Can small nucleolar RNA be a novel molecular target for hepatocellular carcinoma?

Journal Pre-proofs Review Can small nucleolar RNA be a novelmolecular target forhepatocellular carcinoma? Han Shuwen, Yang Xi, Qi Quan, Jin Yin, Da Miao PII: DOI: Reference:

S0378-1119(20)30053-6 https://doi.org/10.1016/j.gene.2020.144384 GENE 144384

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Gene Gene

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Please cite this article as: H. Shuwen, Y. Xi, Q. Quan, J. Yin, D. Miao, Can small nucleolar RNA be a novelmolecular target forhepatocellular carcinoma?, Gene Gene (2020), doi: https://doi.org/10.1016/j.gene.2020.144384

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Can small nucleolar RNA be a novel molecular target for hepatocellular carcinoma? Han Shuwen1, Yang Xi2, Qi Quan3, Jin Yin4, Da Miao5* 1.Department of Oncology, Huzhou Cent Hosp, Affiliated Cent Hops HuZhou University. Address: 198 Hongqi Rd, Huzhou, Zhejiang ,People's R China; Email: [email protected]; 2.Department of Intervention and Radiotherapy, Huzhou Central Hospital, Huzhou, Zhejiang. Address: No. 198 Hongqi Road, Huzhou, Zhejiang Province. 313000; E-mail: [email protected]. 3.Department of Oncology, Huzhou Central Hospital, Huzhou, Zhejiang. Address: No. 198 Hongqi Road, Huzhou, Zhejiang Province. 313000; E-mail: [email protected] 4.Department of Clinical Laboratory, Huzhou Central Hospital, Huzhou, Zhejiang. Address: No. 198 Hongqi Road, Huzhou, Zhejiang Province. 313000; E-mail: [email protected] 5.*Corresponding author: Department of Nursing, Huzhou Third Municipal Hospital, Huzhou, Zhejiang Province, China; Address: No. 2088 east Tiaoxi road, Huzhou, Zhejiang Province, People's R China. 313000; E-mail: [email protected]; Tel: +8605722555750.

Abstract Background: Globally, hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death. Recently, many studies have demonstrated that small nucleolar RNA (snoRNA) was closely related to HCC. Objective: To explore whether snoRNA can be used as a molecular target for HCC. Methods: The PubMed, Embase, and Cochrane databases were searched for the published literatures related to snoRNA and HCC until August 12, 2019. After identification, screening, and verification, this study finally included 26 studies correlating small nucleolar RNA host gene (SNHG) and HCC, and 8 studies correlating snoRNA and HCC. Based on the collation of the relevant literature, the correlation network diagram between snoRNAs and HCC was constructed. Results: The SNHGs, such as SNHG1, SNHG6, SNHG16, and SNHG20 can play varied roles in HCC through different regulatory mechanisms. These SNHGs can promote and inhibit tumorigenesis. SNORD76 can promote the proliferation of tumor tissues and cells in vitro through different pathways. SnoU2_19 and SNORD76 can function through the same pathway. SNHG3, SNHG20, SNHG6, SNORD76, and snoRA47 can modulate epithelial-mesenchymal transition (EMT) to regulate the development of HCC cell or tissue. SNHG16, SNORD76, and SnoU2_19 can regulate the development of HCC through Wnt/β-catenin signaling pathway. Conclusion: snoRNA can regulate the occurrence of HCC by modulating multiple molecular signaling pathways. Hence, snoRNA can be a potential molecular target for

HCC. Key words: hepatocellular carcinoma; small nucleolar RNA; small nucleolar host gene

Introduction Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Globally, more than 700,000 new cases of HCC are diagnosed each year with more than 600,000 reported deaths annually [1]. In the United States, the mortality rate among patients with HCC is increasing faster than any other cancer and is expected to be the fourth leading cause of cancer-related deaths in 2019 [2]. The etiology of HCC is usually associated with factors causing inflammatory liver diseases, such as hepatitis B virus, hepatitis C virus, alcohol, and environmental toxins. After repeated exposure to risk factors, the liver undergoes hyperplasia and dysplasia, which subsequently results in the development of malignant phenotype [3]. Currently, the main therapeutic strategies for HCC include surgical resection, transplantation, and radiofrequency ablation [4]. Some novel treatment strategies have also shown improved efficacy, such as molecular targeted therapy (sorafenib, lenvatinib, regorafenib, and cabozantinib) [5], anti-vascular endothelial growth factor (VEGF) targeted therapy (ramucirumab and bevacizumab) [6], and cancer immune therapy (anti-PD-L1 antibody and anti-CTLA-4 antibody) [7, 8]. However, most patients with HCC are diagnosed at advanced stage due to the lack of accurate early diagnosis. Poor diagnosis along with lack of effective treatment has resulted in poor prognosis of most patients. Therefore, there is an urgent need for identifying new candidate biomarkers for diagnosis, prognosis, and treatment of HCC. The progression of HCC is a complex process, which is driven by the accumulation of various genetic and epigenetic changes. In mammals, about 90% of the genome transcribes non-coding RNA (ncRNA), while only 1.5% encodes proteins. The ncRNA is a functional RNA that is transcribed from DNA but not translated into a protein. The ncRNAs may regulate gene expression by binding to the DNA or RNA, which affects the gene transcription and translation [9]. Small nucleolar RNA (snoRNA) is a large and rich family of ncRNAs. The length of the snoRNA ranges between 70 and 140 nucleotides [10]. There are two main types of snoRNAs that have been reported. The C/D box and H/ACA box snoRNAs directly bind to their substrate via base pairing to induce 2′O-methylation and pseudoacylation, respectively [11]. Most metazoan snoRNAs are encoded in the intron of the host gene, which usually encodes proteins that are involved in translation or ribosomal biogenesis [12]. Although most of the snoRNAs encoded by the introns in these metazoans are processed by external processing of pre-mRNA or removal of introns, some snoRNAs require internal processing of pre-mRNA prior to external pruning up to the mature end [13]. Additionally, there are some snoRNA transcripts that are independently transcribed [14]. The snoRNA is a regulatory RNA that is responsible for post-transcriptional maturation of ribosomal RNA (rRNA) [15].

Ribosomal maturation and functional defects can lead to the dysregulation of vital processes, which transforms the diseased and normal cells into tumor cells [16]. As snoRNA is involved in the regulation of rRNA post-transcriptional modification, snoRNA levels can affect the physiological status of cells, tissues, and organs [16, 17]. Changes in the snoRNA expression levels may lead to a variety of diseases, such as hematological diseases [18],chronic lymphocytic leukemia [19],solid tumor (prostate cancer [20],colorectal cancer [21],and non-small cell lung cancer [22]),human neurodegenerative disorder (Prader-Willi syndrome [23] and autism spectrum disorder [24]), and viral diseases [25]. In recent years, snoRNA has been widely studied. Several studies suggest that snoRNA plays a key role in the development of multiple tumors by regulating the molecular signal networks. SNORD89 is highly expressed in the ovarian cancer stem cells and promotes the dry phenotype of ovarian cancer cells by regulating the Notch1-c-Myc pathway [26]. Similarly, SRPK1 is often upregulated in the gastric cancer cells and promotes the growth of tumor cells by regulating the expression of snoRNA in the gastric cancer [27]. In human pancreatic cancer, the upregulated SNORA23 regulates the expression of nuclear membrane protein 2-containing nucleoprotein repeats and promotes the growth and metastasis of xenograft tumors in mice [28]. snoRNA71A promotes the proliferation, migration, and invasion of lung cancer cells through MAPK/ERK pathway [29]. SNHG5 promotes the breast cancer proliferation by sponging the miR-154-5p/PCNA axis [30]. Long non-coding RNA (lnRNA) snoRNA host gene (SNHG) 12 promotes the growth and invasion of thyroid papillary carcinoma cells by targeting the miR-16-5p [31]. LncRNA SNHG15 regulates the occurrence of prostate cancer through the miR-338-3p/FKBP1A axis[32]. LnRNA SNHG17 driven by gene amplification can regulate the proliferation and migration of human non-small cell lung cancer cells [33]. Recently, several studies have demonstrated that snoRNA plays an important role in HCC. However, the complex correlation between snoRNA and HCC has not been fully understood. Therefore, this study comprehensively analyzed and classified the snoRNA and SNHG published in the literature related to HCC. Further, we constructed the network diagram of snoRNA and HCC. Our research also provides the basis for future studies on the correlation between HCC and snoRNA.

Methods The eligible studies published prior to 12 August 2019 were searched in the following databases: PubMed, Embase, and Cochrane. To maximize the sensitivity of search strategies and identify all studies, the following keywords were used: “Liver cancer, hepatocellular carcinoma, Liver cell carcinoma, Liver neoplasms, HCC, hepatocarcinoma, primary liver cancer, hepatic carcinoma, liver tumor, hepatic cancer, hepatic tumor”) and (“snoRNA or small nucleolus RNA”). All relevant titles and abstracts were independently evaluated by two authors. A comprehensive review of the studies was performed with information available in the system. In total, 34

studies were included after screening and identification. The detailed search strategy is shown in figure 1. Study selection The inclusion criteria for the studies to be included for the analysis were as follows: (1) relevant literature published in English; (2) in vivo or invitro studies involving snoRNA. The exclusion criteria were as follows: (1) abstracts, letters, comments, reports, reviews, or conference presentations; (2) major studies that have not evaluated snoRNA in HCC. Results After the identification, screening, and verification, we obtained 34 studies related to snoRNA and snoRNA host gene (SNHG) published in recent years. Of the 34 related studies, 26 studies evaluated the correlation between SNHG and HCC, while 8 evaluated the correlation between snoRNA and HCC. The studies on HCC and SNHG and those on snoRNA and HCC are shown in Table 1 and Table 2, respectively. In Table 1, molecular biological techniques, such as quantitative real-time polymerase chain reaction (qRT-PCR), luciferase reporter assay, cell proliferation assay, chemoresistance assay, tumorigenicity assay, and mouse xenograft tumor model were used in human, cellular, or animal experiments to explore the correlation between SNHG and HCC. The SNHGs, such as SNHG1, SNHG6, SNHG16, and SNHG20 can play a varied role in HCC. These snoRNAs can promote and inhibit tumorigenesis. SNHG16 is downregulated in both HCC cell lines and HCC tissues. Further, overexpressing SNHG16 suppressed the HCC proliferation and chemoresistance through hsa-miR-93 (panel No. 1.18). In HCC, SNHG16 expression was elevated and was associated with poor prognosis. SNHG16 facilitates HCC cell proliferation through miR-302a-3p/FGF19 axis (panel No. 1.13). As shown in figure 2, based on the related molecules reported in the literature, a network on the SNHG mechanism in HCC was constructed to better visualize the theory behind the experimental study. As shown in Table 2, several studies have used various techniques, such as qRT-PCR, subsequent downstream analysis, cell viability, ethynyl deoxy uridine (EdU), cell cycle assay, apoptosis assay, western blotting, tumor formation assays, and signaling pathway analysis to explore the correlation between snoRNA and HCC in vivo and in vitro. The snoRNA can promote proliferation in tumor tissues and cells in vitro through different pathways. SNORD76 facilitates HCC cell and HCC tissue invasion by inducing the epithelial-mesenchymal transition (EMT) and Wnt/β-catenin pathway, respectively (panel No. 2.4). Different snoRNAs can function through the same pathway. SnoU2_19 facilitates HCC progression (panel No. 2.2) and SNORD76 facilitates HCC tissue invasion through Wnt/β-catenin pathway (panel No. 2.4). As shown in figure 3, a network diagram was constructed on the mechanism of snoRNA in HCC to evaluate the correlation between snoRNA and HCC. As shown in Table 1 and Table 2, EMT is involved in the development of HCC,

which is regulated by snoRNA and SNHG. SNHG3 facilitates HCC invasion and sorafenib resistance by regulating EMT via miR-128/CD151/Akt/PI3K feedback loop signaling (panel No. 1.19). SNHG20 facilitates HCC cancer cell invasion through regulating EMT (panel No. 1.21). SNHG6 induces EMT by increasing the ZEB1-mediated MMP-2/9 expression in the hepatoma cells (panel No. 1.22). SNORD76 facilitates HCC cell invasion by inducing EMT (panel No. 2.4). SnoRA47 facilitates HCC tumorigenesis by regulating EMT markers (panel No. 2.5). Table 1 and Table 2 show that Wnt/β-catenin signaling pathway plays an important role in the development of HCC, which is regulated by snoRNA and SNHG. Wnt/β-catenin signaling is involved in SNHG16-mediated HCC cell proliferation and migration (panel No. 1.8), SNORD76-mediated HCC tissue invasion (panel No. 2.4), and SnoU2_19-mediated HCC progression (panel No. 2.2). Discussion In recent years there is a renewed interest in evaluating the role of snoRNA in the molecular regulation of colorectal cancer [34], lung cancer [29], and gastric cancer [27]. SnoRNA is a specialized and neglected RNA in cancer cells. The main function of snoRNA is post-transcriptional modification of ribosomal RNA(rRNAs), small nuclear RNA(SnRNAs) and transfer RNA(tRNA)[35,36], and it plays a regulatory role in rRNA processing, gene transcription, RNA splicing and RNA folding[37]. SNHG is small nucleolar RNA host gene, and it has the characteristics of long non-coding RNA.SnoRNAs may be regulated by copy number variation and methylation changes of SNHGs[38,39]. SNHGs may be involved in the development, progression, apoptosis and proliferation of cancer[40]. The present study reviewed the related literature of snoRNA and SNHGs in HCC.It has many meanings and novelties. On the one hand, it calls for researchers to pay more attention to the role of such non-coding RNAs including snoRNA and SNHGs in HCC. On the other hand, the summarized HCC related snoRNA and SNHGs provides potential molecular targets for early screening and differential diagnosis of HCC.More,the construction of regulatory network with regard to HCC related snoRNA and SNHGs provides a direction for exploring the mechanism of snoRNA and SNHGs in HCC. The results of this study demonstrate that the SNHGs, such as SNHG1, SNHG6, SNHG16, and SNHG20 can have varied roles in HCC. LncRNA SNHG1 modulates the p38MAPK pathway through Nedd4 and inhibits the osteogenic differentiation of bone marrow mesenchymal stem cells [41]. LncRNA SNHG1 and miR-497/miR-195-5p are involved in the modulation of the epithelial-interstitial transition during the exacerbation of colorectal cancer [42]. SNHG1 facilitates HCC development through miR-195-5p/PDCD4 axis or through suppression of miR-195. LncRNA SNHG6 promotes the migration, invasion, and epithelial-interstitial transformation of colorectal cancer cells through miR-26a/EZH2 axis [43]. LncRNA SNHG6 promotes the cell proliferation and migration of ovarian clear cell carcinoma by sponging miR-4465 [44]. Silencing lnRNA SNHG6 inhibits the proliferation, migration, and invasion of Wilms tumor cell lines by regulating miR-15a [45]. Silencing lncRNA SNHG6 inhibits the proliferation and invasion of breast cancer

cells through the miR-26a/Vasp axis [46]. This study demonstrated that SNHG6 facilitates HCC progression through miR-139-5p/SERPINH1 axis. Additionally, SNHG6 induces EMT by enhancing the ZEB1-mediated MMP-2/9 expression in hepatoma cells. SNHG6 facilitates HCC tumorigenesis by binding UPF1 and activating the TGF-β/Smad pathway. LncRNA SNHG16 promotes the growth of pancreatic cancer by targeting the miR-218-5p [47]. LnRNA SNHG16 silencing suppressed the invasiveness of gastric cancer by upregulating the miRNA-628-3p expression and subsequently decreasing the expression of Nrp1 [48]. SNHG16 upregulates the expression of ATG4B by sponging miR-16 and promotes the progression of osteosarcoma and enhance the resistance to cisplatin [49]. This indicated that SNHG16 facilitates HCC tissue or HCC cell proliferation, invasion, and tumorigenesis through miR-195, miR-186, Wnt/β-catenin signaling pathway, or miR-302a-3p/FGF19 axis. SNHG16 can function to promote tumorigenesis through different pathways and can function to inhibit the tumorigenesis. SNHG16 is downregulated in both HCC cell lines and HCC tissues. Overexpression of SNHG16 suppresses the HCC proliferation and chemoresistance through hsa-miR-93. Meanwhile, SNHG16 expression is elevated and is associated with poor prognosis in HCC. SNHG16 facilitates HCC cell proliferation through the miR-302a-3p/FGF19 axis (panel No. 1.13). LncRNA SNHG20 predicts poor prognosis of glioma and promotes cell proliferation by silencing P21 [50]. Additionally, LncRNA SNHG20 predicts poor prognosis and promotes the epithelial ovarian cancer cell progression [51]. SNHG20 knockout inhibits the proliferation, migration, and invasion of non-small cell lung cancer and promotes apoptosis by sponging miR-154 [52]. This indicated that SNHG20 facilitates cell invasion by regulating EMT. Hepatitis B virus x protein facilitates HCC cell proliferation through the lncRNA SNHG20/PTEN pathway. SnoRNA can promote proliferation in tumor tissues and tumor cells in vitro through different pathways. SNORD76 facilitates HCC cell and HCC tissue invasion by inducing EMT and Wnt/β-catenin pathway, respectively. Different snoRNAs can play a role through the same pathway. SnoU2_19 and SNORD76 also facilitate HCC progression through Wnt/β-catenin signaling. EMT is an important marker of tumor cell invasion and metastasis and is one of the characteristics of invasive carcinoma. EMT is characterized by decrease E-cadherin expression and increased N-cadherin expression (en-switch). The increased expression of FOXC2, an EMT-regulated transcription factor, is associated with the progression and poor prognosis of various malignant tumors [53]. Isorhamnetin inhibits the A549 non-small cell lung cancer cell migration and invasion by inhibiting the Akt/ERK-mediated EMT [54]. Dlx6-AS1/miR-204-5p/OCT1 positive feedback loop promotes the tumor progression and epithelial-interstitial transformation of gastric cancer [55]. In non-small cell lung cancer, FAM83A signaling pathway induces EMT through the PI3K/Akt/Snail pathway [56]. SNHG3 facilitates HCC invasion and sorafenib resistance by regulating the EMT via miR-128/CD151/Akt/PI3K feedback loop signaling. SNHG20 facilitates cell invasion by regulating the EMT. SNHG6 induces EMT by increasing the ZEB1-mediated

MMP-2/9 expression in hepatoma cells. SNORD76 facilitates HCC cell invasion by inducing EMT. SnoRA47 facilitates HCC tumorigenesis by regulating the EMT markers. Wnt signal transduction cascade controls many biological phenomena during the development and adulthood of all animals. However, abnormal Wnt signaling results in pathological manifestations in humans [57]. LncRNA ZEB2-As1 contributes to the carcinogenesis of gastric cancer by activating the Wnt/β-catenin pathway [58]. Overexpression of microRNA-519d-3p inhibits the growth of pancreatic cancer cells by inhibiting the Wnt/β-catenin signal transduction, which is mediated by ribosomal protein S15A [59]. MicroRNA-449b-5p inhibits the growth and invasion of breast cancer cells by inhibiting the CREPT-mediated Wnt/β-catenin signal transduction [60]. This study demonstrated that SNHG16, SNORD76, and SnoU2_19 facilitate HCC cell or tissue proliferation and migration through the Wnt/β-catenin signaling pathway. There are several limitations in this study. Although several keywords were used to search for the relevant studies, not all studies might have been included in the analysis. As the network mapping was performed to visualize the network easily, the network may be different from the original literature. Future research direction 1. The progress in gene sequencing has increased the accuracy of functional annotation and interpretation of non-coding region gene, such as snoRNA. This can be used for further elucidation of the correlation between host gene and snoRNA. This will promote the in-depth study of the correlation between snoRNA and host. 2. The complex molecular network of downstream genes regulated by snoRNA requires many molecular experiments for verification and analysis. The functional study of genes and their related proteins will aid in interpreting the human gene codes. 3. HCC has a high incidence. The current monitoring index of HCC is mainly alpha fetoprotein(AFP). Future studies must focus on inducing factors of HCC, such as fatty liver, liver cirrhosis, and liver cancer. A comparative study of chronic hepatitis, liver cirrhosis and HCC and dynamic monitoring of snoRNA changes in chronic hepatitis, liver cirrhosis, and HCC must be undertaken to provide supporting data for snoRNA as a molecular monitoring target for HCC. 4. The treatment of HCC is limited. Although the use of targeted drugs, such as sorafenib has some benefits in HCC, their efficacy varies in the treatment of liver cancer. Molecular screening of targeted drug-sensitive population based on snoRNA will aid in improving the efficacy of the targeted drugs. The development of targeted drugs or gene therapy based on snoRNA and SNHG will provide a new direction for the treatment of liver cancer. Conclusion The snoRNAs described in this study suggested their potential as a molecular target. snoRNA can regulate the occurrence of HCC by modulating multiple molecular signaling pathways. Hence, snoRNA can be used as a potential molecular

target for HCC. However, further studies are needed to evaluate the role of snoRNA in HCC. Abbreviations Abbreviation Definition AFP ATG4B ceRNA CCK-8 CNV ChIP CTLA ChIRP EdU EMT FISH GAS5 GWAS HCC HBV H&E IHC IF ISH lncRNA MTT MTS ncRNA NRP1 PD-1 PDCD4 PTEN qRT-PCR RIP rRNA snoRNA SNHG SPDD SRPK1 SERPINH1 SCARNA13 TCGA UPF1

alpha fetoprotein Autophagy-related 4B Competitive endogenous RNA Cell counting kit 8 Copy number variation Chromatin immunoprecipitation Cytotoxic T-lymphocyte-associated protein Chromatin isolation by RNA purification Ethynyl deoxy uridine Epithelial-mesenchymal transition Fluorescence in situ hybridization Growth arrest specific transcript 5 Genome-wide association study Hepatocellular carcinoma Hepatitis B virus Hematoxylin and eosin Immunohistochemistry Immunofluorescence In situ hybridization Long non-coding RNA 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium non-coding RNA Neuropilin 1 Programmed cell death protein 1 Programmed cell death 4 Phosphatase and tensin homolog deleted on chromosome 10 Quantitative reverse transcription polymerase chain reaction RNA immunoprecipitation Ribosomal RNA Small nucleolar RNA Small nucleolar RNA host gene Survivin promoter‐E1A 24bp deletion‐E1B deletion SRSF protein kinase 1 Serpin family H member 1 LncRNA small nucleolar RNA host gene 10 (SNHG10) homologous snoRNA The Cancer Genome Atlas Up-frameshift protein 1

VEGF ZEB1

Vascular endothelial growth factor Zinc finger E-box binding homeobox 1

Consent to participate As no human subjects were recruited for this study, obtaining consent is not applicable. Funding This work was supported by Public Welfare Technology Application Research Program of Huzhou (No. 2019GZ39，No.2019GZB01). Authors’ contributions All authors participated in the conception and design of the study. Shuwen Han and Da Miao conceived the study and prepared the manuscript. Shuwen Han and Da Miao designed and drew the network. Yang Xi, Qi Quan, and Jin Yin reviewed and sorted the literature. All authors read and approved the paper.

Competing Interests The authors declare no conflicts

Table 1. The effects of small nucleolar RNA host gene in HCC

No.

Year

Authors

Subject

snoR

Methods

NA

Expres

In

Findings/Results

Ref

sion

vivo/i

eren

level

n

ces

vitro 1.1

2019

Ye

Fifty-eight

paired

Junfeng,

hepatocellular

et al

carcinoma

(HCC)

samples

and

adjacent

matched

SNH

Quantitative

Upreg

In

Enhanced

G15

Real‐time

ulated

vivo/i

expression in HCC cells and

n

tissues.

vitro

SNHG15 facilitated

polymerase

chain

reaction

SNHG15

(qRT-PCR), CCK-8

HCC progression through

normal tissues, and

assay,

miR‐141‐3p.

HCC

cytometric analysis,

cell

lines

flow

(SMMC-7721,

wound

Hep3B,

healing/invasion

HepG2, and Huh-7)

assays,

Transwell

assay, dual-luciferase reporter assay, and RNA-binding protein immunoprecipitatio n

[61]

1.2

2019

Dongli

Human normal liver

SNH

qRT-PCR, CCK-8,

Upreg

In

Enhanced

Huang,

cell line (HL-7702),

G1

Transwell

ulated

et al

HCC

cell

lines

assay,

SNHG1

vivo/i

expression in HCC cells.

nude mice model of

n

SNHG1

vitro

development

(Li-7,

Huh7,

xenograft,

western

HHCC,

H-97,

blot, and RIP

Hep3b,

and

facilitated

[62]

HCC through

miR-195-5p/PDCD4 axis.

assay

SMMC-7721), and BALB/c nude mice

1.3

2019

Xie

Forty pairs of HCC

SNH

qRT-PCR, western

Upreg

In

Enhanced

Xuhua,

and

G16

blotting assay, MTT

ulated

vivo/i

expression in HCC tissues

et al

non-tumor

adjacent

tissues, HCC

SNHG16

liver

assay,

Transwell

n

and cell lines.

human

assay,

luciferase

vitro

SNHG16 facilitated HCC

cell

lines

(HepG2,

reporter

assay,

proliferation, invasion, and

RNA-pull

down

tumorigenesis

SMMC-7721,

assay, and xenograft

Hep3B,

nude mouse model

Bel7402,

[63]

through

miR-195.

and Huh7), normal liver

cell

line

(L-02),

and

BALB/c nude mice 1.4

2019

Wu

Twelve

pairs

Gang, et

HCC

al

adjacent

normal

assay,

tissues,

normal

cytometry,

tissue

hepatic

cell

(HL-7702),

of and

SNH

qRT-PCR,

Upreg

In

Enhanced

G6

Transwell

ulated

vivo/i

expression in HCC tissues.

flow

n

SNHG6

MTT

vitro

progression

line

assay,

HCC

formation

cell

colony

SNHG6 facilitated

[64]

HCC through

miR-139-5p/SERPINH1

assay,

axis.

and western blotting

lines

(HepG2,

Hep3b, HLE, and Huh-7), and female BALB/c mice 1.5

2019

Tu

Twenty

SNH

qRT-PCR, western

Upreg

In

HBV(+)

Wenhui,

HBV-related HCC

G20

blotting,

MTT

ulated

vivo/i

exhibited

enhanced

et al

patients,

assay,

flow

n

SNHG20

expression

vitro

compared to HBV(-) HCC

twenty

HCC

cells

non-HBV-related

cytometric analysis,

HCC

RNA

cells.

normal human liver

immunoprecipitatio

Hepatitis B virus x protein

cell

(L-02),

n, RNA pull-down

facilitated

HBV(-) HCC cell

assay, and animal

proliferation

line

models

lncRNA SNHG20/PTEN

patients, line

(HepG2),

HCC

cell through

[65]

HBV(+) HCC cell

pathway.

line (HepG2.2.15), and male BALB/C mice 1.6

2019

Li

Sorafenib-resistant

SNH

Cell viability and

Upreg

In

miR-21-mediated enhanced

Weidon

HCC

G1

apoptosis assays,

ulated

vitro

SNHG1 expression in HCC

g, et al

(SR-HCC)

cells

qRT-PCR, western

[66]

cells.

blotting, in situ hybridization, and luciferase assays 1.7

2019

Chen

Fifty HCC tissues

SNH

qRT-PCR, CCK-8

Upreg

In

Enhanced SNHG16

Hang, et

and matched

G16

assay, Transwell

ulated

vivo/i

expression in HCC tissues

al

adjacent

migration/invasion

n

and cell lines.

nontumorous liver

assay, bioinformatic

vitro

SNHG16 facilitated HCC

tissues, human

analysis, luciferase

cell proliferation, migration,

HCC cell lines

reporter assay,

and invasion through

(Hep-3B, Huh7,

western blotting,

miR-186.

Sk-hep-1,

and xenograft

SMMC-7721, and

tumor model

[67]

PLC), normal liver cell line (HL-77O2), and female BALB/c nude mice 1.8

2019

Chen, et

Thirty-eight clinical

SNH

qRT-PCR, CCK-8,

Upreg

In

Enhanced

SNHG16

al

HCC tissue samples

G16

Transwell chamber

ulated

vivo/i

expression in HCC tissues

and their adjacent

experiments,

n

and HCC cells.

tissues,

western

vitro

SNHG16 facilitated HCC

HCC

human cell

(Hep-3B,

lines Huh7,

blotting,

and xenograft tumor

cell

experiment

migration

Sk-hep-1, SMMC-7721,

proliferation

and through

Wnt/β-catenin and

[68]

signaling

pathway.

PLC), normal liver cell line (HL-77O2),

and

nude mice 1.9

2019

Zhu

Forty-nine

SNH

RNA-seq

Qingyao

tissues and adjacent

HCC

G1,

survival data

, et al

normal tissues

GAS5

and

,

tissues.

SNH

SNHG4 and GAS5 might be

G3-7,

valuable prognostic markers

SNH

in HCC.

G10-1

and

Upreg

In

Enhanced

ulated

vivo

SNHG1, GAS5, SNHG3-7,

expression

of

SNHG10-12 in HCC

[69]

2

1.10

2019

Lan

Sixty-four

HCC

SNH

RNA fluorescent in

Upreg

In

Enhanced

Tian, et

tissues and adjacent

G10

situ

ulated

vivo/i

expression in HCC tissues.

al

normal

tissues,

(FISH),

n

SNHG10 facilitated HCC

SNU-182,

Huh-7,

immunoprecipitatio

vitro

and

Hep3B,

SK-Hep1,

hybridization RNA

immunoprecipitatio

lines,

male

n assay, chromatin

BALB/c

isolation by RNA

and

athymic nude mice

metastasis

[70]

through

SCARNA13.

n assay, chromatin

and SNU-387 cell

SNHG10

purification (ChIRP)

assay,

coimmunoprecipitat ion, and luciferase reporter assay 1.11

2019

Sun

Fifty-five

HCC

SNH

qRT-PCR,

B-Z, et

tissues and adjacent

al

non-cancer samples,

G7

functional

western blot assay,

HepG2

wound

and

assays,

Upreg

In

Enhanced

ulated

vivo/i

expression in HCC tissues

n

and HCC cells.

vitro

SNHG7 facilitated HCC cell

healing

Bel-7402 HCC cell

assay,

and

lines, and normal

Transwell assay

SNHG7

[71]

invasion and migration by downregulating

liver epithelial cell

RBM5

expression.

line (L02) 1.12

2019

Guo

Ten

fresh

HCC

SNH

qRT-PCR,

ISH

Upreg

In

Enhanced

Zhenli,

tissues and adjacent

G16

staining, Transwell

ulated

vivo/i

expression in HCC tissues

et al

non-cancerous

assay,

n

and cell lines, which was

samples; sixty-one

viability assay

vitro

associated

and

cell

formalin-fixed,

SNHG16

with

[72]

overall

survival.

paraffin-embedded HCC

samples;

normal

liver

line

(HL-7702),

cell

four classic HCC cell lines (SK-Hep-1,

Huh7,

Hep3B,

and

HepG2) 1.13

2019

Li, et al

Thirty-four tissues liver

HCC

SNH

Cell

samples,

G16

qRT-PCR,

cancer

lines HepG2,

cell

(Huh7,

transfection,

luciferase

assay,

biotin

pull-down

assay,

western

Upreg

In

Enhanced

SNHG16

ulated

vivo/i

expression,

n

associated with poor

vitro

prognosis in HCC.

which

was

SNHG16 facilitated HCC

[73]

SMMC-7721,

blotting, and MTS

cell

SK-Hep1, and Hep

assay

miR-302a-3p/FGF19 axis.

3B),

and

proliferation

through

human

fetal hepatocyte cell line (L-02) 1.14

2018

Dong

HCC

Jiayong,

(L-02, Huh6, Huh7,

et al

SK-hep1, and

cell

lines

SNH

qRT-PCR analysis,

Upreg

In

Enhanced

G8

MTT assay, colony

ulated

vivo/i

expression in HCC tissues

n

and cell lines, which was

vitro

associated with

HepG2,

PLC5)

TCGA

and RNA

formation

assay,

Transwell

assays,

mouse

sequencing data

SNHG8

tumor recurrence.

xenograft

tumor model, lung

SNHG8

metastasis

tumorigenesis

western

[74]

model, blotting,

facilitated

HCC through

miR-149-5p.

bioinformatic analysis,

and

luciferase

reporter

assay 1.15

2018

Gao

Fifty

age-

Shoubao

sex-matched

, et al

healthy

and

SNH

Biochemical

Upreg

In

Enhanced

G1

analysis,

ulated

vivo

expression in HCC tissues

subjects,

receiver

operating characteristic

HBV-positive

analysis,

RNA

chronic

isolation,

and

and

cirrhosis,

[75]

and plasma.

fifty patients with hepatitis

SNHG1

microarray analysis

seventy-two patients with HCC 1.16

2018

Li

Human HCC cell

SNH

Yarui, et

lines

G5

al

HepG2,

xenograft

SMMC-7721,

colony

MHCC-97L,

assay, MTT assay,

SNHG5 facilitated HCC cell growth

(Hep3B,

qRT-PCR,

MHCC-97H,

and

flow

Huh7),

and

western

tumors, formation cytometry, blotting,

immortalized

Transwell,

human hepatic cell

healing

line (L-02)

immunofluorescenc e

wound assay,

(IF),

luciferase

reporter

assay,

hematoxylin eosin staining,

and (H&E) and

immunohistochemis try (IHC)

Upreg

In

Enhanced

SNHG5

ulated

vivo/i

expression in HCC, which

n

was correlated with poor

vitro

progression. by

inhibiting

miR-26a-5p/GSK-3β axis.

[76]

1.17

2018

Liu

Seventy-one

Xue-Fan

tissues

HCC

SNH

qRT-PCR

G18

g, et al

1.18

2018

Downr

In

Decreased

egulate

vivo

expression in HCC tissues.

d

Xu

Forty-three

Fengfen

tissues

g, et al

pair-matched healthy

HCC

SNH

qRT-PCR,

and

G16

luciferase

reporter

assay, hepatic

cell

chemoresistance

lines

(Hep3B,

assay,

Huh7,

SNU398,

SNU423, SNU429,

[77]

SNHG18 suppressed HCC.

Downr

In

Decreased

egulate

vivo/i

expression in both HCC cell

d

n

lines and HCC tissues.

vitro

Overexpressing

proliferation assay,

tissues, HCC cell

SNHG18

SNHG16

SNHG16

suppressed and

[78]

HCC

proliferation

and

tumorigenicity

chemoresistance

assay

hsa-miR-93.

through

Hep3G2, SK-HEP-1,

and

PLC/PRF/5) 1.19

2018

Zhang

HCC

cell

lines

Peng-Fe

(PLC/PRF/5,

i, et al

Hep3B,

SNH

Western

blotting,

Upreg

In

Enhanced

G3

IF, qRT-PCR, and

ulated

vivo/i

expression in the highly

invasion assay and

n

metastatic

proliferation assay

vitro

(HCCLM3).

HepG2,

MHCC-97L, Huh 7,

SMMC-7721,

SNHG3

HCCLM3),

invasion

and

1.20

2017

SNHG3 HCC facilitated and

cells HCC

sorafenib

paraffin-embedded

resistance by regulating

specimens

epithelial-mesenchymal

of

normal

transition

human liver, and

miR-128/CD151/Akt/PI3K

HCC tissues

feedback loop signaling.

(EMT)

via

Lan

Forty-eight

HCC

SNH

qRT-PCR, dual

Upreg

In

Enhanced

Tian, et

tissues and adjacent

G12

luciferase

ulated

vivo/i

expression

al

non-tumor

n

tissues.

vitro

SNHG12 facilitated HCC

tissues

western

assay, blotting,

SNHG12 in

the

and SK-Hep1 cell

RNA

line

immunoprecipitatio

tumorigenesis

n

metastasis by targeting

assay,

in

situ

hybridization, flow

[79]

[80]

HCC

and

miR-199a/b-5p.

cytometric analysis, cell

proliferation

assay, cell invasion assay,

cell

migration

assay,

and ChIRP assay 1.21

2017

Liu

Ninety-six

HCC

SNH

qRT-PCR,

Upreg

In

Enhanced

Jinxia,

tissues and normal

G20

Kaplan-Meier

ulated

vivo/i

expression in HCC, which

et al

tissues,

n

was negatively correlated

vitro

with overall survival (OS)

human line

normal

survival

analysis,

liver

cell

log-rank test, CCK8

(L-02),

and

cell

proliferation

time.

SNHG20

[81]

human HCC cell

and

lines (MHCC-97L,

invasion assays, and

SMMC-7721,

western

MHCC-97H,

and

Transwell

SNHG20

facilitated

cell

invasion by regulating EMT.

blotting

analysis

Huh-7) 1.22

2016

Chang Lei,

et

al

HCC specimens and

SNH

qRT-PCR,

ISH,

Upreg

In

Enhanced

the

G6

FISH,

luciferase

ulated

vivo/i

expression in HCC tissues

assay,

flow

n

and cell lines, which was

vitro

associated with histologic

corresponding

adjacent

tissues,

SNHG6

human hepatoma

cytometric analysis,

cell

CCK8

assay,

grade,

hepatitis

Ethynyl

deoxy

DNA,

Barcelona

uridine

(EdU)

Liver Cancer stage.

lines

Hep3B,

(Huh7, HepG2,

QGY-7701, MHCC-97L

with

assay,

IHC,

IF,

B

virus Clinic

SNHG6 induced EMT by

low

western

metastatic potential,

analysis,

HCCLM9 with high

Transwell

metastatic potential,

and wound healing

SNHG6

and

assay

tumorigenesis by binding

HL-7702),

[82]

blot assay,

increasing

ZEB1-mediated

MMP-2/9

expression

in

hepatoma cells. facilitated

HCC

immortalized

UPF1 and activating the

human hepatic cell

TGF-β/Smad pathway.

line (L02), and male athymic 4-week-old BALB/c nude mice 1.23

2016

Zhang Hui,

et

al

One-hundred-twent

SNH

ISH,

y-two HCC tissues

G1

dual-luciferase

and

In

Enhanced

SNHG1

ulated

vivo/i

expression in HCC tissues

report assay, cell

n

and cell lines.

human

proliferation assay,

vitro

SNHG1

cell

(HepG2),

lines

Transwell

and

assay,

facilitated

[83]

HCC

development by suppressing

and wound healing

normal human

Upreg

non-tumor

tissues, HCC

qRT-PCR,

miR-195.

assay liver

cell

line (L02)

1.24

2016

Zhang

TCGA dataset and

Dongya

HCC

n, et al

(HL-7702,

cell

Upreg

In

Enhanced

SNHG20

ulated

vivo/i

expression in HCC tissues,

SNH

evaluation

G20

staining, qRT-PCR,

n

which was associated with

MHCC-97H,

EdU

vitro

shorter overall

HepG2, SK-Hep-1,

incorporation

survival

SMMC-7721,

assays,

survival.

BEL-7402)

lines

ISH staining,

and

migration and

of

Transwell assay, Boyden

chamber invasion assay

and

disease-free

[84]

1.25

2016

Zhang

TCGA database

SNH

qRT-PCR, ISH

Upreg

In

Enhanced

SNHG3

Ting, et

, 151 pairs of fresh

G3

al

HCC samples, 144

ulated

vivo

expression in HCC tissues, which was associated with

paired

malignant status and poor

paraffin-embedded

prognosis.

[85]

HCC specimens,

and

Oncomine database

1.26

2016

Min

Eighty-two

Zhang,

tissues

et al

and paired adjacent

flow

non-tumor

analysis,

tissues, HCC

HCC

liver human

cell

lines

SNH

qRT-PCR,

cell

Upreg

Enhanced

G1

proliferation assay,

ulated

expression in HCC tissues,

cytometric

western blotting

and

SNHG1

which was associated with poor prognosis. SNHG1

facilitated

cells

MHCC-97H,

inhibiting p53 and

HCCLM3, and

p53-target genes expression.

HepG2), normal

human hepatocyte

cell (QSG-7701 L02)

lines and

proliferation

HCC

(SMMC-7721,

by

[86]

Table 2. The effects of small nucleolar RNA in HCC No.

Year

Authors

Subject

snoR

Methods

NA

Expres

In

Findings/Results

Refe

sion

vivo/i

renc

level

n

es

vitro 2.1

2018

Cao

One thousand five

SNO

Polymerase

Pengbo,

hundred thirty-eight

RA18

et al

copy

L5

number

chain

Upreg

In

Enhanced

SNORA18L5

reaction

(PCR),

ulated

vivo/i

expression in HCC tissues

northern

blotting,

n

and cells.

vitro

SNORA18L5

facilitated

variation

polysome profiling

(CNV)-based

assays,

HCC cell proliferation and

genome-wide

co-immunoprecipita

tumor growth at 15q13.3 in

tion,

a CNV-based GWAS.

association

study

(GWAS) cases

immunofluorescenc

and one thousand

e, and immunoblot

five hundred forty

analyses

controls

[87]

(cases,

chronic hepatitis B virus

(HBV)

carriers

with

hepatocellular carcinoma

(HCC)

and controls,

chronic

HBV

carriers

without HCC) and a collection of 205

HCC

trios,

(L-02, HepG2, or TP53–/–)

or

wildtype HCT116 cells, and HepG2,

Bel-7402,

SMMC-7721 cells 2.2

2018

Wang

Eighty patients with

snoU

Quantitative

Haitao,

HCC

2_19

real-time

et al

patients with liver cirrhosis,

and

Ten human

Upreg

In

Enhanced

ulated

vivo/i

expression in HCC tissues

(qRT-PCR),

n

with HBV infection.

subsequent

vitro

SnoU2_19 facilitated HCC

PCR

immortalized

downstream

normal hepatic cell

analysis,

cell

(L-02)

viability

assay,

lines

ethynyl

deoxy

(PLC/PRF/5,

uridine

(EdU)

Hep3B,

HepG2,

assay,

Huh-7,

SK-Hep-1,

assay,

and

HCC

cell

progression

cycle

apoptosis

SnoU2_19

through

Wnt/b-catenin signaling.

[88]

and HCCLM3)

assay,

western

blotting,

tumor

formation

assay,

and

signaling

pathway analysis 2.3

2017

Wu

Ninety-two

Long, et

and

al

non-tumor

HCC adjacent

ACA

qRT-PCR analysis,

Upreg

In

Enhanced

11

cell

ulated

vivo/i

expression in HCC tissues

n

and hepatoma cell lines.

vitro

ACA11 facilitated HCC cell

tissues,

proliferation

assay,

cell

cycle

ACA11

human HCC cell

analysis,

cell

lines

migration

and

proliferation, migration, and

invasion

assay,

invasion by targeting the

HepG2,

western

blotting,

PI3K/Akt

MHCC-97L,

tumorigenesis assay

pathway.

(Hep3B,

SK-Hep1,

Huh7,

SMMC-7721,

[89]

signaling

and

HCCLM9), normal liver

cell

line

(HL-7702),

and

male BALB/c nude mice 2.4

2017

Wu

Sixty-six

Long, et

tissues

al

HCC

and

SNO

qRT-PCR,

cell

Upreg

In

Enhanced

RD76

proliferation assay,

ulated

vivo/i

expression in HCC tissues,

cell cycle analysis,

n

which was associated with

cell apoptosis assay,

vitro

poorer survival.

adjacent

non-tumor tissues, HCC

human cell

lines

SNORD76

cell invasion assay,

SNORD76 facilitated HCC

western

cell and tissue invasion by

blotting,

(Hep3B, SK-Hep1,

and tumorigenicity

inducing

Huh7, HepG2,

assay

epithelial-mesenchymal

and

HCCLM3),

normal

liver

[90]

transition and Wnt/β-catenin

cell

pathway, respectively.

line (HL-7702), and male BALB/c nude mice 2.5

2017

Guangc

Sixty HCC samples

snoR

qRT-PCR,

cell

Upreg

In

Enhanced

ai, et al

and

A47

proliferation assay,

ulated

vivo/i

expression in HCC tissues,

six

different

snoRA47

human HCC cell

cell cycle analysis,

n

which was associated with

lines

cell apoptosis assay,

vitro

poorer

survival

and

cell invasion assay,

recurrence rate.

and

SnoRA47 facilitated HCC

western

analysis

blot

tumorigenesis b regulating epithelial-mesenchymal transition markers.

[91]

2.6

2016

Ma Pei,

Huh-7,

HCCLM9,

et al

Hep3B, SK-Hep-1,

SNO

qRT-PCR,

cell

Upreg

In

Enhanced

RD78

cycle analysis, cell

ulated

SNORD78

vivo/i

expression in HCC tissues,

HepG2 cell lines

apoptosis assay, cell

n

which was associated with

and

viability

vitro

overall

forty-seven

HCC patients

assay,

Transwell migration

survival and recurrence-free

and

survival.

Matrigel

[92]

chamber invasion assays

2.7

2016

Fang

Frozen HCC and

SNO

Xenograft

mouse

Upreg

In

Enhanced

Xianlon

normal tissues and

RD12

model

gene

ulated

vivo/i

expression in HCC tissues.

g, et al

female nude mice

6

expression

n

SNORD126 facilitated HCC

microarray

vitro

cell

and

SNORD126

growth

[93]

through

FGFR2-PI3K−Akt pathway.

2.8

2014

Xu

Human embryonic

SNO

qRT-PCR, plasmid

Downr

In

Decreased

Gang, et

kidney

RD11

construction,

egulate

vivo/i

expression in HCC tumors.

al

(Hek293T), human

3-1

transfection

d

n

SNORD113-1

vitro

HCC development through

HCC

cell cell

line lines

and

luciferase

(HepG2 and Huh7),

reporter

assay,

and male BALB/c

sodium

bisulfite

nude mice

sequencing,

cell

viability,

colony

formation

assay,

cell cycle and apoptosis analysis, tumorigenicity assay,

cell

migration

and

invasion

assays,

immunoblotting, and cancer pathway reporter assays

MAPK/ERK pathways.

SNORD113-1 suppressed and

TGF-β

[94]

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Figure Legends Figure 1. Literature search strategy The PubMed, Embase, and Cochrane databases were searched for literature published up until August 12, 2019. In total, 34 studies were included after identification and screening. Figure 2. Network illustrating the effects of small nucleolar RNA host genes on hepatocellular carcinoma This figure summarizes the literature related to small nucleolar RNA host genes in hepatocellular carcinoma published in recent years and shows the constructed network diagram of the correlation between hepatocellular carcinoma and small nucleolar RNA host genes. The red arrow represents the inhibitory effect, and the black arrow represents the promoting effect. The outermost orange circle represents the different small nucleolar RNAs (snoRNAs), the white inner circle represents the pathway that regulates the different snoRNAs, the light blue circle represents different literature reports, and the innermost circle represents the liver. Figure 3. Network illustrating the effects of small nucleolar RNAs (snoRNAs) in hepatocellular carcinoma This figure summarizes the literature related to small nucleolar RNA in hepatocellular carcinoma published in recent years and shows the constructed network diagram of the correlation between hepatocellular carcinoma and snoRNAs. The red arrow represents the inhibitory effect, and the black arrow represents the promoting effect. The outermost orange circle represents the different snoRNAs, the white inner circle represents the pathway that regulates the different snoRNAs, the light blue circle represents different literature reports, and the innermost circle represents the liver.

Highlights 1.We reviewed the related literature of small nucleolar RNAs and small nucleolar RNA host genes in hepatocellular carcinoma. 2.We constructed the regulatory network with regard to hepatocellular carcinoma related small nucleolar RNAs and small nucleolar RNA host genes. 3.SNHG16, SNORD76, and SnoU2_19 regulate the occurrence and development of hepatocellular carcinoma through Wnt/β-catenin signaling pathway. 4. SNHG3, SNHG20, SNHG6, SNORD76, and snoRA47 regulate the development of hepatocellular carcinoma by modulating epithelial-mesenchymal transition.