjects = 133 GC cases + 152 control samples 2p11.2
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Cell line study
71 pairs of tumorous and adjacent normal tissues + Gastric juice from 17 patients with gastric cancer and 16 normal mucosa or minimal gastritis
CYTOR (C2orf59) or (LINC00152) or (ENSG00000222041)
-
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(Emadi-Andani et al., 2014)
(Li et al., 2015)
Journal Pre-proof FEZF1-AS1
NEAT1
7q31.32
11q13.1
82 matched tumor tissues and adjacent non-tumor tissues
-
associated with tumor size, stage and poor survival
104 matched gastric cancer (GC) tissues and adjacent non-tumor tissues
Wnt/β-catenin signaling pathway
Shorter OS
-
NEAT1-miR-335-5p-ROCK1 axis
20 Fresh-frozen GC tissues and the adjacent non-tumorous tissues
PI3K/AKT and GSK3β Pathways
-
Cell line
-
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131 GAC samples
-
104 freshly frozen gastric cancer samples EMT and 20 paired adjacent normal tissue PVT1
8q24.21
63 paired gastric cancer samples and adjacent
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Angiogenesis, STAT3/VEGFA axis
20 GC tissue samples and matched normal tissue samples
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PVT1
8q24.21
(Liu et al., 2017b)
(Wu et al., 2017c)
Proliferation, migration and invasion
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Cell Viability and Migration
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76 GC and control normal stomach tissues (NT) were
cells proliferation, apoptosis
Chemotherapy Resistance, Apoptosis
-
(Zhang et al., 2018b) (Wang et al., 2018a) (Tan et al., 2018)
(Zhao et al., 2018b)
(Ma et al., 2016d)
Shorter OS
cancer cells migration and invasion, EMT
(Fu et al., 2016)
Shorter OS
cell proliferation, angiogenesis, migration
(Zhao et al., 2018b)
-
(Liu et al., 2017b)
68 cases patients tissues samples and matched adjacent normal tissues
PVT1/miR-186/HIF-1α axis
-
cell proliferation
(Huang et al., 2017b)
190 pairs of gastric cancertissues and adjacent normal mucosa tissues (ANT)
-
Shorter OS
cell proliferation and invasion
(Xu et al., 2017a)
111pairs of gastric cancer and adjacent normal tissues
-
Shorter OS
(Yuan et al., 2016)
70 patients with primary gastric cancer were enrolled in this study.
mTOR/HIF-1α/P-gp and MRP1 signaling pathway.
-
(Zhang et al., 2015a)
80 GC tissues
-
Shorter OS
Proliferation
(Kong et al., 2015)
Journal Pre-proof
circPVT1
8q24.21
33 tumor tissues and corresponding noncancerous tissues
-
-
20 paired normal and cancerous gastric tissues
-
better OS
(Ding et al., 2014)
Proliferation
(Chen et al., 2017b)
Better overall survival, seems to contradict the upregulation of circPVT1 in GC. A possible explanation may be the association of circPVT1 with the tumor suppressor miR125.
H19
11p15.5
22 matched normal gastric tissue samples -
-
24 human gastric cancer tissues
H19/miR-675/RUNX1
-
serum samples from 285 subjects = 133 GC cases + 152 control samples
-
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80 primary GC patients
-
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106 gastric cancer patients
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Plasma of 90 patients and 90 controls
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15 patients with GC and paired adjacent histologically normal tissues
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Proliferation, apoptosis
(Yang et al., 2012)
cell proliferation, cell growth, cell apoptosis
(Zhuang et al., 2014) (Yang et al., 2016a)
Shorter OS
cell viability and colony formation
(Zhang et al., 2014a)
Shorter OS
Proliferation, cell migration and invasion, metastasis
(Li et al., 2014)
-
-
-
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(Zhou et al., 2015d) cell proliferation and invasion
23 endoscopic biopsy samples and 91 AKT/mTOR Pathway surgery samples from patients with gastric cancer tumor specimens from 39 patients
H19
11p15
EMT
128 paired GC samples and adjacent normal tissues + Gastric from 56 subjects
(Zhou et al., 2015c)
(Liu et al., 2016a)
-
proliferation, invasion, chemo-resistance, EMT
(Ishii et al., 2017)
Shorter OS
cell migration and invasion
(Chen et al., 2016b)
Journal Pre-proof
ANRIL (CDKN2BAS1)
GAPLINC
9p21.3
18p11.31
Plasma from 32 GC patients and 30 age and sex matched healthy.
-
-
(Hashad et al., 2016)
34 Paired gastric cancer tissue samples and adjacent tissues
H19/miR-675/ FADD/caspase 8/caspase 3
-
Cant access full article
-
Shorter OS
(Wei et al., 2018)
Plasma from 40 GC patients and 42 age and sex-matched controls.
-
-
(Yoruker et al., 2018)
20 paired human gastric cancer tissues
Notch and mTOR signal pathways
-
83 tumor tissue samples
-
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184 cases of gastric cancer + 23 biopsytissue specimens
-
120 paired GC tissues and adjacent normal tissues
-
cell proliferation and cell apoptosis
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cell viability, migration, and invasion and apoptosis
(Yan et al., 2017a)
(Liu et al., 2018e)
cell proliferation, cell migration and invasion, (Lan et al., 2016) apoptosis Proliferation and Colony Formation
(Deng et al., 2016b)
associated with tumor size, TNM stage and poor prognosis
cell proliferation
(Zhang et al., 2014b)
-
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cell proliferation
(Diao et al., 2018)
18 normal gastric tissues (NGT), 17 highly differentiated gastric adenocarcinoma (HDAC), and 16 poorly differentiated gastric adenocarcinoma (PDAC) tissues
Tumor angiogenesis
Shorter OS
cell proliferation, migration, and invasion, apoptosis
(Liu et al., 2016b)
48 paired normal gastric tissues and gastric cancer tissues
-
Shorter OS
proliferation and invasion
(Hu et al., 2014)
proliferation and metastasis
(Lin et al., 2018b)
53 tumor and paired adjacent para-tumor tissues
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l a
Jo
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GCRL1 (SMIM25)
20q13.13
26 pairs of human GC tissues and matched adjacent tissues
GCRL1, miR-885-3p, and CDK4 Axis
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PlncRNA-1 (CBR3AS1)
21q22.12
35 Snap-frozen tumoral and adjacent nontumoral paired tissue
-
-
(Baratieh et al., 2017)
Journal Pre-proof LINC00941 (lncRNAMUF)
12p11.21
82 Fresh tumor tissues and adjacent tissues
-
-
(Luo et al., 2018a)
TUG1
22q12.2
35 Snap-frozen tumoral and adjacent nontumoral paired tissue
-
-
(Baratieh et al., 2017)
40 pairs of gastric carcinoma and paracarcinoma RNA specimens
-
-
100 paired GC tissues and adjacent normal tissues using
-
Shorter OS
Cell line
-
-
146 paired GC samples
-
shorter 5-year OS rates
PANDAR (PANDA)
6p21.2
100 paired noncancerous and cancer tissue samples SOX2-OT (NCRNA00043)
3q26.33
30 gastric cancer tissues and 30 adjacent histological normal tissues
invasion
f o
ro
-p
cell proliferation
(Zhang et al., 2016d)
Proliferation and Invasion, Tumor Growth
(Ren et al., 2017)
Proliferation, apoptosis
(Liu et al., 2018c)
Shorter OS
e r P
SOX2/miR-194-5p/AKT2 axis
(Ji et al., 2016)
(Ma et al., 2016b)
-
cells proliferation and metastasis ,invasion
(Qu and Cao, 2018)
Shorter OS
cell growth, cell migration and invasion
(Zhang et al., 2016d)
155 Human gastric cancer tissue and the adjacent normal tissue
-
l a
shorter 5-year and 5year DFS
-
-
proliferative activity and colony formation capacity, apoptosis
(Xu et al., 2018b)
-
Shorter OS
cell invasion and migration capacities
(Liu et al., 2018f)
76 GC tissues and adjacent nontumor tissues were collected
-
correlated with advanced proliferation and invasion, cell growth TNM stage, lymph node metastasis, and poor OS
(Zhang et al., 2018c)
124 gastric cancer tissues, 20 adjacent normal tissues and metastatic lymph nodes, and 20 gastritis tissues
EMT
unfavorable prognosis
(Li et al., 2017c)
132 fresh gastric cancer samples + 20 paired adjacent normal tissue
CCHE1 (CCEPR)
10q21.1
-
ZEB1-AS1
10p11.22
75 patients
n r u
Jo
-
(Zou et al., 2016)
cells migration, invasion and EMT process
Journal Pre-proof AK096174 (LINC01089) (LIMT)
12q24.31
32 GC tissue and paired-adjacent tissue
-
Shorter OS
proliferation, migration, and invasiveness
(Zhang et al., 2018g)
DGCR9 (DGS-A)
22q11.21
102 FFPE gastric cancer tissues and adjacent noncancer tissues (NAT)
-
-
cellular proliferation, migration, and glucose metabolism
(Ni et al., 2018)
DQ786243
1q22 (chr1:155234457155239960)
172 cases of GC, along with the noncancerous tissues
-
Shorter OS
82 Paired tumor tissue and adjacent healthy tissue BLACAT1 (linc-UBC1) 1q32.1
-
85 gastric cancer and matched adjacent normal non-tumor tissues
-
long noncoding RNA M26317
?
103 gastric cancer tissues by real timePCR + 436 gastric cancer tissues by in situ hybridization
CASC15
6p22.3
88 paired GC tissues and matched healthy EMT tissues
l a
o r p
-
e
Shorter OS
r P
rn
u o
f o
-
23 pairs of oxaliplatin-resistant gastric cancer and matched oxaliplatin-sensitive GC patients
42 normal gastric epithelial tissues and 60 gastric cancer tissues
(Zhang et al., 2018d) (Shan et al., 2017a)
apoptosis and invasion, tumor growth
(Wu et al., 2018b)
proliferation and invasion
(Hu et al., 2015)
Shorter OS
(Li et al., 2018b)
Shorter OS
cell proliferation, migration, EMT
(Wu et al., 2018a)
Shorter OS
proliferation and cell cloning
(Yao et al., 2017)
DLEU1
13q14.2-q14.3
68 pairs of GC tissues and normal tissues -
Shorter OS
cellular proliferative
(Li et al., 2018c)
LINC01234 (LCAL84)
12q24.13
50 paired GC and adjacent non-tumor tissues
LINC01234-miR-204-5pCBFB axis
Shorter OS
cell proliferation, apoptosis, gastric cancer cell growth
(Chen et al., 2018d)
Long non-coding RNA MSTO2P
1q22
80 paired gastric cancer tissues
-
Shorter OS
cell growth, colony formation, migration, and (Xu et al., 2017b) invasion
TCONS_00068220
8q11.21
GC tissues and matched NATs were collected from 15 patients
-
-
viability of GC cells, apoptosis
(Zhao et al., 2017b)
BCAR4
16p13.13
113 cases of gastric cancer tissue and adjacent tissue
β-catenin -Wnt signaling pathway
-
cisplatin-resistant
(Yang et al., 2017b)
J
Journal Pre-proof CRNDE (ENSG00000245694)
16q12.2
118 GC tissues and adjacent non-tumor tissues
PI3K/Akt Pathway
Shorter OS
Proliferation, Invasion and Migration
(Du et al., 2017)
20 pairs of GC tissues and adjacent nonmalignant gastric tissue samples
CRNDE/miR-145/E2F3 signaling pathway
-
proliferation
(Hu et al., 2017a)
SUMO1P3
1q23.2
96 Fresh gastric cancer tissues and adjacent nontumor tissues
-
-
(Mei et al., 2013)
HOTTIP
7p15.2
Serum exosomal HOTTIP from 126 GC patients and 120 healthy people
-
Shorter OS
98 Fresh primary GC tumor tissues and matched NATs
-
Shorter OS
50 paired gastric tissue samples
-
-
94 fresh gastric cancer tissues and matched NATs
-
l a
o r p
f o
e
(Zhao et al., 2018c)
cell proliferation and cell apoptosis, invasion/migration
(Ye et al., 2016)
cell growth, cell migration and invasion
(Chang et al., 2016)
MAP3K20-AS1 (MLK7-AS1)
2q31.1
123 gastric cancer specimens and 77 adjacent normal gastric mucosa
r P
-
Shorter OS
cell proliferation, apoptosis
(Quan et al., 2018)
ZFAS1
20q13.13
20 pairs of fresh gastric cancer specimens EMT, Wnt/β-catenin signaling.
-
Proliferation, migration, invasion, EMT, resistance to chemotherapeutic
(Xu et al., 2018d)
ZFAS1
20q13.13
94 paired GC tissue and adjacent normal tissue
-
proliferation and migration, cell apoptosis
(Pan et al., 2017)
ZFAS1
20q13.13
66 fresh paired human gastric tumor EMT tissues and 77 paired plasma (preoperative and postoperative) samples
ZFAS1
20q13.13
54 pair gastric cancer and normal tissues
HAGLR (HOXD-AS1)
2q31.1
HAGLROS (HAGLR 2q31.1 opposite strand lncRNA)
n r u
-
EMT
(Yang et al., 2017b)
Jo
-
(Zhou et al., 2016b)
Shorter OS
Proliferation, Apoptosis
(Nie et al., 2017)
104 biopsy samples of gastric tumor were JAK2/STAT3 pathway collected
-
cell proliferation, colony formation, cell growth
(Zheng et al., 2017)
84 paired GC and adjacent non-cancerous tissues from patients
Shorter OS
cell proliferation and invasion, sponge for miR-100-5p
(Chen et al., 2018c)
Journal Pre-proof LINC01296/miR-122/MMP- Shorter OS 9 pathway
LINC01296 (DUXAP9) 14q11.2
60 cases of gastric cancer specimens and matched adjacent normal tissue
LINC00673
79 paired GC tissues and adjacent normal tissues
Shorter OS and DFS
cell proliferation, cell migration and invasion (Ba et al., 2017)
73 paired GC tumors and adjacent nontumor tissues
-
Shorter OS
Cell Growth, Apoptosis, Cell Migration, Invasion, and Metastasis
Cell cycle
-
17q24.3
LINC00668
18p11.31
106 paired GC tissues and adjacent normal tissues
DUXAP8
22q11.1
72 paired GC tissues and adjacent normal tissues
Shorter OS
PCAT-1
8q24.21
110 pairs of primary gastric patients' cancer tissues and normal tissues
-
175 patients
-
f o
(Qin et al., 2018b)
(Huang et al., 2017a)
Proliferation
(Zhang et al., 2016a)
cell proliferation, apoptosis, cell migration
(Ma et al., 2017a)
Shorter OS
cell proliferation and migration
(Bi et al., 2017)
Shorter OS
cell proliferation, migration and invasion
(Cui et al., 2017)
o r p
e
r P
Proliferation, cells invasion and migration, apoptosis, tumor growth
LINC00978 (MIR4435- 2q13 2HG)
72 paired gastric cancer and adjacent non- TGF-β/ SMAD pathway cancerous tissues EMT
-
Apoptosis, migration and invasion
(Fu et al., 2018)
GACAT3 (LINC01458) 2p24.3 (lncRNA-AC130710)
42 paired GC and corresponding adjacent noncancerous tissues
Shorter OS
cell proliferation, colony formation, cell migration and invasion, tumor growth
(Feng et al., 2018)
rn
l a
78 Gastric cancer tissues and adjacent tissues
u o
J
cell line Study
-
-
STAT3 signaling pathway
-
(Xu et al., 2014a)
cell growth, cell proliferation, apoptosis, competing endogenous RNAs
(Lin et al., 2018a)
GACAT2 (MTCL1AS1) (lncRNA HMlincRNA717)
18p11.22
plasma from 80 healthy individuals, 29 patients with GD, 117 preoperative and 117 postoperative patients with GC
-
-
(Tan et al., 2016)
RP11-62F24.2 (BNC2AS1)
9p22.2
Cant access full text
-
-
(Xu et al., 2017b)
XIAP-AS1
Xq25
285 stomach adenocarcinoma and 33 normal tissues from TCGA were analyzed
-
Apoptosis, Proliferation
(Cai et al., 2017)
Journal Pre-proof lncRNA MRUL (MDR- 400 kb downstream 40 paired primary GC tissues and related and upregulated of ABCB1(=MDR1) noncancerous gastric mucosa lncRNA) 7q21.12
-
Shorter OS
apoptosis
(Wang et al., 2014c)
AK058003
chr10:8694778086950770
95 pairs of human primary GC tissues and AK058003/SNCG pathway adjacent gastric tissues
-
GC migration and invasion, Metastasis
(Wang et al., 2014b)
HIF1A-AS2
14q23.2
83 cancer tissues with matched paracarcinoma tissues
-
Shorter OS
Proliferation
(Chen et al., 2015)
SPRY4-IT1 (AK024556)
5q31.3
175 Paired tumor and adjacent normal tissues
-
-
BC032469
5p15.33
68 GC tissues and corresponding adjacent tissues
-
TINCR
19p13.3
56 paired tumor and adjacent nontumor tissue samples
80 patients underwent primary GC
XIST
LSINCT5
Xq13.2
5p15.33
e
TINCR/miR-375/PDK1
167 blood samples of GC patients and 110 blood samples from healthy controls + 20 paired GC tissues with matched adjacent normal tissues
n r u
l a
o r p
r P
-
f o
cell proliferation, colony formation, and cell migration/invasion.
(Peng et al., 2015b)
Proliferation
(Lu et al., 2016)
Proliferation
(Chen et al., 2017e)
-
E2F1/TINCR/STAU1/CDKN Shorter OS 2B signaling axis
(Zhang et al., 2017a)
Proliferation
(Xu et al., 2017b)
55 tumor tissues with adjacent nontumorous tissues
-
Shorter OS
cell proliferation, colony formation, apoptosis, (Xu et al., 2015) cell growth
98 GC and matched-normal tissue samples
miR-497/MACC1 axis
-
cell proliferation and invasion, tumor growth
(Ma et al., 2017b)
Cell line study
XIST-miR-185/TGF-β1 axis -
GC cell growth, migration and invasion
(Zhang et al., 2018e)
Jo
106 Fresh-frozen cancer tissues and paired miR-101/EZH2 pathway normal tissues
Shorter OS
cell proliferation, migration and invasion, tumor growth and metastasis
(Chen et al., 2016a)
71 GC tissues and paired adjacent noncancerous tissues 74 CRC tissues and paired adjacent noncancerous tissues
Shorter OS
proliferation
(Xu et al., 2014b)
-
Journal Pre-proof 71 GC tissues compared with nonmetastatic tissues.
-
-
cell migration and invasion, EMT
(Qi, 2018)
ABHD11-AS
7q11.23
Cant access to full text
-
-
(Lin et al., 2014)
ABHD11-AS
7q11.23
Tissue of 37 HGM, 34 BL, 29 GD, and 73 GC tissues + gastric juices from 45 normal mucosa or minimal gastritis, 16 atrophic gastritis, 30 gastric ulcers, and 39 GC
-
(Yang et al., 2016c)
SDMGC
located on chromosome 17
10 samples from non-stage IV GC tissues,10 samples from stage IV GC
-
Shorter OS
C21orf96 (RUNX1-IT1) 21q22.12
Cant access to full text
-
-
FRLnc1 (FOXM1related LncRNA 1) (GeneSymbol: RP11721K1.1)
41 tissue samples and neighboring noncancerous tissue
TGFβ1
Chr 17: 1353695413538079
l a
173 GC tissue samples with adjacent normal tissues
n r u
-
o r p
e
r P
-
f o
invasion and migration
(Yan et al., 2015)
tubular formation, migration and invasion. tumor progression
(Yang et al., 2016d)
cell migration, metastasis
(Cai et al., 2015)
Better OS
(Chong et al., 2018)
-
-
(Ma et al., 2016a)
-
-
(Dang et al., 2015b)
KRT18P55
17q11.2
97 GC patients
PCNA-AS1
20p12.3
90 tissue samples
Non-Coding RNA OTUB1-isoform 2
11q13.1
tissue samples from 156 patients
-
Shorter OS and DFS
linc-POU3F3 (PANTR1)
2q12.1
peripheral blood of 40 gastric cancer patients and 40 controls.
-
-
OR3A4 (OR3A4P)
17p13.3
25 paired gastric cancer tissues.
-
-
Metastasis, Invasion, cell migration, angiogenesis, tumor progression
HOXA11-AS
7p15.2
85 paired gastric cancer and adjacent nontumor tissues
EZH2/HOXA11-AS/LSD1 complex and HOXA11AS/miR-1297/EZH2 crosstalk
Shorter OS
cell proliferation, migration, and invasion and (Sun et al., 2016a) inhibits apoptosis, tumorigenesis
Jo
Apoptosis, tumor growth and tumor metastasis
(Wang et al., 2016b) (Xiong et al., 2015)
(Guo et al., 2016b)
Journal Pre-proof lncRNA ROR (LINCROR)
18q21.31
Tumor tissues were collected from 33 patients with gastric cancer
-
-
proliferation and invasion
(Wang et al., 2016a)
lncRNA-ATB
chr14:19,858,66719,941,024
20 paired GC tissue compared with adjacent normal tissiues
lnc-ATB/miR-141-3p/TGFβ2
Shorter OS
proliferation
(Lei et al., 2017)
HNF1A-AS1
12q24.31
99 fresh GC tissues and 8 non-tumorous gastric tissues
EGR1-mediated transcription of lncRNA-HNF1A-AS1
Proliferation
(Liu et al., 2018b)
CASC9 (linc-JPH1) (LINC00981)
8q21.13
89 GC tissues, compared with control NST
-
-
AGAP2-AS1 (PUNISHER)
12q14.1
50 paired GC and adjacent nontumor tissue samples
-
Shorter OS
RP11-357H14.17 (ENSG00000272763)
Chr17: 46,713,28546,724,385
48 Fresh primary DGC tumor tissues and matched normal adjacent tissues
AC010761.9
chr17:2707258727074670
145 fresh GA tissues +serum samples from the same patients
-
AK093735
chr12:9469752794700087
30 tumour and adjacent non-tumour tissues
l a
BC003519
chr10:9763279697635709
NR_003573 (ANXA2P2)
KRT7-AS
-
o r p
e
r P
-
f o
chemoresistance
(Shang et al., 2017)
cell proliferation, cell migration and invasion (Qi et al., 2017)
Proliferation, Apoptosis, cell migration and invasion
(Yang et al., 2017a) (Zhao et al., 2018a)
JAK-STAT Rap1 signaling pathway, RIG-I like receptor signalling pathway pancreas cancer pathway
(Fan et al., 2016)
tumour and adjacent non-tumour tissues from 30 GC patients
JAK-STAT chemokine signalling pathway VEGF signalling pathway and proteoglycans
-
(Fan et al., 2016)
9p13.3
tumour and adjacent non-tumour tissues from 30 GC patients
JAK-STAT NF-KB signalling pathway chemokine signalling pathway HIF-1 signalling pathway
-
(Fan et al., 2016)
12q13.13
matched NC-GC tissue pairs obtained from 31 GC patient
-
-
n r u
Jo
Proliferation and Migration
(Huang et al., 2016a)
Journal Pre-proof LINC00473
6q27
120 GC tissue samples and pared adjacent normal
independent unfavorable Metastasis ,cell migration and invasion factor
(Zhang and Song, 2018)
LINC00857
10q22.3
167 blood samples of GC patients and 110 blood samples from healthy controls + 20 paired GC tissues with matched adjacent normal tissues
-
(Zhang et al., 2017a)
60 pairs of fresh GC tissues and adjacent non‑tumor tissues
cell cycle signaling pathway regulate G1/S transition
Shorter OS
NNT-AS1
5p12
48 GC tissue samples with adjacent normal tissue
cell cycle
Shorter OS
ZFPM2-AS1
8q23.1
73 paired gastric tumor and normal adjacent gastric tissue specimens
p53 signaling pathway and apoptosis
GClnc1 (BC041951)
chr6:160100149160102293
165 cases of fresh gastric cancer and adjacent tissues
-
CTD-2541M15(MCPH1 8p23.1 -AS1)
82 GC tissues and adjacent non‑ tumor tissues
RP5-919F19 OR (AL109947.1) OR (LOC105377935) OR (ENSG00000223537)
6q21
82 GC tissues and adjacent non-tumor tissues
linc-UFC1 (LOC112543491)
Chr 1
AFAP1‑AS1 (LOC84740)
4p16.1
n r u
l a -
f o
(Pang et al., 2018)
cell cycle
(Chen et al., 2018a)
Shorter OS
tumor growth, proliferation, apoptosis
(Kong et al., 2018)
-
proliferation, invasiveness, and metastasis
(Sun et al., 2016b)
o r p
e
r P
-
cell proliferation
associated with TNM stage
(Li et al., 2018a)
associated with tumor differentiation degree; lymph node metastasis and TNM stage
Metastasis, significantly increased risk of lymph node metastasis
(Li et al., 2018a)
79 paired gastric cancer and adjacent non- UFC1/miR-498/Lin28b cancerous tissues + 60 serum samples signaling from GC, 35 from gastritis patients, and 40 from healthy donors
Shorter OS
cell proliferation, migration and invasion, cancer growth
(Li et al., 2018d)
80 pairs of tumor and matched normal tissues
EMT
Shorter OS
proliferation, migration and invasion, EMT, metastasis
(Zhao et al., 2018a)
10 pairs of human GC tissues and matched normal tissues, and 56 samples of unmatched GC tissues
-
associated with GC progression
cell proliferation, cell migration and invasion (Ye et al., 2018)
Jo
Journal Pre-proof 20 GC samples and the paired adjacent normal GC samples
PTEN/p-AKT pathway.
-
cell viability, cell proliferation and apoptosis
(Guo et al., 2017a)
91 primary GC tissues and their paired adjacent normal tissues
EMT
Shorter OS
Cell Proliferation, EMT
(Feng et al., 2017)
f o
Table 2. Down-regulated lncRNAs in GC (OS: overall survival, DFS: disease free survival). LncRNA
Chromosomal location Number of cases
SNHG5
6q14.3
o r p
Signaling pathway Correlation with patients' Function outcome
10 paired GC and non-tumor tissues+23 normal gastric tissues + 87 paired tissues Fresh GC tissues and paired noncancerous tissues
l a
r P
e -
SNHG5/miR-32 axis
-
-
-
EMT
-
Reference
cell proliferation, migration and invasion, (Zhao et al., 2016b) growth and metastasis Migration, cell migration, cell proliferation (Zhao et al., 2017a) We previously identified that SNHG5 is significantly down-regulated
SMIM10L2A (LINC0086)
Xq26.3
20 GC tissues and the matched normal tissues
RP11-789C1.1 (LINC01612)
4q33
Cell line
AP000459 (ENSG00000227716)
21q21.2
82 GC tissues and adjacent non-tumor tissues
LOC101928316
11p14.1
82 GC tissues and adjacent non‑tumor tissues
-
associated with tumor differentiation degree; and the sex of the patient
(Li et al., 2018a)
LINC01071 (TUSC8)
13q14.11
82 GC tissues and adjacent non‑tumor tissues
-
associated with patient age
(Li et al., 2018a)
u o
rn
J
(Yang et al., 2018)
Proliferation, migration, invasion, and EMT
(Liu et al., 2018g)
(Li et al., 2018a)
Journal Pre-proof pseudogene-derived long noncoding RNA SFTA1P
10p14
68 pairs of GC tissues and adjacent normal tissues
-
Shorter OS
cell proliferation, apoptosis, migration and (Luo et al., 2018b) invasion
MDC1-AS1
6p21.33
80 Tumor tissues and adjacent noncancerous tissues
-
-
Metastasis, cell proliferation
(Qin et al., 2018c)
GAS5
1q25.1
GC cell study
GAS5/miR-222 axis PTEN/Akt/ mTOR pathway
Cell Proliferation
(Mello et al., 2017)
40 Paired GC tissues and adjacent normal gastric mucosae
modulation of cell associated with larger cycle tumor sizes and more advanced stages
cell proliferation
(Guo et al., 2015)
paired tissue specimens were collected from 55 stomach cancer patients
GAS5/YBX1 pathway.
r P
-
cell cycle (Liu et al., 2015a) lncRNA GAS5 knock-down abolishes cell cycle arrest at the G1 phase.
cell cycle
larger tumor size and advanced pathologic stage, poorer DFS and OS
-
-
15 paired gastric cancer tissues and adjacent normal tissues
-
-
Apoptosis
(Zhang et al., 2016b)
cell migration, cell invasion, apoptosis, EMT
(Zhao et al., 2018d)
l a
89 gastric cancer
n r u
24 paired GC tissues
Jo
f o
o r p
e
ENST00000434223 (ENSG00000236914, (LINC01852 )
15q14
104 GC tissues and paracancerous tissues
Wnt/β-catenin signaling EMT
-
RP11-363E7.4 (ENST00000563205.1, lncACER2-1:1, AL158206.1-201)
9p22.1
GEO database (12 paired adjacent normal and tumor-matched tissues) + 5 pairs of GC tissues and non-cancerous tissues
-
better OS
cell proliferation and apoptosis
(Sun et al., 2014b)
(Sun et al., 2014b)
(Wang et al., 2018c)
Journal Pre-proof PWRN1
15q11.2
25 GC tissues and matched normal adjacent tissues
Modulate PTEN/Akt/MDM2 /p53 axis via repressing miR425-5p
cells viability, metastasis capacity, apoptosis, invasion, cell proliferation
(Chen et al., 2018e)
MEF2C-AS1
5q14.3
42 paired GC tissues and adjacent normal tissues
-
-
cell proliferation, cell migration
(Luo et al., 2018b)
LEIGC
2q14.1
35 paired GC samples and adjacent normal tissues
EMT
-
TUSC7
3q13.31
78 paired GC/nontumoral tissues
-
lncRNA BG981369
6q22.2
44 GC tissues and normal tissues
-
14q32.2
30 GC tissues and 30 normal tissues
EMT
(Han et al., 2014)
shorter DFS and DSS
tumor cell growth
(Qi et al., 2015)
-
Proliferation, Apoptosis, cell migration and invasion
(Dong et al., 2018)
-
invasion and migration, EMT, cell mobility, tumor growth and metastasis
(Xu et al., 2018a)
-
poor prognosis
cell proliferation, apoptosis
(Sun et al., 2014b)
-
associated with tumor lymph node metastasis differentiation degree and lymph node metastasis
(Li et al., 2018a)
30 GC tissues and 30 adjacent histological normal tissues
MEG3/miR-21 axis
-
proliferation and metastasis
(Dan et al., 2018)
GC tissue and adjacent tissue
-
-
proliferation and metastasis
(Wei and Wang, 2017)
50 pairs of GC tissue and matched adjacent normal tissue samples
-
-
cell proliferation, migration, invasion, and (Peng et al., 2015a) cell apoptosis
75 GC samples and 75 normal tissues
-
-
cell proliferation and cell cycle (Zhou et al., 2015b) progression and cell apoptosis, cell growth
134 Primary GCA tissues and adjacent normal tissues
-
-
cell proliferation and invasion
l a
72 paired GC samples and adjacent histological normal tissues
n r u
82 GC tissues and adjacent non‑tumor tissues
Jo
o r p
e
(LOC10537796) MEG3 (GTL2)
f o
EMT
r P
(Guo et al., 2017b)
Journal Pre-proof
MT1JP
16q13
52 gastric cancer samples
-
99 pairs of GC tissues and neighboring noncancerous tissues
MT1JP/MiR-214- 3p/RUNX3 Axis
cell proliferation, invasion and migration, (Xu et al., 2018e) and promoting apoptosis
80 pairs of matched normal and GC tissues
-
Poor Survival
cell proliferation, migration, invasion and (Zhang et al., 2018a) cell apoptosis, tumor growth and metastasis
50 pairs of primary gastric patients’ cancer tissues and paired adjacent nontumor tissue
-
-
-
-
LINC01006
7q36.3
187 gastric cancer tissues and their paired adjacent non-cancerous tissues
TMEM238L (LINC00675)
17p13.1-p12
in 45 pairs of GC and the adjacent non- tumor tissues, 20 healthy tissues,
SLC7A11-AS1
4q28.3
100 GC tissues and the paired adjacent non-cancerous tissues + from 33 GC patients before surgery and 20 healthy volunteers
MT1DP (MTM)
16q13
92 matched adjacent normal gastric mucosa (NGM) -GC tissue pairs
GACAT1 (AC096655.1-002) (LINC00876)
2q12.3
78 Paired gastric carcinomas tissues and normal tissue
GACAT2 (MTCL1-AS1) (lncRNA-HMlincRNA717)
18p11.22
107 gastric cancer tissues and paired adjacent nontumorous tissues + 37 human healthy gastric mucosa + 34 gastritis mucosa + 28 gastric precancerous lesions (dysplasia)
VPS9D1-AS1 (MYU)
16q24.3
126 primary GC tissues and matched adjacent non-tumorous tissues
lincRNA-p21 (TP53COR1) (linc- 6p21.2 p21)
l a
n r u
-
cell proliferation
o r p
e -
f o
cell proliferation, cell migration and invasion
(Yan et al., 2014)
(Lv et al., 2018)
(Zhu et al., 2017b)
proliferation, migration and invasion, growth, metastases
(Zeng et al., 2018)
ASK1 poor prognosis p38MAPK/JNK signaling pathway
Proliferation
(Luo et al., 2017)
-
cell migration and invasion, proliferation, (Lin et al., 2017) apoptosis
r P
Jo
shorter OS
-
(Sun et al., 2013)
(Shao et al., 2014a)
-
40 pairs of fresh GC tissues and adjacent EMT non-tumor tissues
Shorter OS
-
(Chen et al., 2017c)
EMT
(Chen et al., 2017d)
Journal Pre-proof MLLT4-AS1 (AFDN-DT)
6q27
98 pairs of human gastric cancer and adjacent non-cancerous tissues
-
Shorter OS
CASC2
10q26.11
69 fresh GC tissue specimens, with matched adjacent non-tumorous tissue
-
Shorter OS
(Lai et al., 2017)
67 fresh gastric cancer tissues and paired ERK1/2 and JNK adjacent non-tumor tissues pathway FER1L4
FENDRR (FOXF1-AS1)
20q11.22
16q24.1
61 gastric cancer tissues with the marched adjacent normal tissues + 80 healthy blood, 83 preoperative GC blood, and 83 postoperative blood
-
-
20 gastric cancer tissue samples
-
-
158 paired gastric cancer samples and adjacent histologically normal tissues
-
42 paired gastric cancer tissues and adjacent normal tissues
-
l a
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(Zhou et al., 2017)
cell proliferation
(Du et al., 2016)
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ro
-p
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proliferation, cell invasion and angiogenesis
(Liu et al., 2014d)
(Xia et al., 2015)
Shorter OS
(Xu et al., 2014c)
associated with advanced cell proliferation, cell migration stage, poor differentiation and lymphatic metastasis
(Luo et al., 2018b)
NCRUPAR (ncR-uPAR)
5q13.3
fresh tissue samples were collected from 138 gastric cancer patients
-
(Liu et al., 2014a)
nc886 (VTRNA2-1)
5q31.1
88 pairs of a tumor and its adjacent normal gastric tissue sample
-
-
(Lee et al., 2014a)
AC138128.1
located on chromosome 94 fresh GC tissue samples and matched 19 normal adjacent tissue
-
(Chen et al., 2014)
RP11-119F7.4 (AL513534.1)
10q21.3
96 patients with gastric cancer, matched non-tumor adjacent tissues
-
(Xie et al., 2015a)
LINC00982
1p36.32
106 paired gastric cancer samples and adjacent histologically normal tissues
-
Shorter OS and DFS
HNF1A-AS1
12q24.31
161 GC tissue and non-neoplastic tissues
-
-
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cell proliferation and cell cycle progression
(Fei et al., 2016)
(Dang et al., 2015a)
Journal Pre-proof LINC00261 (ALIEN) (DEANR1) 20p11.21
80 tumor tissues + adjacent normal tissues
EMT
Shorter OS
cell cycle progression and apoptosis, invasion, tumour metastasis
(Yu et al., 2017)
WT1-AS
11p13
91 in tumor tissues + matched adjacent non-tumor tissues.
ERK signaling
-
Proliferation, migration and invasion, tumor growth and metastasis
(Du et al., 2016)
lncRNA AI364715
chromosome 15
75 gastric cancer tissues and paired adjacent non-tumorous tissues + 18 human healthy gastric mucosa and 18 gastric precancerous lesions (dysplasia) from biopsy.
-
LncRNA-LOWEG
5p13.2
94 samples of matched non-tumor adjacent tissue
-
-
long noncoding RNA ZMAT1 transcript variant 2
Xq22.1
89 pairs of human gastric cancer and adjacent noncancerous tissues
-
LINC00628
in the 2nd intron of PLEKHA6 in chromosome 1q32.1
82 GC patients
AK001091
chr2:1129558211318987
tumor and adjacent non-tumor tissues from 30 GC patients
AK024171
chr5:8069660580699107
lncRNA-LET (NPTN-IT1)
15q24.1
SPRY4-IT1 (AK024556)
5q31.3
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cell invasion
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(Zhu et al., 2015b)
(Zhao et al., 2016a)
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Shorter OS
-
Shorter OS
JAK-STAT CAMs and the TNF pathway
-
(Fan et al., 2016)
tumor and adjacent non-tumor tissues from 30 GC patients
JAK-STAT Notch pathway, AMPK pathway
-
(Fan et al., 2016)
93 gastric cancer samples
-
Shorter OS
(Zhou et al., 2014)
37 cases of paired gastric cancer specimens
-
-
cell proliferation, cell migration, apoptosis (Tian et al., 2017a)
61 Paired gastric cancer tissues and normal tissues
EMT
Shorter OS
Metastasis, EMT
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(Lai et al., 2015)
cells proliferation, migration and invasion (Shao et al., 2016)
(Xie et al., 2015a)
Journal Pre-proof LOC100130476
6q23.3
121 primary GCA tissues and adjacent normal tissues
PTENP1
9p13.3
36 GC biopsies and their paired adjacent PTENP1∼miRNA normal tissues ∼PTEN ceRNA network
RP11-19P22.6-001 (ENST00000579660)
17q11.2
110 astric cancer tissues and paired adjacent non-tumorous tissues
-
-
LOC101927497
chromosome 7: 92854909-92917151
Cell line
LOC101927497miR-574-5p axis
-
Uc.160
5q14.1
51 GC samples and nonneoplastic gastric mucosa
-
-
AA174084
chr13:103562012103562617
134 GC tissues and paired non-tumorous tissues
lncRNA-AF147447 (AC009084.3) Chr16: 6694466066945096
75 pairs of H. pylori positive and negative tissues + 50 pairs of H. pylori positive and negative tumor tissues
LncRNA-RMRP (RMRP)
132 paired gastric cancer tissues and non-tumorous tissues
9p13.3
l a
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-
Shorter OS
-
cell growth and induced apoptosis, migration and invasion
-
(Zhang et al., 2017b)
(Sun et al., 2017)
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cell proliferation and migration
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e
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-
-
(Guo et al., 2016a)
(Luo et al., 2018c)
(Honma et al., 2017)
(Shao et al., 2014b)
Cell proliferation and cell migration, (Zhou et al., 2016c) LncRNA AF147447 was decreased expressed in H. pylori infected tissues and cells (Shao et al., 2016)
Association between lncRNAs expression and H. pylori infection
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H. pylori alters inflammatory and autophagy mechanisms of host cells to strengthen its pathogenic effects. Various genetic factors in the host influence the initiation of GC by this bacterium. Certainly, epigenetic modifications through lncRNAs are among important host factors (Vaziri et al., 2018). Microarray analyses have shown differential expression of a number of lncRNAs in human gastric epithelial cell in relation with H. pylori infection (Yang et al., 2015). Assessment of expression profile of GES-1 cells with or without H.pylori infection has led to identification of a number of down-regulated (n345630, XLOC_004787, n378726
Journal Pre-proof and LINC00473) and up-regulated lncRNAs (XLOC_005517, LINC00152, XLOC_13370 and n408024) after H. pylori infection (Zhu et al., 2015a). A previous study has assessed the contribution of H. pylori infection in GC in relation with alterations in lncRNAs expression and found that H. pylori positive tissues have a particular lncRNAs signature. In vitro studies showed that expression of the tumor suppressor lncRNA-AF147447 is diminished by H. pylori infection (Zhou et al., 2016c). Another study has
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measured expression levels of three lncRNAs (H19, LINC00152, uc001lsz) in sera of GC patients and healthy subjects and reported
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significant associations between high expression of both H19 and LINC00152 and susceptibility to GC. Elevated expression levels of
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both lncRNAs cooperate with H. pylori infection to increase risk of GC. Consequently, serum H19 and LINC00152 have been
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suggested as possible biomarkers for identification of GC especially in H. pylori infected individuals (Yang et al., 2016b).
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Association between lncRNAs expression and EBV infection
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The relations between lncRNAs and EBV have been assessed by Huang et al. through sequencing of thousands of lncRNAs in a non-
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EBV-infected GC sample, an EBV-associated GC sample and their neighboring normal tissues. SNHG8 has been shown to have EBVassociated expression pattern as confirmed in an independent cohort patients as well. The interactions between this lncRNA and numerous GC-specific pathways and EBV target genes have been also demonstrated via bioinformatics tools (Huang et al., 2016c). More recently, Liu et al. reported over-expression of SNHG8 in the cultured EBV-associated GC cells compared with normal human gastric mucosal cells and EBV-negative GC cells. Notably, SNHG8 silencing has suppressed cell proliferation both in vitro and in vivo (Liu et al., 2018d).
Journal Pre-proof Role of lncRNAs in determination of GC patients’ outcome Aberrant expression of several lncRNAs has been associated with poor patients’ outcome in independent studies (Tables 1 and 2). Moreover, meta-analysis of available data has confirmed associations between elevated levels of a number of lncRNAs including
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ANRIL, ATB, BANCR, UCA1 and XIST and poor prognosis. On the other hand, down-regulation of FENDRR, FER1L4, GAS5, LET, and LINC00982 was associated with poor overall survival (Zhu et al., 2017a). Such revealed associations between transcript levels of
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lncRNAs and patients’ survival reflect the contribution of these transcripts in crucial steps of tumorigenesis. Tian et al. have assessed
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expression profile of lncRNAs in ten paired GC and adjacent normal tissues. They have constructed a 12-lncRNA signature which was
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associated with patients’ survival and confirmed it in an independent GEO dataset. The accuracy of this lncRNA profile was
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calculated as 0.869 through depiction of receiver operating characteristic (ROC) curve and calculation of the area under curve (AUC)
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value. The clinical relevance of such lncRNA signature was also validated through demonstration of enrichment of drug resistance and metastasis related pathways in the high risk patients (Tian et al., 2017b).
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Potential application of lncRNAs as diagnostic markers in GC Based on the aberrant expression of lncRNAs in GC tissues or peripheral blood of patients, their transcript levels can be used as diagnostic markers in GC. A number of studies have assessed diagnostic power of lncRNAs in GC through plotting ROC curve and calculation of AUC values. For instance, Xian et al. have reported higher expression levels of ZNFX1-AS1 and HULC in the plasma of preoperative GC patients compared with their levels in the plasma of gastrointestinal stromal tumor (GIST) patients, gastritis/peptic
Journal Pre-proof ulcer patients and normal controls. They reported AUC values of 0.85 and 0.65 for ZNFX1-AS1 and HULC, respectively and concluded that these lncRNAs are putative markers for non-invasive diagnosis of GC (Xian et al., 2018). Higher plasma H19 levels in GC patients compared with healthy individuals can be used as diagnostic marker in GC with accuracy of 64% (Arita et al., 2013). Li et al. have reported higher expression of LINC00152 in plasma samples of GC patients compared with normal controls. They also
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reported 48.1% sensitivity and 85.2% specificity of plasma LINC00152 levels in detection of GC patients. Based on the observed
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stability of LINC00152 in plasma, they hypothesized it is included in exosomes (Li et al., 2015). Sun et al. have shown down-
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regulation of the lncRNA RP11-119F7.4 in the GC tissues compared with the matched non-tumoral samples and reported the
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diagnostic accuracy of 63.7% for its transcript levels based on AUC value (Sun et al., 2015). Another study has estimated the
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diagnostic value of 71% for GAPLINC (Hu et al., 2014).
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Involvement of lncRNAs in GC-related signaling pathways
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The regulatory roles of lncRNAs in different levels of expression imply that they can alter function of cancer-related pathways. Both in vitro and in vivo studies have demonstrated such effects on a number of pathways including the mitogen-activated protein kinase (MAPK) pathway (Tasharrofi and Ghafouri-Fard, 2018). Other pathways have also been recognized as targets of lncRNAs in GC tissues. For instance, the lncRNA AK023391 induces the PI3K/Akt signaling pathway (Huang et al., 2017c). On the other hand, MEG3 prevents proliferation and metastasis of GC via p53 signaling cascade (Wei and Wang, 2017). HOTAIR accelerates EMT process and ANRIL activates mTOR pathway via different mechanisms. As demonstrated in Figure 1, HOTAIR recruits PRC2 to the promoter
Journal Pre-proof region of miR34a to suppress its expression. Liu et al. have shown down-regulation of miR-34a and negative correlation between this miRNA and HOTAIR in GC tissues. miR-34a has direct effects on regulation of Snail and c-Met expressions through binding to their 3′UTR regions. Reinstatement of miR-34a expression has suppressed migration and invasion of GC cells, and inhibited EMT process through modulation of Met and Snail expressions. Upregulation of HOTAIR leads to down-regulation of miR-34a and over-
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expression of C-Met, snail and EMT markers such as N-cadherin and vimentin (Liu et al., 2015b). In addition, HOTAIR acts as a
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sponge for miR-331-3p to regulate HER2 expression in GC. The positive interaction between HOTAIR and HER2 is possibly involved
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in conferring aggressive phenotype in these cells (Liu et al., 2014b). ANRIL as another oncogenic lncRNA epigenetically inhibits
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expression of miR-99a/miR-449a through recruitment of PRC2, therefore regulating mTOR and CDK6/E2F1 pathway and
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participating in cancer progression (Zhang et al., 2014b).
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e
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Journal Pre-proof Figure 1. HOTAIR inhibits miR-34a expression and subsequently induces c-MET and SNAIL expressions leading to EMT. miR-34a has inhibitory effect on EMT though suppression of expression of c-MET and SNAIL . HOTAIR also facilitates tumorigenesis process through sponging miR-331 and modulating HER2 expression (A). ANRIL suppresses expression of p15 and p16, sponges miR-99a and miR-449a and activates mTOR pathway (B).
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In addition, H19 participates in the pathogenesis of GC through different mechanisms (Figure 2). First, H19 is a precursor of miR-675.
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Both H19 and miR-675 have been over-expressed in gastric cancer cell lines and tissues. Such altered expression has been associated
e
with higher cell proliferation and lower cell apoptosis. The H19/miR-675 axis has been shown to suppress expression of FADD
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leading to inhibition of caspase cleavage cascades (Yan et al., 2017a). In addition, H19 acts a competing endogenous RNA for miR-
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141 which leads to over-expression of ZEB1 and STAT4 (Zhou et al., 2015c). Considering the role of ZEB1 and STAT4 in EMT and
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invasiveness of GC cells, H19 has been regarded as a facilitator of metastasis.
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Journal Pre-proof
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e
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Journal Pre-proof Figure 2. H19 is a precursor of miR-675. Both are over-expressed in gastric cancer tissues leading to inhibition of apoptosis (A). H19 induces ZEB1 expression and EMT process through sponging miR-141. This miRNA has a role in suppression of expression of ZEB1 and STAT4, thus binding of H19 with miR-141 leads to over-expression of ZEB1 and STAT4 (B).
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Although regulation of AKt, Wnt/ beta-catenin, Myc and TGF-beta pathways by GC-related lncRNAs have been reported in several cancers (Chen et al., 2018b), evidences for specific role of these lncRNAs in regulation of these pathways in the context of GC are not
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sufficient. Consequently, future studies are needed to elaborate the role of these lncRNAs in GC in association with these signaling pathways. Discussion
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LncRNA expression profile has been extensively altered during the pathogenic course of GC. Notably, several lines of evidences
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confirm the association between expression levels of lncRNAs and clinicopathological factors in GC. Associations between
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FENDRR expression and lymph node involvement (Xu et al., 2014d), GAS5 expression and tumor differentiation (Sun et al., 2014a), HULC expression and metastasis potential (Jin et al., 2016b) and UCA1 expression and both invasion depth and TNM stage (Zheng et al., 2015b) are only few examples in this regard. It is expected that lncRNA profiling leads to better classification of GC in a way that such classification predicts tumor behavior in a more efficient way. A previous in silico study has demonstrated differential expression of 1,294 lncRNAs in gastric cancer compared with adjacent normal tissues. Notably, authors have detected differential expression of 247 lncRNAs between intestinal and diffuse subtypes of GC (Han et al., 2017b). Several studies have shown clinical
Journal Pre-proof relevance of lncRNA expression through assessment of their diagnostic or prognostic values. As anticipated, panels of lncRNAs were superior to individual lncRNAs in terms of biomarker discovery. Based on the established role of exosome-originated lncRNAs in conferring immune evasion and promoting cancer-associated phenotypes, these lncRNAs are of special importance in the field of biomarker recognition (Sun et al., 2018b). The feasibility of detection of lncRNAs in peripheral blood or other body fluids by
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relatively simple methods and the fact that they are functional without needing to be translated into proteins are the main advantages
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of lncRNAs as biomarkers for cancer detection.
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Notably, H. pylori and EBV, as two important environmental risk factors for GC change expression of lncRNAs in gastric tissues.
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These pathogens recruit diverse tools to inhibit the host effective immune response and permit chronic colonization. Simultaneously,
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they trigger inflammatory responses that result in oncogenic alterations (Polakovicova et al., 2018). LncRNAs are anticipated to
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contribute in many aspects of these processes. However, future studies are needed to explore exact mechanisms of their contribution in GC.
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Considering the role of lncRNAs in conferring resistance to conventional anti-cancer therapies (Jiang et al., 2019), lncRNA profiling would facilitate selection of patients for each treatment modality and personalized design of therapeutic options. Besides, a number of studies have identified some GC-associated lncRNAs that could be targeted with bioactive peptides and chemotherapy drugs. This approach has been performed through identification of differentially expressed lncRNAs in GC cells after treatment with a novel anticancer bioactive peptide and the chemotherapy drug oxaliplatin (Han et al., 2017a). Certain lncRNAs are involved in the process of
Journal Pre-proof immune evasion. For instance, the lncRNA SNHG14 participates in regulation of the miR-5590-3p/ZEB1 axis and immune evasion through regulating PD-1/PD-L1 checkpoint. Thus, therapeutic targeting of this lncRNA has been suggested as a way for enhancing the efficacy of immunotherapy (Zhao et al., 2019). However, the regulatory role of SNHG14 on PD-L1 expression has been found in lymphoma and its impact on GC pathogenesis remains unknown. Taken together, lncRNAs are regarded as putative markers for
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therapeutic response as well as targets for design of therapeutic options or improvement of response to conventional therapies.
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However, understanding the mechanisms of lncRNAs function is the main challenge in implementation of lncRNAs in clinical
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practice. This process is complicated by the multifaceted function of lncRNAs and their interactions with several mRNAs, miRNAs and transcription factors.
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Figure 1
Figure 2
Soudeh Ghafouri-Fard, Mohammad Taheri PII:
S0014-4800(19)30823-8
DOI:
https://doi.org/10.1016/j.yexmp.2019.104365
Reference:
YEXMP 104365
To appear in:
Experimental and Molecular Pathology
Received date:
28 October 2019
Revised date:
18 December 2019
Accepted date:
28 December 2019
Please cite this article as: S. Ghafouri-Fard and M. Taheri, Long non-coding RNA signature in gastric cancer, Experimental and Molecular Pathology(2019), https://doi.org/ 10.1016/j.yexmp.2019.104365
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© 2019 Published by Elsevier.
Journal Pre-proof Long non-coding RNA signature in gastric cancer Soudeh Ghafouri-Fard1, Mohammad Taheri 2* 1. Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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2. Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Corresponding author: Mahammad Taheri Tel & Fax: 00982323872572 Email: [email protected]
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Journal Pre-proof Abstract Gastric cancer as a common human malignancy has been associated with aberrant expressions of several coding and non-coding genes. Long non-coding RNAs (lncRNAs) as regulators of gene expressions at different genomic, transcriptomic and post-
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transcriptomic levels are among putative biomarkers and therapeutic targets in gastric cancer. In the present study, we have searched available literature and listed lncRNAs that are involved in the pathogenesis of gastric cancer. In addition, we discuss associations
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between expressions of these lncRNAs and tumoral features or risk factors for gastric cancer. Based on the established role of
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lncRNAs in regulation of genomic stability, cell cycle, apoptosis, angiogenesis and other aspects of cell physiology, the potential of
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these transcripts as therapeutic targets in gastric cancer should be evaluated in future studies.
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Key words: lncRNA, gastric cancer, expression
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Journal Pre-proof Introduction Long non-coding RNAs (lncRNAs) are a group of transcripts that modulate many cellular functions (Soudyab et al., 2016, Taheri et al., 2018). With a total length of more than 200 nucleotides, they regulate expression of genes through chromatin remodeling as well
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as transcriptional and post-transcriptional alterations (Dykes and Emanueli, 2017, Kaikkonen et al., 2011). Aberrant expression of lncRNAs in a variety of human malignancies has implied their role in the pathogenesis of cancer(Ghafouri-Fard et al., 2019).
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Moreover, a number of recent studies have shown associations between lncRNA genomic variants and risk of common cancers
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(Taheri et al., 2017a, Taheri et al., 2017b). Taken together, lncRNAs are putative culprits in the pathogenesis of cancer and potential biomarkers and therapeutic targets in this regard.
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Globally, gastric cancer (GC) is the fourth most prevalent malignancy and has ranked the second position in cancer-related mortality
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(Sitarz et al., 2018). Both environmental and genetic factors are involved in the pathogenesis of this cancer (Sitarz et al., 2018). Diet,
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infection with Helicobacter pylori (H. pylori) or Epstein–Barr virus (EBV), obesity, pernicious anemia, blood type A and germline mutations in some genes including CDH1 are among the recognized risk factors for GC (Sitarz et al., 2018). A recent study has shown associations between some single nucleotide polymorphisms (SNPs) within lncRNAs and reduced risk of GC through in silico screening of differentially expressed lncRNAs and confirmation of the results in a population of GC patients and normal subjects (Duan et al., 2018). Others have assessed expression profile of selected lncRNAs in GC tissues/ cell line compared with normal tissues/ cell lines (Chen et al., 2017c). Several studies have reported associations between expression levels of lncRNAs in GC tissues
Journal Pre-proof and tumor features such as depth, distant metastasis, lymph node involvement and clinical stage (Zhu et al., 2017a, Esfandi et al., 2019b, Esfandi et al., 2019a, Esfandi et al., 2019d, Esfandi et al., 2019c). Based on the results of previous studies regarding aberrant expression of lncRNAs in GC, we conducted the current study to systematically search for lncRNAs with putative roles in the pathogenesis of GC.
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Search method
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PubMed, Google scholar, Web of Science and Scopus databases were searched with the key words "gastric cancer" or "gastric
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malignancy" AND "long non-coding RNA" or "lncRNA". We included only English original articles for subsequent assessments.
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Next, we screened them based on the number of specimens used for expression analysis and report of the clinical data of patients. We
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also included in vitro studies with adequate mechanistic evaluations. Based on their expression levels in tumoral tissues compared
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with non-tumoral tissues and functional experiments they can be divided to oncogenic lncRNAs and tumor suppressor lncRNAs.
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Tables 1 and 2 summarize information of these two subsets of lncRNAs respectively. Table 1. Up-regulated lncRNAs in GC (OS: overall survival, DFS: disease free survival). LncRNA
Chromosomal location
Number of cases
Signaling pathway
Correlation with patients' outcome
Function
Reference
Journal Pre-proof TP73-AS1
1p36.32
58 pairs of GC tissues and adjacent nontumor tissues
HMGB1signaling, RAGE signaling , NF-κB
Shorter OS
cell proliferation, cell cycle and apoptosis
76 paired GC samples and matched nontumor tissues
Bcl-2/caspase-3 pathway
Shorter OS
cell proliferation, metastatic properties, EMT, (Zhang et al., tumor growth 2018f)
-
Shorter OS
cell proliferation
SNHG1
11q12.3
50 GC tissues and pair-matched adjacent normal
SNHG6
8q13.1; 8q13
data mining from Oncomine database (69 MAPK pathways, JNK tissue samples) + serum of 114 GC pathway patients and 99 healthy subjects
-
78 GC tissues with matched adjacent normal tissues
EMT
Shorter OS
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(Peng, 2018)
(Hu et al., 2017b)
cell proliferation and senescence , tumor growth
(Li et al., 2018d)
cell growth, cell migration, EMT
(Yan et al., 2017b)
Proliferation
(Wang et al., 2017a)
-
SNHG8 lncRNA was found to affect several gastric cancer-specific pathways and target genes of EBV
(Huang et al., 2016b)
Shorter OS
cell growth, colony formation, proliferation and invasion
(Zhang and Lu, 2018)
miR-145/SOX9 axis and PI3 K/AKT/mTOR
-
cell viability, migration, invasion, and cell apoptosis
(Liu et al., 2018g)
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SNHG7
9q34.3
68 GC tissues with matched adjacent normal tissues
-
SNHG8
4q26
88 paired GC and adjacent tissues
-
SNHG12
1p35.3
SNHG14
15q11.2
20 GC patients
SNHG13 (DANCR)
4q12
65 pairs of GC tissues and adjacent normal tissues+ 55 serum samples of GC patients and 39 healthy controls
EMT
-
proliferation, apoptosis, migration and invasion
(Pan et al., 2018)
60 pairs of GC and corresponding nontumor gastric tissues
DANCR–lncRNA-LET axis
-
migration and invasion
(Mao et al., 2017)
GC tissues of the 118-patient cohort
-
Shorter OS
proliferation, cell metabolism
(Hao et al., 2017)
106 paired GC samples and adjacent histologically normal tissues
-
Shorter OS
cell proliferation
(Chen et al., 2016c)
SNHG15
7p13
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Journal Pre-proof SNHG16
17q25.1
122 tumor tissue and the corresponding adjacent tissues
-
-
proliferation, apoptosis, invasion, migration, tumor growth
(Lian et al., 2017)
SNHG20
17q25.2
Cell line study
EMT, GSK-3β/β-catenin signaling pathway
-
proliferation and invasion, EMT
(Liu et al., 2017a)
UCA1
19p13.12
Cell Line study
UCA1-miR-7-5p-EGFR axis -
cell migration
(Liu et al., 2018d)
82 GC tissues and adjacent non-tumor tissues
-
GC tissues and matched normal tissues were collected from 39 patients
AKT/GSK-3B/cyclin D1 axis -
102 paired GC tissues and adjacent noncancerous
PI3K-Akt-mTOR signaling pathway
-
49 primary cancer tissues and the paired adjacent non-tumor tissue
-
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28 GC tissues and adjacent normal tissues UCA1
19p13.12
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associated with lymph node metastasis, TNM stage, tumor size
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Metastasis, Proliferation
(Wang et al., 2017b)
cell migration and invasion, metastasis
(Wang et al., 2017b) (Ke et al., 2017)
regulation of chemosensitivity
(Fang et al., 2016)
UCA1/miR-590-3p/ CREB1 associated with lymph axis node metastasis, TNM stage , worse survival
cell proliferation and cell invasion
(Gu et al., 2018)
GC tissues and matched non-tumour tissues were collected from 48 patients
ERK-MMP9 signalling pathway, ubiquitinproteasome pathway
-
migration and invasiveness, metastasis, ubiquitination
(Wang et al., 2017c)
Cell line Study
PI3K/AKT/GSK3β and NFκB signal pathways
-
Apoptosis, cell viability, migration, invasion
(Qin et al., 2018a)
37 paired GC tissues and the corresponding adjacent normal tissues
TGFb1/UCA1-EMT
Poor clinicopathological Cell proliferation, and invasion and migration, (Zuo et al., 2017) parameters and shorter EMT OS
77 GC and adjacent normal tissues
PI3K/AKT pathway
Shorter OS
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62 GC tissue samples and matched adjacent normal tissues
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(Li et al., 2018a)
Proliferation, Apoptosis, chemotherapy resistance
(Shang et al., 2016)
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GHET1
7q36.1
112 tumor tissue samples and matched normal adjacent tissue
-
shorter 5-year OS and DFS
42 GC tissues and pair-matched adjacent normal gastric tissues
-
Shorter OS
Proliferation
GC tissues and paired adjacent tissues (>5 cm from the tumor) from 42 GC patients
-
cell proliferation, cell migration and invasion, (Xia et al., 2018) metastasis
20 pairs of gastric cancer tissues and Numb/Cyclin D1 and adjacent tumor tissues from gastric cancer Numb/MMP2/9. patients
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40 gastric carcinoma tissues that 20 samples from cisplatin sensitive patients and another 20 from drug-resistant patients were obtain
-
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2p16.1
21 paired GC tissues and adjacent normal MAPK, JAK-STAT and tissues ERBB signaling pathway
CCAT1 (CARLO5)
8q24.21
57 GC tissue samples than in 57 paired adjacent normal tissue
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51 paired GC and adjacent non-tumor gastic tissues
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ERK/MAPK pathway.
(Huang et al., 2017c)
apoptosis
(Huang et al., 2017c)
Shorter OS
cell cycle, apoptosis, invasion, metastasis
(Huang and Chen, 2018)
-
cell proliferation, apoptosis, invasion
(Huang et al., 2017c)
-
Proliferation, apoptosis
(Zhang et al., 2014c)
cell migration
(Zhou et al., 2016a)
30 paired GC/nontumor specimens
CCAT1/miR-490/hnRNPA1 axis
240 GC tissue samples and matched normal tissues
-
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(Yang et al., 2014)
cell cycle, invasion and migration
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LINC01793
(Zheng et al., 2015a)
Shorter OS
(Liu and Shangguan, 2017)
19 paired gastric carcinoma Tissue samples +19 Normal gastric tissues from obese patients, undergoing laparoscopic sleeve gastrectomy.
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Within the normal gastric tissue samples, no significant difference in CCAT1 expression was observed in helicobacter pylori negative and positive patients.
(Mizrahi et al., 2015)
20 gastric carcinoma tissues and their pair-matched adjacent normal gastric tissues
-
proliferation and migration
(Yang et al., 2013)
-
Journal Pre-proof CCAT2
8q24.21
85 gastric cancer and adjacent non-tumor tissues
Shorter OS
108 gastric cancer tissue and adjacent normal tissue
EMT
Shorter DFS and OS
cell proliferation, migration and invasion, EMT
(Wang et al., 2016c)
208 paired normal and cancerous gastric tissues
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unfavorable prognostic factor
cell proliferation and invasion
(Wu et al., 2017b)
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167 blood samples of GC patients and 110 blood samples from healthy controls + 20 paired GC tissues with matched adjacent normal tissues
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associated with tumor size, TNM stage and shorter OS
cell proliferation, apoptosis
(Xie et al., 2015b)
Shorter OS
cell growth
(Xu et al., 2018c)
tumor promoter via PTENAKT-slug pathway
Shorter OS
proliferation, migration and invasion
(Luo et al., 2018d)
NF-κB1
-
GC cell growth, Apoptosis
(Zhou et al., 2015b)
HOXA-AS2
7p15.2
55 paired GC and corresponding adjacent HOXA-AS2non-tumorous gastric samples P21/PLK3/DDIT3- EZH2
FOXD2-AS1
1p33
106 The tumor/adjacent non-tumor tissue -
linc-GPR65-1 14q31.3 (LINC01146-202) (ENST00000553929.5)
50 gastric cancer tissues and paired normal tissues
BANCR
30 paired gastric adenocarcinoma tissues and adjacent tissues,
9q21.11-q21.12
(Liu et al., 2015b)
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(Zhang et al., 2017a)
167 blood samples of GC patients and 110 blood samples from healthy controls + 20 paired GC tissues with matched adjacent normal tissues
-
(Zhang et al., 2017a)
-
(Zhang et al., 2017a)
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AOC4P
17q21.31
167 blood samples of GC patients and 110 blood samples from healthy controls + 20 paired GC tissues with matched adjacent normal tissues
LINC01606
8q12
75 human GC tissues and respective ANTs
Wnt/β-catenin signaling, contributes to poor working as a ceRNA of miR- nutritional status in 423-5p in GC cells patients with GC
invasion and metastasis
(Luo et al., 2018d)
Journal Pre-proof EGFR-AS1
7p11.2
58 GC tissues and pair adjacent normal gastric tissues
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-
LINC00324
17p13.1
66 paired GC and corresponding normal adjacent tissues
“LINC00324-HuRFAM83B” axis
Shorter DFS (P < 0.001) Proliferation, Apoptosis, migration and OS (P < 0.001).
MACC1-AS1
7p21.1
123 pairs of GC tissues and matched adjacent normal gastric mucosa tissues (FFPE)
promotes MACC1 mRNA Shorter OS stability via the AMPK/Lin28 pathway
EGOT (EGO)
3p26.1
39 GC patients
Hedgehog Pathway
ETS1-AS1 (pancEts-1)
11q24.3
30 Normal gastric tissues from biopsies + pancEts-1/ NONO/ERG/Ets- Shorter OS Fresh cancer and precancerous specimens 1 axis from 81 primary cases of gastric cancer
MALAT1
11q13.1
cell line study
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25 Gastric adenocarcinoma tissues and matched normal adjacent tissues 11q13.1
cell viability, metabolic plasticity, cell proliferation, metastasis
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150 pairs of GC tissues and corresponding non-cancerous gastric mucosa
MALAT1
cell proliferation
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the cell proliferation, cell differentiation
-
(Zou et al., 2018)
(Zhao et al., 2018c)
(Peng et al., 2017)
(Luo et al., 2018a)
(Wang et al., 2014a) (Okugawa et al., 2014)
-
migration and invasion, metastasis
(Deng et al., 2016a)
plasma samples from 72 GC patients and miR-122-IGF-1R axis 36 healthy controls+ 25 pairs gastric cancer tissue
Shorter OS
proliferation, cell cycle progression and apoptosis, migration and invasion
(Xia et al., 2016)
60 cases fresh-frozen gastric cancer tissues and adjacent normal tissues
MALAT1/miR-202/Gli2 pathway
-
proliferation and cell apoptosis
(Zhang et al., 2017c)
50 fresh gastric cancer tissue and paired adjacent
β-catenin signaling
-
cell proliferation and apoptosis, invasiveness and migration
(Lee et al., 2017)
150 GC and 15 peritumoral paraffinembedded tissues
VE-cadherin/β-catenin, Shorter OS ERK/MMP and FAK/paxillin
migration and invasion, angiogenesis
(Li et al., 2017a)
20 GC and 20 adjacent normal
EMT
migration and invasion, metastasis, EMT
(Chen et al., 2017a)
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(Hu et al., 2018)
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Journal Pre-proof
TRERNA1
20q13.13
78 GC tissues and adjacent non-cancerous MALAT1/miRtissues 1297/HMGB2
Shorter OS
38 pairs of gastric tumor and adjacent normal paraffin-embedded tissue
EMT
-
cell proliferation, cell cycle progression and cell apoptosis, EMT
(Li et al., 2017b)
Cell line study
-
-
autophagy
(YiRen et al., 2017)
48 paired fresh gastric cancer tissues and adjacent non tumorous
TFAP4-TRERNA1 axis
-
48 fresh GC tissues and paired adjacent non-tumor tissues
EMT
-
DLEU2
13q14.2
12 paired GC tissues, compared with adjacent normal tissues
-
DDX11-AS1 (SCAT4)
12p11.21
12 paired GC tissues, compared with adjacent normal tissues
-
MIAT
22q12.1
120 Paired gastric cancer and normal gastric tissue
HOTAIR
6p24.3
12q13.13
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(Liu et al., 2018a)
cell invasion and migration, metastasis, EMT (Wu et al., 2017a)
Cell Proliferation, cell proliferation
-
(Liu et al., 2018a)
(Liu et al., 2018a)
MIAT/miR-141/DDX5
-
cell proliferation, apoptosis, migration, invasion, metastasis
(Sha et al., 2018)
miR-29a-3p/HDAC4 axis
-
proliferation, migration and invasion
(Du et al., 2017)
GC tissue samples from 42 GC + Plasma samples from 42 GC patients and 25 volunteers
EMT
Shorter OS
Apoptosis, chemoresistance
(Zhang et al., 2016c)
Serum samples from 173 GC, 30 gastric polyps, 30 high atypical hyperplasia or intestinal metaplasia, patients and 110 age-matched healthy controls
-
Shorter OS
serum HULC expression was significantly correlated with H. pylori infection
(Jin et al., 2016a)
58 of GC tissues and adjacent non-cancer EMT tissues
-
Proliferation, Apoptosis, Autophagy
(Zhao et al., 2014)
30 of GC samples and paired non-tumor tissues
-
drug resistance, cell proliferation, cell cycle, and migration
(Wang et al., 2018b)
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HULC
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migration and invasion
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(Li et al., 2017a)
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Journal Pre-proof 150 pairs of GC tissues and noncancerous gastric mucosa
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associated with cell proliferation, tumorigenicity, migration peritoneal metastasis and and invasion poor outcome
(Okugawa et al., 2014)
Plasma from 50 patients with newly diagnosed gastric cancer and 50 age- and sex-matched healthy controls
-
metastasis
(Elsayed et al., 2018)
32 pairs of GC tumor tissues
-
Shorter OS
cell proliferation, chemosensitivity, invasion, (Feng and Huang, metastasis 2017)
27 GC and adjacent normal tissues
PI3K/Akt Wnt/β-catenin
-
65 primary GC patients
EMT
Shorter OS
30 paired primary gastric cancer and adjacent noncancerous tissues
PI3K/AKT/MRP1
-
Gastric cancer tissues were obtained from 40 patients
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GA tissues from 168 patients
HOTAIR
12q13.13
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migration and invasion
(Wu et al., 2017a)
cell resistance to cisplatin
(Yan et al., 2016)
cell proliferation
(Ma et al., 2016c)
-
(Zhang et al., 2015b)
60 GC tissues and matched adjacent tissue -
-
(Song et al., 2015)
61 matched tumor tissues and adjacent non-tumor tissues
Shorter OS
invasion and metastasis, EMT
(Liu et al., 2015b)
50 FFPE gastric cancer and adjacent non- tumors gastric tissues
Shorter OS
cell motility and invasion, metastasis, tumor growth
(Zhang et al., 2015b)
83 pairs of human GC and adjacent noncancerous tissues.
EMT
Shorter OS
Metastasis, EMT, Invasiveness
(Xu et al., 2013)
31 pairs of specimens, tumor tissues and their adjacent normal ones,
-
-
(Hajjari et al., 2013)
68 gastric cancer tissues
-
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(Endo et al., 2013)
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Apoptosis, multidrug-resistance tumor growth (Cheng et al., 2018)
HGF/C-Met/Snail pathway, EMT
Journal Pre-proof 78 paired gastric cancer and adjacent samples
CYTOR (C2orf59) or (LINC00152) or (ENSG00000222041)
2p11.2
-
Shorter OS
cell proliferation and apoptosis, migration and (Liu et al., 2014c) invasion
60 specimens of gastric cancer tissues and adjacent benign tissues
-
metastasis
50 gastric cancer tissue and paired adjacent tissue
EMT
-
cell proliferation and apoptosis, cell motility, (Lee et al., 2014b) EMT, invasion and migration
60 paired GC samples
EMT
-
20 GC tissues and adjacent normal tissue LINC00152/miR-193asamples 3p/MCL1 pathway -
Cell line study
Wnt/beta-Catenin Pathway
Shorter OS
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72 cases of patients who underwent gastric cancer radical resection
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cell viability and colony formation, apoptosis, (Zhao et al., 2015) cell proliferation, EMT, migration and invasion cells proliferation, tumor growth
(Huang et al., 2018)
cell glycolysis
(Sun et al., 2018a)
Cell Proliferation and Metastasis
(Shan et al., 2017b) (Pang et al., 2014)
PI3K/AKT
-
cell proliferation, tumor growth
(Zhou et al., 2015a)
-
Shorter OS
cell proliferation
(Chen et al., 2016d)
-
-
-
(Yang et al., 2016a)
Paired plasma samples (preoperative and postoperative) from 79 GC patients + 31 plasma samples from patients with GED + Control samples from 81 healthy volunteers
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97 primary GC patients
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serum samples from 285 subjects = 133 GC cases + 152 control samples 2p11.2
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Cell line study
71 pairs of tumorous and adjacent normal tissues + Gastric juice from 17 patients with gastric cancer and 16 normal mucosa or minimal gastritis
CYTOR (C2orf59) or (LINC00152) or (ENSG00000222041)
-
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(Emadi-Andani et al., 2014)
(Li et al., 2015)
Journal Pre-proof FEZF1-AS1
NEAT1
7q31.32
11q13.1
82 matched tumor tissues and adjacent non-tumor tissues
-
associated with tumor size, stage and poor survival
104 matched gastric cancer (GC) tissues and adjacent non-tumor tissues
Wnt/β-catenin signaling pathway
Shorter OS
-
NEAT1-miR-335-5p-ROCK1 axis
20 Fresh-frozen GC tissues and the adjacent non-tumorous tissues
PI3K/AKT and GSK3β Pathways
-
Cell line
-
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131 GAC samples
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104 freshly frozen gastric cancer samples EMT and 20 paired adjacent normal tissue PVT1
8q24.21
63 paired gastric cancer samples and adjacent
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Angiogenesis, STAT3/VEGFA axis
20 GC tissue samples and matched normal tissue samples
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PVT1
8q24.21
(Liu et al., 2017b)
(Wu et al., 2017c)
Proliferation, migration and invasion
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Cell Viability and Migration
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76 GC and control normal stomach tissues (NT) were
cells proliferation, apoptosis
Chemotherapy Resistance, Apoptosis
-
(Zhang et al., 2018b) (Wang et al., 2018a) (Tan et al., 2018)
(Zhao et al., 2018b)
(Ma et al., 2016d)
Shorter OS
cancer cells migration and invasion, EMT
(Fu et al., 2016)
Shorter OS
cell proliferation, angiogenesis, migration
(Zhao et al., 2018b)
-
(Liu et al., 2017b)
68 cases patients tissues samples and matched adjacent normal tissues
PVT1/miR-186/HIF-1α axis
-
cell proliferation
(Huang et al., 2017b)
190 pairs of gastric cancertissues and adjacent normal mucosa tissues (ANT)
-
Shorter OS
cell proliferation and invasion
(Xu et al., 2017a)
111pairs of gastric cancer and adjacent normal tissues
-
Shorter OS
(Yuan et al., 2016)
70 patients with primary gastric cancer were enrolled in this study.
mTOR/HIF-1α/P-gp and MRP1 signaling pathway.
-
(Zhang et al., 2015a)
80 GC tissues
-
Shorter OS
Proliferation
(Kong et al., 2015)
Journal Pre-proof
circPVT1
8q24.21
33 tumor tissues and corresponding noncancerous tissues
-
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20 paired normal and cancerous gastric tissues
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better OS
(Ding et al., 2014)
Proliferation
(Chen et al., 2017b)
Better overall survival, seems to contradict the upregulation of circPVT1 in GC. A possible explanation may be the association of circPVT1 with the tumor suppressor miR125.
H19
11p15.5
22 matched normal gastric tissue samples -
-
24 human gastric cancer tissues
H19/miR-675/RUNX1
-
serum samples from 285 subjects = 133 GC cases + 152 control samples
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80 primary GC patients
-
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106 gastric cancer patients
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Plasma of 90 patients and 90 controls
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15 patients with GC and paired adjacent histologically normal tissues
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Proliferation, apoptosis
(Yang et al., 2012)
cell proliferation, cell growth, cell apoptosis
(Zhuang et al., 2014) (Yang et al., 2016a)
Shorter OS
cell viability and colony formation
(Zhang et al., 2014a)
Shorter OS
Proliferation, cell migration and invasion, metastasis
(Li et al., 2014)
-
-
-
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(Zhou et al., 2015d) cell proliferation and invasion
23 endoscopic biopsy samples and 91 AKT/mTOR Pathway surgery samples from patients with gastric cancer tumor specimens from 39 patients
H19
11p15
EMT
128 paired GC samples and adjacent normal tissues + Gastric from 56 subjects
(Zhou et al., 2015c)
(Liu et al., 2016a)
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proliferation, invasion, chemo-resistance, EMT
(Ishii et al., 2017)
Shorter OS
cell migration and invasion
(Chen et al., 2016b)
Journal Pre-proof
ANRIL (CDKN2BAS1)
GAPLINC
9p21.3
18p11.31
Plasma from 32 GC patients and 30 age and sex matched healthy.
-
-
(Hashad et al., 2016)
34 Paired gastric cancer tissue samples and adjacent tissues
H19/miR-675/ FADD/caspase 8/caspase 3
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Cant access full article
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Shorter OS
(Wei et al., 2018)
Plasma from 40 GC patients and 42 age and sex-matched controls.
-
-
(Yoruker et al., 2018)
20 paired human gastric cancer tissues
Notch and mTOR signal pathways
-
83 tumor tissue samples
-
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184 cases of gastric cancer + 23 biopsytissue specimens
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120 paired GC tissues and adjacent normal tissues
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cell proliferation and cell apoptosis
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cell viability, migration, and invasion and apoptosis
(Yan et al., 2017a)
(Liu et al., 2018e)
cell proliferation, cell migration and invasion, (Lan et al., 2016) apoptosis Proliferation and Colony Formation
(Deng et al., 2016b)
associated with tumor size, TNM stage and poor prognosis
cell proliferation
(Zhang et al., 2014b)
-
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cell proliferation
(Diao et al., 2018)
18 normal gastric tissues (NGT), 17 highly differentiated gastric adenocarcinoma (HDAC), and 16 poorly differentiated gastric adenocarcinoma (PDAC) tissues
Tumor angiogenesis
Shorter OS
cell proliferation, migration, and invasion, apoptosis
(Liu et al., 2016b)
48 paired normal gastric tissues and gastric cancer tissues
-
Shorter OS
proliferation and invasion
(Hu et al., 2014)
proliferation and metastasis
(Lin et al., 2018b)
53 tumor and paired adjacent para-tumor tissues
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Jo
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GCRL1 (SMIM25)
20q13.13
26 pairs of human GC tissues and matched adjacent tissues
GCRL1, miR-885-3p, and CDK4 Axis
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PlncRNA-1 (CBR3AS1)
21q22.12
35 Snap-frozen tumoral and adjacent nontumoral paired tissue
-
-
(Baratieh et al., 2017)
Journal Pre-proof LINC00941 (lncRNAMUF)
12p11.21
82 Fresh tumor tissues and adjacent tissues
-
-
(Luo et al., 2018a)
TUG1
22q12.2
35 Snap-frozen tumoral and adjacent nontumoral paired tissue
-
-
(Baratieh et al., 2017)
40 pairs of gastric carcinoma and paracarcinoma RNA specimens
-
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100 paired GC tissues and adjacent normal tissues using
-
Shorter OS
Cell line
-
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146 paired GC samples
-
shorter 5-year OS rates
PANDAR (PANDA)
6p21.2
100 paired noncancerous and cancer tissue samples SOX2-OT (NCRNA00043)
3q26.33
30 gastric cancer tissues and 30 adjacent histological normal tissues
invasion
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cell proliferation
(Zhang et al., 2016d)
Proliferation and Invasion, Tumor Growth
(Ren et al., 2017)
Proliferation, apoptosis
(Liu et al., 2018c)
Shorter OS
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SOX2/miR-194-5p/AKT2 axis
(Ji et al., 2016)
(Ma et al., 2016b)
-
cells proliferation and metastasis ,invasion
(Qu and Cao, 2018)
Shorter OS
cell growth, cell migration and invasion
(Zhang et al., 2016d)
155 Human gastric cancer tissue and the adjacent normal tissue
-
l a
shorter 5-year and 5year DFS
-
-
proliferative activity and colony formation capacity, apoptosis
(Xu et al., 2018b)
-
Shorter OS
cell invasion and migration capacities
(Liu et al., 2018f)
76 GC tissues and adjacent nontumor tissues were collected
-
correlated with advanced proliferation and invasion, cell growth TNM stage, lymph node metastasis, and poor OS
(Zhang et al., 2018c)
124 gastric cancer tissues, 20 adjacent normal tissues and metastatic lymph nodes, and 20 gastritis tissues
EMT
unfavorable prognosis
(Li et al., 2017c)
132 fresh gastric cancer samples + 20 paired adjacent normal tissue
CCHE1 (CCEPR)
10q21.1
-
ZEB1-AS1
10p11.22
75 patients
n r u
Jo
-
(Zou et al., 2016)
cells migration, invasion and EMT process
Journal Pre-proof AK096174 (LINC01089) (LIMT)
12q24.31
32 GC tissue and paired-adjacent tissue
-
Shorter OS
proliferation, migration, and invasiveness
(Zhang et al., 2018g)
DGCR9 (DGS-A)
22q11.21
102 FFPE gastric cancer tissues and adjacent noncancer tissues (NAT)
-
-
cellular proliferation, migration, and glucose metabolism
(Ni et al., 2018)
DQ786243
1q22 (chr1:155234457155239960)
172 cases of GC, along with the noncancerous tissues
-
Shorter OS
82 Paired tumor tissue and adjacent healthy tissue BLACAT1 (linc-UBC1) 1q32.1
-
85 gastric cancer and matched adjacent normal non-tumor tissues
-
long noncoding RNA M26317
?
103 gastric cancer tissues by real timePCR + 436 gastric cancer tissues by in situ hybridization
CASC15
6p22.3
88 paired GC tissues and matched healthy EMT tissues
l a
o r p
-
e
Shorter OS
r P
rn
u o
f o
-
23 pairs of oxaliplatin-resistant gastric cancer and matched oxaliplatin-sensitive GC patients
42 normal gastric epithelial tissues and 60 gastric cancer tissues
(Zhang et al., 2018d) (Shan et al., 2017a)
apoptosis and invasion, tumor growth
(Wu et al., 2018b)
proliferation and invasion
(Hu et al., 2015)
Shorter OS
(Li et al., 2018b)
Shorter OS
cell proliferation, migration, EMT
(Wu et al., 2018a)
Shorter OS
proliferation and cell cloning
(Yao et al., 2017)
DLEU1
13q14.2-q14.3
68 pairs of GC tissues and normal tissues -
Shorter OS
cellular proliferative
(Li et al., 2018c)
LINC01234 (LCAL84)
12q24.13
50 paired GC and adjacent non-tumor tissues
LINC01234-miR-204-5pCBFB axis
Shorter OS
cell proliferation, apoptosis, gastric cancer cell growth
(Chen et al., 2018d)
Long non-coding RNA MSTO2P
1q22
80 paired gastric cancer tissues
-
Shorter OS
cell growth, colony formation, migration, and (Xu et al., 2017b) invasion
TCONS_00068220
8q11.21
GC tissues and matched NATs were collected from 15 patients
-
-
viability of GC cells, apoptosis
(Zhao et al., 2017b)
BCAR4
16p13.13
113 cases of gastric cancer tissue and adjacent tissue
β-catenin -Wnt signaling pathway
-
cisplatin-resistant
(Yang et al., 2017b)
J
Journal Pre-proof CRNDE (ENSG00000245694)
16q12.2
118 GC tissues and adjacent non-tumor tissues
PI3K/Akt Pathway
Shorter OS
Proliferation, Invasion and Migration
(Du et al., 2017)
20 pairs of GC tissues and adjacent nonmalignant gastric tissue samples
CRNDE/miR-145/E2F3 signaling pathway
-
proliferation
(Hu et al., 2017a)
SUMO1P3
1q23.2
96 Fresh gastric cancer tissues and adjacent nontumor tissues
-
-
(Mei et al., 2013)
HOTTIP
7p15.2
Serum exosomal HOTTIP from 126 GC patients and 120 healthy people
-
Shorter OS
98 Fresh primary GC tumor tissues and matched NATs
-
Shorter OS
50 paired gastric tissue samples
-
-
94 fresh gastric cancer tissues and matched NATs
-
l a
o r p
f o
e
(Zhao et al., 2018c)
cell proliferation and cell apoptosis, invasion/migration
(Ye et al., 2016)
cell growth, cell migration and invasion
(Chang et al., 2016)
MAP3K20-AS1 (MLK7-AS1)
2q31.1
123 gastric cancer specimens and 77 adjacent normal gastric mucosa
r P
-
Shorter OS
cell proliferation, apoptosis
(Quan et al., 2018)
ZFAS1
20q13.13
20 pairs of fresh gastric cancer specimens EMT, Wnt/β-catenin signaling.
-
Proliferation, migration, invasion, EMT, resistance to chemotherapeutic
(Xu et al., 2018d)
ZFAS1
20q13.13
94 paired GC tissue and adjacent normal tissue
-
proliferation and migration, cell apoptosis
(Pan et al., 2017)
ZFAS1
20q13.13
66 fresh paired human gastric tumor EMT tissues and 77 paired plasma (preoperative and postoperative) samples
ZFAS1
20q13.13
54 pair gastric cancer and normal tissues
HAGLR (HOXD-AS1)
2q31.1
HAGLROS (HAGLR 2q31.1 opposite strand lncRNA)
n r u
-
EMT
(Yang et al., 2017b)
Jo
-
(Zhou et al., 2016b)
Shorter OS
Proliferation, Apoptosis
(Nie et al., 2017)
104 biopsy samples of gastric tumor were JAK2/STAT3 pathway collected
-
cell proliferation, colony formation, cell growth
(Zheng et al., 2017)
84 paired GC and adjacent non-cancerous tissues from patients
Shorter OS
cell proliferation and invasion, sponge for miR-100-5p
(Chen et al., 2018c)
Journal Pre-proof LINC01296/miR-122/MMP- Shorter OS 9 pathway
LINC01296 (DUXAP9) 14q11.2
60 cases of gastric cancer specimens and matched adjacent normal tissue
LINC00673
79 paired GC tissues and adjacent normal tissues
Shorter OS and DFS
cell proliferation, cell migration and invasion (Ba et al., 2017)
73 paired GC tumors and adjacent nontumor tissues
-
Shorter OS
Cell Growth, Apoptosis, Cell Migration, Invasion, and Metastasis
Cell cycle
-
17q24.3
LINC00668
18p11.31
106 paired GC tissues and adjacent normal tissues
DUXAP8
22q11.1
72 paired GC tissues and adjacent normal tissues
Shorter OS
PCAT-1
8q24.21
110 pairs of primary gastric patients' cancer tissues and normal tissues
-
175 patients
-
f o
(Qin et al., 2018b)
(Huang et al., 2017a)
Proliferation
(Zhang et al., 2016a)
cell proliferation, apoptosis, cell migration
(Ma et al., 2017a)
Shorter OS
cell proliferation and migration
(Bi et al., 2017)
Shorter OS
cell proliferation, migration and invasion
(Cui et al., 2017)
o r p
e
r P
Proliferation, cells invasion and migration, apoptosis, tumor growth
LINC00978 (MIR4435- 2q13 2HG)
72 paired gastric cancer and adjacent non- TGF-β/ SMAD pathway cancerous tissues EMT
-
Apoptosis, migration and invasion
(Fu et al., 2018)
GACAT3 (LINC01458) 2p24.3 (lncRNA-AC130710)
42 paired GC and corresponding adjacent noncancerous tissues
Shorter OS
cell proliferation, colony formation, cell migration and invasion, tumor growth
(Feng et al., 2018)
rn
l a
78 Gastric cancer tissues and adjacent tissues
u o
J
cell line Study
-
-
STAT3 signaling pathway
-
(Xu et al., 2014a)
cell growth, cell proliferation, apoptosis, competing endogenous RNAs
(Lin et al., 2018a)
GACAT2 (MTCL1AS1) (lncRNA HMlincRNA717)
18p11.22
plasma from 80 healthy individuals, 29 patients with GD, 117 preoperative and 117 postoperative patients with GC
-
-
(Tan et al., 2016)
RP11-62F24.2 (BNC2AS1)
9p22.2
Cant access full text
-
-
(Xu et al., 2017b)
XIAP-AS1
Xq25
285 stomach adenocarcinoma and 33 normal tissues from TCGA were analyzed
-
Apoptosis, Proliferation
(Cai et al., 2017)
Journal Pre-proof lncRNA MRUL (MDR- 400 kb downstream 40 paired primary GC tissues and related and upregulated of ABCB1(=MDR1) noncancerous gastric mucosa lncRNA) 7q21.12
-
Shorter OS
apoptosis
(Wang et al., 2014c)
AK058003
chr10:8694778086950770
95 pairs of human primary GC tissues and AK058003/SNCG pathway adjacent gastric tissues
-
GC migration and invasion, Metastasis
(Wang et al., 2014b)
HIF1A-AS2
14q23.2
83 cancer tissues with matched paracarcinoma tissues
-
Shorter OS
Proliferation
(Chen et al., 2015)
SPRY4-IT1 (AK024556)
5q31.3
175 Paired tumor and adjacent normal tissues
-
-
BC032469
5p15.33
68 GC tissues and corresponding adjacent tissues
-
TINCR
19p13.3
56 paired tumor and adjacent nontumor tissue samples
80 patients underwent primary GC
XIST
LSINCT5
Xq13.2
5p15.33
e
TINCR/miR-375/PDK1
167 blood samples of GC patients and 110 blood samples from healthy controls + 20 paired GC tissues with matched adjacent normal tissues
n r u
l a
o r p
r P
-
f o
cell proliferation, colony formation, and cell migration/invasion.
(Peng et al., 2015b)
Proliferation
(Lu et al., 2016)
Proliferation
(Chen et al., 2017e)
-
E2F1/TINCR/STAU1/CDKN Shorter OS 2B signaling axis
(Zhang et al., 2017a)
Proliferation
(Xu et al., 2017b)
55 tumor tissues with adjacent nontumorous tissues
-
Shorter OS
cell proliferation, colony formation, apoptosis, (Xu et al., 2015) cell growth
98 GC and matched-normal tissue samples
miR-497/MACC1 axis
-
cell proliferation and invasion, tumor growth
(Ma et al., 2017b)
Cell line study
XIST-miR-185/TGF-β1 axis -
GC cell growth, migration and invasion
(Zhang et al., 2018e)
Jo
106 Fresh-frozen cancer tissues and paired miR-101/EZH2 pathway normal tissues
Shorter OS
cell proliferation, migration and invasion, tumor growth and metastasis
(Chen et al., 2016a)
71 GC tissues and paired adjacent noncancerous tissues 74 CRC tissues and paired adjacent noncancerous tissues
Shorter OS
proliferation
(Xu et al., 2014b)
-
Journal Pre-proof 71 GC tissues compared with nonmetastatic tissues.
-
-
cell migration and invasion, EMT
(Qi, 2018)
ABHD11-AS
7q11.23
Cant access to full text
-
-
(Lin et al., 2014)
ABHD11-AS
7q11.23
Tissue of 37 HGM, 34 BL, 29 GD, and 73 GC tissues + gastric juices from 45 normal mucosa or minimal gastritis, 16 atrophic gastritis, 30 gastric ulcers, and 39 GC
-
(Yang et al., 2016c)
SDMGC
located on chromosome 17
10 samples from non-stage IV GC tissues,10 samples from stage IV GC
-
Shorter OS
C21orf96 (RUNX1-IT1) 21q22.12
Cant access to full text
-
-
FRLnc1 (FOXM1related LncRNA 1) (GeneSymbol: RP11721K1.1)
41 tissue samples and neighboring noncancerous tissue
TGFβ1
Chr 17: 1353695413538079
l a
173 GC tissue samples with adjacent normal tissues
n r u
-
o r p
e
r P
-
f o
invasion and migration
(Yan et al., 2015)
tubular formation, migration and invasion. tumor progression
(Yang et al., 2016d)
cell migration, metastasis
(Cai et al., 2015)
Better OS
(Chong et al., 2018)
-
-
(Ma et al., 2016a)
-
-
(Dang et al., 2015b)
KRT18P55
17q11.2
97 GC patients
PCNA-AS1
20p12.3
90 tissue samples
Non-Coding RNA OTUB1-isoform 2
11q13.1
tissue samples from 156 patients
-
Shorter OS and DFS
linc-POU3F3 (PANTR1)
2q12.1
peripheral blood of 40 gastric cancer patients and 40 controls.
-
-
OR3A4 (OR3A4P)
17p13.3
25 paired gastric cancer tissues.
-
-
Metastasis, Invasion, cell migration, angiogenesis, tumor progression
HOXA11-AS
7p15.2
85 paired gastric cancer and adjacent nontumor tissues
EZH2/HOXA11-AS/LSD1 complex and HOXA11AS/miR-1297/EZH2 crosstalk
Shorter OS
cell proliferation, migration, and invasion and (Sun et al., 2016a) inhibits apoptosis, tumorigenesis
Jo
Apoptosis, tumor growth and tumor metastasis
(Wang et al., 2016b) (Xiong et al., 2015)
(Guo et al., 2016b)
Journal Pre-proof lncRNA ROR (LINCROR)
18q21.31
Tumor tissues were collected from 33 patients with gastric cancer
-
-
proliferation and invasion
(Wang et al., 2016a)
lncRNA-ATB
chr14:19,858,66719,941,024
20 paired GC tissue compared with adjacent normal tissiues
lnc-ATB/miR-141-3p/TGFβ2
Shorter OS
proliferation
(Lei et al., 2017)
HNF1A-AS1
12q24.31
99 fresh GC tissues and 8 non-tumorous gastric tissues
EGR1-mediated transcription of lncRNA-HNF1A-AS1
Proliferation
(Liu et al., 2018b)
CASC9 (linc-JPH1) (LINC00981)
8q21.13
89 GC tissues, compared with control NST
-
-
AGAP2-AS1 (PUNISHER)
12q14.1
50 paired GC and adjacent nontumor tissue samples
-
Shorter OS
RP11-357H14.17 (ENSG00000272763)
Chr17: 46,713,28546,724,385
48 Fresh primary DGC tumor tissues and matched normal adjacent tissues
AC010761.9
chr17:2707258727074670
145 fresh GA tissues +serum samples from the same patients
-
AK093735
chr12:9469752794700087
30 tumour and adjacent non-tumour tissues
l a
BC003519
chr10:9763279697635709
NR_003573 (ANXA2P2)
KRT7-AS
-
o r p
e
r P
-
f o
chemoresistance
(Shang et al., 2017)
cell proliferation, cell migration and invasion (Qi et al., 2017)
Proliferation, Apoptosis, cell migration and invasion
(Yang et al., 2017a) (Zhao et al., 2018a)
JAK-STAT Rap1 signaling pathway, RIG-I like receptor signalling pathway pancreas cancer pathway
(Fan et al., 2016)
tumour and adjacent non-tumour tissues from 30 GC patients
JAK-STAT chemokine signalling pathway VEGF signalling pathway and proteoglycans
-
(Fan et al., 2016)
9p13.3
tumour and adjacent non-tumour tissues from 30 GC patients
JAK-STAT NF-KB signalling pathway chemokine signalling pathway HIF-1 signalling pathway
-
(Fan et al., 2016)
12q13.13
matched NC-GC tissue pairs obtained from 31 GC patient
-
-
n r u
Jo
Proliferation and Migration
(Huang et al., 2016a)
Journal Pre-proof LINC00473
6q27
120 GC tissue samples and pared adjacent normal
independent unfavorable Metastasis ,cell migration and invasion factor
(Zhang and Song, 2018)
LINC00857
10q22.3
167 blood samples of GC patients and 110 blood samples from healthy controls + 20 paired GC tissues with matched adjacent normal tissues
-
(Zhang et al., 2017a)
60 pairs of fresh GC tissues and adjacent non‑tumor tissues
cell cycle signaling pathway regulate G1/S transition
Shorter OS
NNT-AS1
5p12
48 GC tissue samples with adjacent normal tissue
cell cycle
Shorter OS
ZFPM2-AS1
8q23.1
73 paired gastric tumor and normal adjacent gastric tissue specimens
p53 signaling pathway and apoptosis
GClnc1 (BC041951)
chr6:160100149160102293
165 cases of fresh gastric cancer and adjacent tissues
-
CTD-2541M15(MCPH1 8p23.1 -AS1)
82 GC tissues and adjacent non‑ tumor tissues
RP5-919F19 OR (AL109947.1) OR (LOC105377935) OR (ENSG00000223537)
6q21
82 GC tissues and adjacent non-tumor tissues
linc-UFC1 (LOC112543491)
Chr 1
AFAP1‑AS1 (LOC84740)
4p16.1
n r u
l a -
f o
(Pang et al., 2018)
cell cycle
(Chen et al., 2018a)
Shorter OS
tumor growth, proliferation, apoptosis
(Kong et al., 2018)
-
proliferation, invasiveness, and metastasis
(Sun et al., 2016b)
o r p
e
r P
-
cell proliferation
associated with TNM stage
(Li et al., 2018a)
associated with tumor differentiation degree; lymph node metastasis and TNM stage
Metastasis, significantly increased risk of lymph node metastasis
(Li et al., 2018a)
79 paired gastric cancer and adjacent non- UFC1/miR-498/Lin28b cancerous tissues + 60 serum samples signaling from GC, 35 from gastritis patients, and 40 from healthy donors
Shorter OS
cell proliferation, migration and invasion, cancer growth
(Li et al., 2018d)
80 pairs of tumor and matched normal tissues
EMT
Shorter OS
proliferation, migration and invasion, EMT, metastasis
(Zhao et al., 2018a)
10 pairs of human GC tissues and matched normal tissues, and 56 samples of unmatched GC tissues
-
associated with GC progression
cell proliferation, cell migration and invasion (Ye et al., 2018)
Jo
Journal Pre-proof 20 GC samples and the paired adjacent normal GC samples
PTEN/p-AKT pathway.
-
cell viability, cell proliferation and apoptosis
(Guo et al., 2017a)
91 primary GC tissues and their paired adjacent normal tissues
EMT
Shorter OS
Cell Proliferation, EMT
(Feng et al., 2017)
f o
Table 2. Down-regulated lncRNAs in GC (OS: overall survival, DFS: disease free survival). LncRNA
Chromosomal location Number of cases
SNHG5
6q14.3
o r p
Signaling pathway Correlation with patients' Function outcome
10 paired GC and non-tumor tissues+23 normal gastric tissues + 87 paired tissues Fresh GC tissues and paired noncancerous tissues
l a
r P
e -
SNHG5/miR-32 axis
-
-
-
EMT
-
Reference
cell proliferation, migration and invasion, (Zhao et al., 2016b) growth and metastasis Migration, cell migration, cell proliferation (Zhao et al., 2017a) We previously identified that SNHG5 is significantly down-regulated
SMIM10L2A (LINC0086)
Xq26.3
20 GC tissues and the matched normal tissues
RP11-789C1.1 (LINC01612)
4q33
Cell line
AP000459 (ENSG00000227716)
21q21.2
82 GC tissues and adjacent non-tumor tissues
LOC101928316
11p14.1
82 GC tissues and adjacent non‑tumor tissues
-
associated with tumor differentiation degree; and the sex of the patient
(Li et al., 2018a)
LINC01071 (TUSC8)
13q14.11
82 GC tissues and adjacent non‑tumor tissues
-
associated with patient age
(Li et al., 2018a)
u o
rn
J
(Yang et al., 2018)
Proliferation, migration, invasion, and EMT
(Liu et al., 2018g)
(Li et al., 2018a)
Journal Pre-proof pseudogene-derived long noncoding RNA SFTA1P
10p14
68 pairs of GC tissues and adjacent normal tissues
-
Shorter OS
cell proliferation, apoptosis, migration and (Luo et al., 2018b) invasion
MDC1-AS1
6p21.33
80 Tumor tissues and adjacent noncancerous tissues
-
-
Metastasis, cell proliferation
(Qin et al., 2018c)
GAS5
1q25.1
GC cell study
GAS5/miR-222 axis PTEN/Akt/ mTOR pathway
Cell Proliferation
(Mello et al., 2017)
40 Paired GC tissues and adjacent normal gastric mucosae
modulation of cell associated with larger cycle tumor sizes and more advanced stages
cell proliferation
(Guo et al., 2015)
paired tissue specimens were collected from 55 stomach cancer patients
GAS5/YBX1 pathway.
r P
-
cell cycle (Liu et al., 2015a) lncRNA GAS5 knock-down abolishes cell cycle arrest at the G1 phase.
cell cycle
larger tumor size and advanced pathologic stage, poorer DFS and OS
-
-
15 paired gastric cancer tissues and adjacent normal tissues
-
-
Apoptosis
(Zhang et al., 2016b)
cell migration, cell invasion, apoptosis, EMT
(Zhao et al., 2018d)
l a
89 gastric cancer
n r u
24 paired GC tissues
Jo
f o
o r p
e
ENST00000434223 (ENSG00000236914, (LINC01852 )
15q14
104 GC tissues and paracancerous tissues
Wnt/β-catenin signaling EMT
-
RP11-363E7.4 (ENST00000563205.1, lncACER2-1:1, AL158206.1-201)
9p22.1
GEO database (12 paired adjacent normal and tumor-matched tissues) + 5 pairs of GC tissues and non-cancerous tissues
-
better OS
cell proliferation and apoptosis
(Sun et al., 2014b)
(Sun et al., 2014b)
(Wang et al., 2018c)
Journal Pre-proof PWRN1
15q11.2
25 GC tissues and matched normal adjacent tissues
Modulate PTEN/Akt/MDM2 /p53 axis via repressing miR425-5p
cells viability, metastasis capacity, apoptosis, invasion, cell proliferation
(Chen et al., 2018e)
MEF2C-AS1
5q14.3
42 paired GC tissues and adjacent normal tissues
-
-
cell proliferation, cell migration
(Luo et al., 2018b)
LEIGC
2q14.1
35 paired GC samples and adjacent normal tissues
EMT
-
TUSC7
3q13.31
78 paired GC/nontumoral tissues
-
lncRNA BG981369
6q22.2
44 GC tissues and normal tissues
-
14q32.2
30 GC tissues and 30 normal tissues
EMT
(Han et al., 2014)
shorter DFS and DSS
tumor cell growth
(Qi et al., 2015)
-
Proliferation, Apoptosis, cell migration and invasion
(Dong et al., 2018)
-
invasion and migration, EMT, cell mobility, tumor growth and metastasis
(Xu et al., 2018a)
-
poor prognosis
cell proliferation, apoptosis
(Sun et al., 2014b)
-
associated with tumor lymph node metastasis differentiation degree and lymph node metastasis
(Li et al., 2018a)
30 GC tissues and 30 adjacent histological normal tissues
MEG3/miR-21 axis
-
proliferation and metastasis
(Dan et al., 2018)
GC tissue and adjacent tissue
-
-
proliferation and metastasis
(Wei and Wang, 2017)
50 pairs of GC tissue and matched adjacent normal tissue samples
-
-
cell proliferation, migration, invasion, and (Peng et al., 2015a) cell apoptosis
75 GC samples and 75 normal tissues
-
-
cell proliferation and cell cycle (Zhou et al., 2015b) progression and cell apoptosis, cell growth
134 Primary GCA tissues and adjacent normal tissues
-
-
cell proliferation and invasion
l a
72 paired GC samples and adjacent histological normal tissues
n r u
82 GC tissues and adjacent non‑tumor tissues
Jo
o r p
e
(LOC10537796) MEG3 (GTL2)
f o
EMT
r P
(Guo et al., 2017b)
Journal Pre-proof
MT1JP
16q13
52 gastric cancer samples
-
99 pairs of GC tissues and neighboring noncancerous tissues
MT1JP/MiR-214- 3p/RUNX3 Axis
cell proliferation, invasion and migration, (Xu et al., 2018e) and promoting apoptosis
80 pairs of matched normal and GC tissues
-
Poor Survival
cell proliferation, migration, invasion and (Zhang et al., 2018a) cell apoptosis, tumor growth and metastasis
50 pairs of primary gastric patients’ cancer tissues and paired adjacent nontumor tissue
-
-
-
-
LINC01006
7q36.3
187 gastric cancer tissues and their paired adjacent non-cancerous tissues
TMEM238L (LINC00675)
17p13.1-p12
in 45 pairs of GC and the adjacent non- tumor tissues, 20 healthy tissues,
SLC7A11-AS1
4q28.3
100 GC tissues and the paired adjacent non-cancerous tissues + from 33 GC patients before surgery and 20 healthy volunteers
MT1DP (MTM)
16q13
92 matched adjacent normal gastric mucosa (NGM) -GC tissue pairs
GACAT1 (AC096655.1-002) (LINC00876)
2q12.3
78 Paired gastric carcinomas tissues and normal tissue
GACAT2 (MTCL1-AS1) (lncRNA-HMlincRNA717)
18p11.22
107 gastric cancer tissues and paired adjacent nontumorous tissues + 37 human healthy gastric mucosa + 34 gastritis mucosa + 28 gastric precancerous lesions (dysplasia)
VPS9D1-AS1 (MYU)
16q24.3
126 primary GC tissues and matched adjacent non-tumorous tissues
lincRNA-p21 (TP53COR1) (linc- 6p21.2 p21)
l a
n r u
-
cell proliferation
o r p
e -
f o
cell proliferation, cell migration and invasion
(Yan et al., 2014)
(Lv et al., 2018)
(Zhu et al., 2017b)
proliferation, migration and invasion, growth, metastases
(Zeng et al., 2018)
ASK1 poor prognosis p38MAPK/JNK signaling pathway
Proliferation
(Luo et al., 2017)
-
cell migration and invasion, proliferation, (Lin et al., 2017) apoptosis
r P
Jo
shorter OS
-
(Sun et al., 2013)
(Shao et al., 2014a)
-
40 pairs of fresh GC tissues and adjacent EMT non-tumor tissues
Shorter OS
-
(Chen et al., 2017c)
EMT
(Chen et al., 2017d)
Journal Pre-proof MLLT4-AS1 (AFDN-DT)
6q27
98 pairs of human gastric cancer and adjacent non-cancerous tissues
-
Shorter OS
CASC2
10q26.11
69 fresh GC tissue specimens, with matched adjacent non-tumorous tissue
-
Shorter OS
(Lai et al., 2017)
67 fresh gastric cancer tissues and paired ERK1/2 and JNK adjacent non-tumor tissues pathway FER1L4
FENDRR (FOXF1-AS1)
20q11.22
16q24.1
61 gastric cancer tissues with the marched adjacent normal tissues + 80 healthy blood, 83 preoperative GC blood, and 83 postoperative blood
-
-
20 gastric cancer tissue samples
-
-
158 paired gastric cancer samples and adjacent histologically normal tissues
-
42 paired gastric cancer tissues and adjacent normal tissues
-
l a
n r u
(Zhou et al., 2017)
cell proliferation
(Du et al., 2016)
f o
ro
-p
e r P
proliferation, cell invasion and angiogenesis
(Liu et al., 2014d)
(Xia et al., 2015)
Shorter OS
(Xu et al., 2014c)
associated with advanced cell proliferation, cell migration stage, poor differentiation and lymphatic metastasis
(Luo et al., 2018b)
NCRUPAR (ncR-uPAR)
5q13.3
fresh tissue samples were collected from 138 gastric cancer patients
-
(Liu et al., 2014a)
nc886 (VTRNA2-1)
5q31.1
88 pairs of a tumor and its adjacent normal gastric tissue sample
-
-
(Lee et al., 2014a)
AC138128.1
located on chromosome 94 fresh GC tissue samples and matched 19 normal adjacent tissue
-
(Chen et al., 2014)
RP11-119F7.4 (AL513534.1)
10q21.3
96 patients with gastric cancer, matched non-tumor adjacent tissues
-
(Xie et al., 2015a)
LINC00982
1p36.32
106 paired gastric cancer samples and adjacent histologically normal tissues
-
Shorter OS and DFS
HNF1A-AS1
12q24.31
161 GC tissue and non-neoplastic tissues
-
-
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cell proliferation and cell cycle progression
(Fei et al., 2016)
(Dang et al., 2015a)
Journal Pre-proof LINC00261 (ALIEN) (DEANR1) 20p11.21
80 tumor tissues + adjacent normal tissues
EMT
Shorter OS
cell cycle progression and apoptosis, invasion, tumour metastasis
(Yu et al., 2017)
WT1-AS
11p13
91 in tumor tissues + matched adjacent non-tumor tissues.
ERK signaling
-
Proliferation, migration and invasion, tumor growth and metastasis
(Du et al., 2016)
lncRNA AI364715
chromosome 15
75 gastric cancer tissues and paired adjacent non-tumorous tissues + 18 human healthy gastric mucosa and 18 gastric precancerous lesions (dysplasia) from biopsy.
-
LncRNA-LOWEG
5p13.2
94 samples of matched non-tumor adjacent tissue
-
-
long noncoding RNA ZMAT1 transcript variant 2
Xq22.1
89 pairs of human gastric cancer and adjacent noncancerous tissues
-
LINC00628
in the 2nd intron of PLEKHA6 in chromosome 1q32.1
82 GC patients
AK001091
chr2:1129558211318987
tumor and adjacent non-tumor tissues from 30 GC patients
AK024171
chr5:8069660580699107
lncRNA-LET (NPTN-IT1)
15q24.1
SPRY4-IT1 (AK024556)
5q31.3
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cell invasion
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(Zhu et al., 2015b)
(Zhao et al., 2016a)
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Shorter OS
-
Shorter OS
JAK-STAT CAMs and the TNF pathway
-
(Fan et al., 2016)
tumor and adjacent non-tumor tissues from 30 GC patients
JAK-STAT Notch pathway, AMPK pathway
-
(Fan et al., 2016)
93 gastric cancer samples
-
Shorter OS
(Zhou et al., 2014)
37 cases of paired gastric cancer specimens
-
-
cell proliferation, cell migration, apoptosis (Tian et al., 2017a)
61 Paired gastric cancer tissues and normal tissues
EMT
Shorter OS
Metastasis, EMT
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(Lai et al., 2015)
cells proliferation, migration and invasion (Shao et al., 2016)
(Xie et al., 2015a)
Journal Pre-proof LOC100130476
6q23.3
121 primary GCA tissues and adjacent normal tissues
PTENP1
9p13.3
36 GC biopsies and their paired adjacent PTENP1∼miRNA normal tissues ∼PTEN ceRNA network
RP11-19P22.6-001 (ENST00000579660)
17q11.2
110 astric cancer tissues and paired adjacent non-tumorous tissues
-
-
LOC101927497
chromosome 7: 92854909-92917151
Cell line
LOC101927497miR-574-5p axis
-
Uc.160
5q14.1
51 GC samples and nonneoplastic gastric mucosa
-
-
AA174084
chr13:103562012103562617
134 GC tissues and paired non-tumorous tissues
lncRNA-AF147447 (AC009084.3) Chr16: 6694466066945096
75 pairs of H. pylori positive and negative tissues + 50 pairs of H. pylori positive and negative tumor tissues
LncRNA-RMRP (RMRP)
132 paired gastric cancer tissues and non-tumorous tissues
9p13.3
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-
Shorter OS
-
cell growth and induced apoptosis, migration and invasion
-
(Zhang et al., 2017b)
(Sun et al., 2017)
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cell proliferation and migration
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e
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-
-
(Guo et al., 2016a)
(Luo et al., 2018c)
(Honma et al., 2017)
(Shao et al., 2014b)
Cell proliferation and cell migration, (Zhou et al., 2016c) LncRNA AF147447 was decreased expressed in H. pylori infected tissues and cells (Shao et al., 2016)
Association between lncRNAs expression and H. pylori infection
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H. pylori alters inflammatory and autophagy mechanisms of host cells to strengthen its pathogenic effects. Various genetic factors in the host influence the initiation of GC by this bacterium. Certainly, epigenetic modifications through lncRNAs are among important host factors (Vaziri et al., 2018). Microarray analyses have shown differential expression of a number of lncRNAs in human gastric epithelial cell in relation with H. pylori infection (Yang et al., 2015). Assessment of expression profile of GES-1 cells with or without H.pylori infection has led to identification of a number of down-regulated (n345630, XLOC_004787, n378726
Journal Pre-proof and LINC00473) and up-regulated lncRNAs (XLOC_005517, LINC00152, XLOC_13370 and n408024) after H. pylori infection (Zhu et al., 2015a). A previous study has assessed the contribution of H. pylori infection in GC in relation with alterations in lncRNAs expression and found that H. pylori positive tissues have a particular lncRNAs signature. In vitro studies showed that expression of the tumor suppressor lncRNA-AF147447 is diminished by H. pylori infection (Zhou et al., 2016c). Another study has
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measured expression levels of three lncRNAs (H19, LINC00152, uc001lsz) in sera of GC patients and healthy subjects and reported
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significant associations between high expression of both H19 and LINC00152 and susceptibility to GC. Elevated expression levels of
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both lncRNAs cooperate with H. pylori infection to increase risk of GC. Consequently, serum H19 and LINC00152 have been
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suggested as possible biomarkers for identification of GC especially in H. pylori infected individuals (Yang et al., 2016b).
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Association between lncRNAs expression and EBV infection
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The relations between lncRNAs and EBV have been assessed by Huang et al. through sequencing of thousands of lncRNAs in a non-
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EBV-infected GC sample, an EBV-associated GC sample and their neighboring normal tissues. SNHG8 has been shown to have EBVassociated expression pattern as confirmed in an independent cohort patients as well. The interactions between this lncRNA and numerous GC-specific pathways and EBV target genes have been also demonstrated via bioinformatics tools (Huang et al., 2016c). More recently, Liu et al. reported over-expression of SNHG8 in the cultured EBV-associated GC cells compared with normal human gastric mucosal cells and EBV-negative GC cells. Notably, SNHG8 silencing has suppressed cell proliferation both in vitro and in vivo (Liu et al., 2018d).
Journal Pre-proof Role of lncRNAs in determination of GC patients’ outcome Aberrant expression of several lncRNAs has been associated with poor patients’ outcome in independent studies (Tables 1 and 2). Moreover, meta-analysis of available data has confirmed associations between elevated levels of a number of lncRNAs including
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ANRIL, ATB, BANCR, UCA1 and XIST and poor prognosis. On the other hand, down-regulation of FENDRR, FER1L4, GAS5, LET, and LINC00982 was associated with poor overall survival (Zhu et al., 2017a). Such revealed associations between transcript levels of
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lncRNAs and patients’ survival reflect the contribution of these transcripts in crucial steps of tumorigenesis. Tian et al. have assessed
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expression profile of lncRNAs in ten paired GC and adjacent normal tissues. They have constructed a 12-lncRNA signature which was
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associated with patients’ survival and confirmed it in an independent GEO dataset. The accuracy of this lncRNA profile was
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calculated as 0.869 through depiction of receiver operating characteristic (ROC) curve and calculation of the area under curve (AUC)
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value. The clinical relevance of such lncRNA signature was also validated through demonstration of enrichment of drug resistance and metastasis related pathways in the high risk patients (Tian et al., 2017b).
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Potential application of lncRNAs as diagnostic markers in GC Based on the aberrant expression of lncRNAs in GC tissues or peripheral blood of patients, their transcript levels can be used as diagnostic markers in GC. A number of studies have assessed diagnostic power of lncRNAs in GC through plotting ROC curve and calculation of AUC values. For instance, Xian et al. have reported higher expression levels of ZNFX1-AS1 and HULC in the plasma of preoperative GC patients compared with their levels in the plasma of gastrointestinal stromal tumor (GIST) patients, gastritis/peptic
Journal Pre-proof ulcer patients and normal controls. They reported AUC values of 0.85 and 0.65 for ZNFX1-AS1 and HULC, respectively and concluded that these lncRNAs are putative markers for non-invasive diagnosis of GC (Xian et al., 2018). Higher plasma H19 levels in GC patients compared with healthy individuals can be used as diagnostic marker in GC with accuracy of 64% (Arita et al., 2013). Li et al. have reported higher expression of LINC00152 in plasma samples of GC patients compared with normal controls. They also
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reported 48.1% sensitivity and 85.2% specificity of plasma LINC00152 levels in detection of GC patients. Based on the observed
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stability of LINC00152 in plasma, they hypothesized it is included in exosomes (Li et al., 2015). Sun et al. have shown down-
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regulation of the lncRNA RP11-119F7.4 in the GC tissues compared with the matched non-tumoral samples and reported the
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diagnostic accuracy of 63.7% for its transcript levels based on AUC value (Sun et al., 2015). Another study has estimated the
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diagnostic value of 71% for GAPLINC (Hu et al., 2014).
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Involvement of lncRNAs in GC-related signaling pathways
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The regulatory roles of lncRNAs in different levels of expression imply that they can alter function of cancer-related pathways. Both in vitro and in vivo studies have demonstrated such effects on a number of pathways including the mitogen-activated protein kinase (MAPK) pathway (Tasharrofi and Ghafouri-Fard, 2018). Other pathways have also been recognized as targets of lncRNAs in GC tissues. For instance, the lncRNA AK023391 induces the PI3K/Akt signaling pathway (Huang et al., 2017c). On the other hand, MEG3 prevents proliferation and metastasis of GC via p53 signaling cascade (Wei and Wang, 2017). HOTAIR accelerates EMT process and ANRIL activates mTOR pathway via different mechanisms. As demonstrated in Figure 1, HOTAIR recruits PRC2 to the promoter
Journal Pre-proof region of miR34a to suppress its expression. Liu et al. have shown down-regulation of miR-34a and negative correlation between this miRNA and HOTAIR in GC tissues. miR-34a has direct effects on regulation of Snail and c-Met expressions through binding to their 3′UTR regions. Reinstatement of miR-34a expression has suppressed migration and invasion of GC cells, and inhibited EMT process through modulation of Met and Snail expressions. Upregulation of HOTAIR leads to down-regulation of miR-34a and over-
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expression of C-Met, snail and EMT markers such as N-cadherin and vimentin (Liu et al., 2015b). In addition, HOTAIR acts as a
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sponge for miR-331-3p to regulate HER2 expression in GC. The positive interaction between HOTAIR and HER2 is possibly involved
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in conferring aggressive phenotype in these cells (Liu et al., 2014b). ANRIL as another oncogenic lncRNA epigenetically inhibits
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expression of miR-99a/miR-449a through recruitment of PRC2, therefore regulating mTOR and CDK6/E2F1 pathway and
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participating in cancer progression (Zhang et al., 2014b).
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Journal Pre-proof Figure 1. HOTAIR inhibits miR-34a expression and subsequently induces c-MET and SNAIL expressions leading to EMT. miR-34a has inhibitory effect on EMT though suppression of expression of c-MET and SNAIL . HOTAIR also facilitates tumorigenesis process through sponging miR-331 and modulating HER2 expression (A). ANRIL suppresses expression of p15 and p16, sponges miR-99a and miR-449a and activates mTOR pathway (B).
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In addition, H19 participates in the pathogenesis of GC through different mechanisms (Figure 2). First, H19 is a precursor of miR-675.
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Both H19 and miR-675 have been over-expressed in gastric cancer cell lines and tissues. Such altered expression has been associated
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with higher cell proliferation and lower cell apoptosis. The H19/miR-675 axis has been shown to suppress expression of FADD
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leading to inhibition of caspase cleavage cascades (Yan et al., 2017a). In addition, H19 acts a competing endogenous RNA for miR-
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141 which leads to over-expression of ZEB1 and STAT4 (Zhou et al., 2015c). Considering the role of ZEB1 and STAT4 in EMT and
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invasiveness of GC cells, H19 has been regarded as a facilitator of metastasis.
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Journal Pre-proof
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Journal Pre-proof Figure 2. H19 is a precursor of miR-675. Both are over-expressed in gastric cancer tissues leading to inhibition of apoptosis (A). H19 induces ZEB1 expression and EMT process through sponging miR-141. This miRNA has a role in suppression of expression of ZEB1 and STAT4, thus binding of H19 with miR-141 leads to over-expression of ZEB1 and STAT4 (B).
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Although regulation of AKt, Wnt/ beta-catenin, Myc and TGF-beta pathways by GC-related lncRNAs have been reported in several cancers (Chen et al., 2018b), evidences for specific role of these lncRNAs in regulation of these pathways in the context of GC are not
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sufficient. Consequently, future studies are needed to elaborate the role of these lncRNAs in GC in association with these signaling pathways. Discussion
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LncRNA expression profile has been extensively altered during the pathogenic course of GC. Notably, several lines of evidences
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confirm the association between expression levels of lncRNAs and clinicopathological factors in GC. Associations between
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FENDRR expression and lymph node involvement (Xu et al., 2014d), GAS5 expression and tumor differentiation (Sun et al., 2014a), HULC expression and metastasis potential (Jin et al., 2016b) and UCA1 expression and both invasion depth and TNM stage (Zheng et al., 2015b) are only few examples in this regard. It is expected that lncRNA profiling leads to better classification of GC in a way that such classification predicts tumor behavior in a more efficient way. A previous in silico study has demonstrated differential expression of 1,294 lncRNAs in gastric cancer compared with adjacent normal tissues. Notably, authors have detected differential expression of 247 lncRNAs between intestinal and diffuse subtypes of GC (Han et al., 2017b). Several studies have shown clinical
Journal Pre-proof relevance of lncRNA expression through assessment of their diagnostic or prognostic values. As anticipated, panels of lncRNAs were superior to individual lncRNAs in terms of biomarker discovery. Based on the established role of exosome-originated lncRNAs in conferring immune evasion and promoting cancer-associated phenotypes, these lncRNAs are of special importance in the field of biomarker recognition (Sun et al., 2018b). The feasibility of detection of lncRNAs in peripheral blood or other body fluids by
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relatively simple methods and the fact that they are functional without needing to be translated into proteins are the main advantages
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of lncRNAs as biomarkers for cancer detection.
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Notably, H. pylori and EBV, as two important environmental risk factors for GC change expression of lncRNAs in gastric tissues.
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These pathogens recruit diverse tools to inhibit the host effective immune response and permit chronic colonization. Simultaneously,
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they trigger inflammatory responses that result in oncogenic alterations (Polakovicova et al., 2018). LncRNAs are anticipated to
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contribute in many aspects of these processes. However, future studies are needed to explore exact mechanisms of their contribution in GC.
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Considering the role of lncRNAs in conferring resistance to conventional anti-cancer therapies (Jiang et al., 2019), lncRNA profiling would facilitate selection of patients for each treatment modality and personalized design of therapeutic options. Besides, a number of studies have identified some GC-associated lncRNAs that could be targeted with bioactive peptides and chemotherapy drugs. This approach has been performed through identification of differentially expressed lncRNAs in GC cells after treatment with a novel anticancer bioactive peptide and the chemotherapy drug oxaliplatin (Han et al., 2017a). Certain lncRNAs are involved in the process of
Journal Pre-proof immune evasion. For instance, the lncRNA SNHG14 participates in regulation of the miR-5590-3p/ZEB1 axis and immune evasion through regulating PD-1/PD-L1 checkpoint. Thus, therapeutic targeting of this lncRNA has been suggested as a way for enhancing the efficacy of immunotherapy (Zhao et al., 2019). However, the regulatory role of SNHG14 on PD-L1 expression has been found in lymphoma and its impact on GC pathogenesis remains unknown. Taken together, lncRNAs are regarded as putative markers for
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therapeutic response as well as targets for design of therapeutic options or improvement of response to conventional therapies.
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However, understanding the mechanisms of lncRNAs function is the main challenge in implementation of lncRNAs in clinical
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practice. This process is complicated by the multifaceted function of lncRNAs and their interactions with several mRNAs, miRNAs and transcription factors.
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