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SNHG7: A novel vital oncogenic lncRNA in human cancers
Biomedicine & Pharmacotherapy 124 (2020) 109921
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Review
SNHG7: A novel vital oncogenic lncRNA in human cancers a,1
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Yong Zhou , Bo Tian , Jinming Tang , Jie Wu , Hui Wang , Zhining Wu , Xu Li , Desong Yanga, Baihua Zhanga, Yuhang Xiaoc, Ying Wangb, Junliang Maa, Wenxiang Wanga,b,*, Min Sua,b,* a Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China b Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China c Department of Pharmacy, Xiangya Hospital of Xiangya School of Medicine, Central South University, Changsha, China
A R T I C LE I N FO
A B S T R A C T
Keywords: Long noncoding RNA SNHG7 Human cancers Functional role Molecular mechanism
Long noncoding RNAs (lncRNAs) are a group of RNAs that lack protein-coding ability, with lengths greater than 200 nucleotides. Increasing evidence has indicated that they mediate multiple physiological and pathological processes by regulating gene expression at the epigenetic, transcriptional, post-transcriptional, and translational levels. The deregulation of lncRNAs was demonstrated to have tumor suppressive or oncogenic effects, and thus, these molecules play vital regulatory roles in tumor initiation and progression. Small nucleolar RNA hostgene 7 (SNHG7) is a lncRNA located on chromosome 9q34.3. Different studies have explored the potential role of SNHG7 in the development and progression of multiple human malignancies such as bladder, breast, colorectal, esophageal, gastric, and prostate cancer, as well as osteosarcoma, among others, and high expression predicts poor prognosis and poor survival for such patients. Moreover, this molecule can promote proliferation and metastasis, while inhibiting apoptosis in cancer cells. The present review highlights the latest insights into the expression, functional roles, and molecular mechanisms of SNHG7 in different human malignancies.
1. Introduction Cancer is the leading cause of death worldwide and is a serious public health problem [1,2]. It comprises a group of malignant diseases involving uncontrolled cell growth, migration, and invasion. The cancer incidence and mortality rates have been rapidly growing in recent years. 2 In 2018, there was an estimated 18.1 million newly diagnosed cancer cases and 9.6 million cancer-related deaths [3]. Even though diagnostic and therapeutic approaches including surgical techniques, radiochemotherapy, and targeted drugs have continuously been developed in recent decades, most patients still have a dismal prognosis due to a lack of early diagnostic biomarkers and efficient treatment targets [1]. Hence, further research should be initiated to detect new biomarkers and therapeutic targets, which could provide a crucial theoretical basis for clinical cancer treatment. In recent years, researchers have focused on long noncoding RNAs (lncRNAs), which are defined as noncoding RNA molecules longer than 200 nucleotides lacking protein coding potential [4,5]. LncRNAs are
mainly transcribed by RNA polymerase II and are frequently spliced and polyadenylated [6]. Whereas they were once thought to be transcriptional noise, in the last few decades, an increasing number of studies has revealed that lncRNAs can contribute to the gene expression network through various mechanisms including sponging miRNAs, modifying histone and chromatin, and regulating translation, among others [7,8]. Currently, lncRNAs are known to play a critical role in various aspects of cell biology and potentially contribute to tumor occurrence and development by regulating cell proliferation, apoptosis, metastasis, stemness, and therapy resistance [4]. Notably, these molecules also potentially represent effective biomarkers or therapeutic targets for the diagnosis and management of tumors [9]. However, to date, only a small portion of lncRNAs have been identified, with the function of the majority of them remaining largely unclear; therefore, this requires further investigation. Small nucleolar RNA hostgene 7 (SNHG7) is an example of lncRNA that palys an important role in cancer. Herein, we summarize recent studies on the role of SNHG7 in cancers, including those focused on its aberrant expression, biological
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Corresponding authors at: Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. E-mail addresses: [email protected] (W. Wang), [email protected] (M. Su). 1 Contributed equally. https://doi.org/10.1016/j.biopha.2020.109921 Received 6 September 2019; Received in revised form 30 December 2019; Accepted 30 December 2019 0753-3322/ © 2020 Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
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2.3. Colorectal cancer
functions, and associated clinical features, in addition to its regulatory network.
Li et al. [17] and Shan et al. [18] found that SNHG7 expression is expressed at high levels in colorectal cancer. SNHG7 expression is also significantly related to risk factors of disease such as tumor size, clinical stage, lymphatic metastasis, and distant metastasis, as well as poor DFS and OS, in colorectal cancer patients. Furthermore, in vitro studies showed that this molecule promotes cell proliferation, migration, and invasion in colorectal cancer cells, while accelerating apoptosis rates. Results also indicated that SNHG7 exhibits oncogenic properties as a competitive endogenous RNA (ceRNA) to regulate the miR-34a/ GALNT7 [17] and miR-216b/GALNT1 axis [18]. GALNT7 and GALNT1 are members of the family of acetylgalactosaminyl transferase, which are involved in O-linked oligosaccharide biosynthesis and play a pivotal role in malignancy [29,30]. These findings indicate that SNHG7 might serve as a pivotal carcinogenic lncRNA in colorectal cancer and could be a novel therapeutic target.
2. Deregulation and functional role of SNHG7 in human cancers SNHG7 is located on chromosome 9q34.3 with a length of 2157 bp [10]. It has been firstly reported in 2013 by Chaudhry [11] as being a small nucleolar RNA host gene that expressed in lymphoblastoid cell lines TK6 and WTK1. Further, it has been reported that this molecule is upregulated and plays important role in various cancers, including bladder cancer [12–14], breast cancer [15,16], colorectal cancer [17,18], esophageal cancer [19], gastric cancer [20], glioblastoma [21], hypopharyngeal cancer [22], lung cancer [23,24], osteosarcoma [25,26], pancreatic cancer [27] and prostate cancer [28]. The highest expression of SNHG7 was reported in breast cancer cell line SKBR3 by Luo et al. [15], which is about 20–25 fold higher than that in the normal mammary epithelial cell line MCF-10A. However, in another study conducted by Sun et.al [16], the fold change of SNHG7 expression in SKBR3 cells was only 1.5–2.0 compared to that in MCF-10A. The discrepancy between the two studies cannot be explained by differences in cell lines or methodology and need further investigation. Beyond that, SNHG7 expression was much higher in bladder cancer cell line T24 and glioblastoma cell line U87, compared to that in relative normal cells [13,21]. All together the expression of SNHG7 was upregulated in tumor tissues and cancer cells. In addition, SNHG7 has been demonstrated to act as an oncogene in tumors and positively related to clinicopathological characteristics and poor prognosis of patients. The involvement of SNHG7 in biology of various cancers will be discussed in this section (Table 1 and Fig. 1).
2.4. Esophageal cancer One study from Xu et al. [19] revealed that the expression of SNHG7 in esophageal cancer clinical specimens and representative cells is significantly upregulated and positively associated with lymph node metastasis. In vitro experiments further showed that after SNHG7 expression was inhibited, the proliferation of EC cells was suppressed, apoptosis rate was increased, and cell cycle was blocked in the G1-G0 phase. Mechanistically, SNHG7 knockdown significantly upregulated the expression of p15 and p16 [19], two well-known tumor suppressors that are often suppressed in malignancy [31]. However, how p15 and p16 are regulated by SNHG7 is unclear and this requires further investigation. Taken together, SNHG7 plays a crucial role in the development of esophageal cancer and might act as a prognostic biomarker.
2.1. Bladder cancer Several studies have shown than SNHG7 is highly expressed in bladder cancer tissues compared to levels in adjacent normal tissues; further, the expression of SNHG7 was found to be higher in invasive tumors than in non-invasive tumors [12–14]. Its expression is also strongly related to tumor range, pathological stage, lymph node metastasis, and poor overall survival (OS) [12–14]. Accordingly, the knockdown of SNHG7 was determined to suppress cell viability, proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT), while inducing apoptosis in bladder cancer cell lines [12–14]. Several proteins were found to be regulated after SNHG7 knockdown; for example, the levels of Bax and p21 were increased [12], while the levels of β-catenin and its target molecules c-myc and cyclin D1 were reduced [13]. In addition, rescue assays performed in SNHG7 knockdown cells showed that the re-activation of Wnt/β-catenin signaling could partly restore the effects of SNHG7 on the biological behaviors of bladder cancer cells, indicating that this pathway might be a potential downstream target of SNHG7 [13]. However, the underlying signaling mechanisms still need to be further investigated. Taken together, these results revealed that SNHG7 acts as an oncogenic lncRNA and might provide a potential therapeutic target for bladder cancer.
2.5. Gastric cancer Wang et al. [20] found that SNHG7 is overexpressed in gastric cancer tissues and cell lines. After si-SNHG7 intervention, the proliferation of gastric cancer cells was inhibited, which was associated with an increase in apoptotic rate and arrest of the cell cycle at the G1/ G0 phase. In terms of the underlying mechanism, p15 and p16 comprise potential targets of SNHG7. These two proteins have been reported to act as tumor-suppressor genes in a variety of cancer. In conclusion, these results suggest that SNHG7 might serve as an oncogene and a therapeutic target for gastric cancer. 2.6. Glioblastoma A study performed by Ren et al. [21] demonstrated that SNHG7 is significantly overexpressed in glioblastoma tissues and cell lines. Further, clinical data showed that high levels of SNHG7 is related to poorer prognosis and shorter OS. Accordingly, the knockdown of SNHG7 markedly was found to markedly inhibit proliferation, migration, and invasion and promote apoptosis in glioblastoma cells. Further mechanistic studies revealed that SNHG7 directly inhibits miR-5095 and thus regulates its target CTNNB1 [21], which encodes a vital protein of the Wnt/b-catenin signaling pathway, ultimately resulting in activation of this pathway [32]. These findings suggest that SNHG7 might act as a cancer-promoting gene and a promising therapeutic target for glioblastoma.
2.2. Breast cancer The relative expression of SNHG7 was shown to be upregulated in breast cancer tissues and cells in comparison to that in normal tissues [15,16]. Further, high SNHG7 expression is strongly related to tumor stage, distant metastasis, lymph node metastasis, and OS in breast cancer patients [15]. si-SNHG7 intervention led to inhibited proliferation, invasion, and EMT in breast cancer cells [15,16]. Further mechanistic studies revealed that SNHG7 could act as an miRNA sponge to regulate the miR-34a/Notch-1 axis [16], as well as miR-186 [15] in breast cancer cells. Thus, SNHG7 acts as a crucial tumor-promoting lncRNA, suggesting its potential value as a novel therapeutic target for breast cancer treatment.
2.7. Hypopharyngeal cancer Wu and colleagues [22] showed that the expression of SNHG7 was much higher in taxol-resistant patients than in taxol-sensitive patients, and was positively related to advanced tumor stage and OS for hypopharyngeal cancer patients. This indicates that SNHG7 overexpression 2
3
up
up
up
pancreatic cancer
prostate cancer
up
up
TNM stage, lymph node metastasis
up up
hypopharyngeal cancer lung cancer
Osteosarcoma
tumor stage, OS –
up
glioblastoma
OS
OS
Enneking stage, distant metastasis, and OS tumor stage
OS
up
gastric cancer
tumor size, tumor stage, lymphatic metastasis, distant metastasis, DFS and OS clinical stage, lymph node metastasis, distant metastasis and OS lymph node metastasis –
up
up
up
esophageal cancer
colorectal cancer
up
tumor stage, lymph node metastasis, distant metastasis, OS –
tumor size, metastasis and stage.
up
up
OS
up
breast cancer
tumor grade
up
bladder cancer
Associated clinical features
Expression in tissues
Cancer type
Table 1 Functional characterization of SNHG7 in various tumors.
WPMY1
HPDE6-C7
–
–
BEAS-2B
– –
HEB
GES-1
HEEC
FHC
FHC
MCF-10A
MCF-10A
SV-HUC-1
SV-HUC-1
–
Relative normal cell lines
BxPC-3 (∼2-3), AsPC-1 (∼3-4), AW1990 (∼3-4), PANC-1 (∼4-5), PaCa-2 (∼4-5) LNCaP (∼4-6), VCaP(∼2-4), 22RV1(∼2-4), DU145(∼4-6), PC-3(∼2-4)
H125 (∼2-3), 95D (∼2-3), A594 (∼3-4)
SW620 (∼4-5), SW480 (∼1-2), LOVO (∼3-4), HCT-116 (∼1-2) Eca109 (∼5-6), EC9706 (∼4-5), TE-10 (∼3-4), TE-11 (∼2-3) BGC823 (∼4-5), MGC803 (∼4-5), SGC7901 (∼6-7), N87 (∼3-4), AGS (∼6-7) A172 (∼4-6), U87 (∼6-8), T98 G (∼4-6), SHG44 (∼2-4)
MDA-MB-231 (∼5-10), MCF-7 (∼10-15), SKBR3 (∼20–25) MCF-7 (∼2-2.5), MDA-MB-231 (∼1.5-2), MDA-MB-157 (∼1.5-), MDA-MB-435 (∼1.5-), T47D (∼1-1.5), SK-BR-3 (∼1.5-2) caco2 (∼1-2), SW620 (∼3-4), SW480 (∼1-2), Hct116 (∼1-2), LoVo (∼3-4)
T24 (∼7-8), 5637 (∼5-6), 253 J (∼2-3), TCC (∼3-4), J82 (∼3-4), EJ (∼3-4) T24 (∼2-4), J82 (∼4-6), SW780 (∼6-8)
Expression in cancer cell lines and relative fold change
promote cell proliferation, migration, invasion and EMT promote cell proliferation, inhibit cell apoptosis promote cell proliferation, inhibit cell apoptosis promote cell proliferation, migration, invasion promote chemo- and radio- therapy promote cell proliferation, migration, invasion, inhibit apoptosis promote cell proliferation, migration, invasion, inhibit apoptosis promote cell vitality, migration, invasion, inhibit apoptosis promote cell proliferation, inhibit apoptosis promote cell proliferation, migration, invasion promote cell proliferation
promote cell proliferation, metastasis, inhibit apoptosis
promote cell proliferation, invasion, inhibit cell apoptosis promote cell proliferation, migretion and invasion promote cell proliferation, invasion and EMT
promote cell proliferation, metastasis, inhibit apoptosis promote cell migration
Associated cell process
[14] [15] [16]
E-cadherin, N-cadherin, vimentin and snail miR-186 miR-34a/Notch-1
miR-503/cyclin D1
miR-342-3p/ID4
p53
[28]
[27]
[26]
[25]
[24]
miR-193b/FAIM2
miR-34a
[22] [23]
[21]
miR-5095/CTNNB1 – FAIM2
[20]
[19]
[18]
p15, p16
p15, p16
miR-216b/GALNT1
[17]
[13]
β-catenin pathway
miR-34a/GALNT7
[12]
Ref.
Bax, p21, E-cadherin
Targets
Y. Zhou, et al.
Biomedicine & Pharmacotherapy 124 (2020) 109921
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Fig. 1. The different regulatory mechanisms of SNHG7 in multiple human cancers.
vitality, migration, invasion, and EMT induced by TGF-b, in addition to accelerating apoptosis and inducing G1/S arrest. Mechanistically, SNHG7 inhibition induced the restoration of miR-34, a classic tumorsuppressive miRNA that is implicated in tumor proliferation, cell cycle, EMT, and apoptosis. Subsequently, the targets of miR-34a could be upregulated by SNHG7, including proliferation-related Notch1, apoptosis-related BCL-2, cell cycle-related CDK6, and EMT-related SMAD4 [25]. In addition, SNHG7 was also found to inhibit p53 expression by binding DNMT1 and recruiting it to the promoter of p53 [26]. Taken together, SNHG7 might act as an oncogene in osteosarcoma, with both epigenetic and genetic regulatory mechanisms affecting gene expression.
is involved in hypopharyngeal cancer chemotherapy resistance. Further, patients with high SNHG7 exhibit poor OS. Moreover, the expression of this molecule was also found to be upregulated in hypopharyngeal cancer cells and could remarkably promote cell viability and inhibit apoptosis mediated by metformin treatment. In conclusion, these findings present evidence that SNHG7 has potential value as a candidate prognostic marker and therapeutic target for hypopharyngeal cancer. 2.8. Lung cancer She et al. reported that the expression levels of SNHG7 are obviously increased in lung cancer tissues [23,24]. Loss-of-function assays also revealed that SNHG7 silencing by siRNA inhibits cell proliferation, migration, and invasion, while inducing apoptosis in lung cancer cells in vitro. Subsequent mechanistic studies demonstrated that this molecule directly inhibits miR-193b and subsequently upregulates its target FAIM2 [24], an anti-apoptotic protein [33]. These findings strongly indicate that SNHG7 might function as a potential therapeutic target for lung cancer.
2.10. Pancreatic cancer Chen et al. [27] showed that the expression level of SNHG7 is high in pancreatic cancer tissues and was positively correlates with poor OS. It was also found to be upregulated in pancreatic cancer cell lines. Lossof-function assays confirmed that SNHG7 knockdown suppresses PC cell proliferation, migration and invasion. In addition, this molecule was found to act as a ceRNA to sponge miR-342-3p and regulate its target ID4 [27], a member of the dominant-negative regulators of the basic helix-loop-helix transcription factor family that functions as a tumor suppressor [34]. Consequently, SNHG7 can effectively promote pancreatic cancer carcinogenesis and might serve as a potential biomarker for prognosis and treatment.
2.9. Osteosarcoma SNHG7 was found to be highly expressed in osteosarcoma and correlate with high Enneking stage, distant metastasis, and short patient OS [25,26]. Further, its knockdown markedly impairs the cell 4
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Fig. 2. Upstream regulatory and downstream molecular mechanisms underlying SNHG7 in human cancers.
regulate their target genes, such as the miR-34a/GALNT7 [17], miR216b/GALNT1 [18], miR-5095/CTNNB1 [21], miR-193b/FAIM2 [24], miR-342-3p/ID4 [27], and miR-503/cyclin D1 [28] axes.
2.11. Prostate cancer Qi et al. [28] found that SNHG7 was significantly overexpressed in prostate cancer tissues and cell lines. Further, its upregulation is closely related to tumor stage and OS for prostate cancer patients. Further in vitro assays using prostate cancer cell lines showed that SNHG7 knockdown markedly suppresses cell proliferation and induces cell cycle arrest at the G0/G1 phase. Mechanistically, SNHG7 was found to mediate the expression of Cyclin D1 by sponging miR-503. These results suggest that SNHG7 might play a vital role in prostate cancer development and could be used as a therapeutic target for this disease.
3.3. SNHG7 regulates various genes SNHG7 was also reported to be localized to the cell nucleus [26]. Here, it was found to directly bind DNMT1, which in turn binds the p53 promoter region, thus inhibiting its expression at the epigenetic level [26]. In addition, several proteins can be regulated by SNHG7, including Bax and p21 [12], p15 and p16 [19,20], and β-catenin pathway members [13], but the underlying mechanisms require further elucidation (Fig. 2).
3. Regulatory network of SNHG7 3.1. SNHG7 is regulated by methylation
4. Conclusions
Metformin, a typical hypoglycemic agent with potential anti-tumor activity, has been demonstrated to reduce the risk of cancer by promoting global DNA methylation and activating S-adenosylhomocysteine (SAHH), rather than altering its expression, in cancer cells [35,36]. Wu et al. [22] reported that in hypopharyngeal cancer cells, metformin increases SAHH activity and upregulates DNMT1 expression, subsequently leading to hypermethylation of the SNHG7 promotor and decreasing its expression. In addition, the downregulation of NMT1 was found to diminish hypermethylation of the SNHG7 promoter, indicating that the expression of SNHG7 can be regulated by methylation.
Based on the literature discussed above, it is clear that SNHG7 is upregulated and can promote the progression of multiple tumors. Studies have demonstrated that SNHG7 influences cancer cell proliferation, apoptosis, migration and invasion via the regulation of miRNAs, and the modulation of protein levels. In addition, SNHG7 expression was positively related to the prognosis of patients with various tumors. Many authors have concluded the high levels of SNHG7 can be used as a potential prognostic biomarker for various cancers. Although targeting SNHG7 may serve as a potential strategy for the treatment of a variety of cancers. Further studies are necessary to better investigate the involvement of SNHG7 in cancer and verify the clinical value of SNHG7.
3.2. SNHG7 functions as a competitive endogenous RNA It is well known that subcellular location can dictate the function of lncRNAs [37]. LncRNAs that are enriched in the cytoplasm typically interact with miRNAs to regulate gene expression at the post-transcriptional level, whereas those in the nucleus exert regulatory effects at the transcriptional level [37]. SNHG7 is reported to localize to the cell cytoplasm [18], and thus, itcould act as a ceRNA to sponge miRNAs and
Declaration of Competing Interest The authors declare that there is no conflict of interest regarding the publication of this article. 5
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Acknowledgements
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This work is supported by grants from the National Natural Science Foundation of China (81802947, 81603207), the Natural Science Foundation of Hunan Province (2019JJ50968, 2019JJ50358, 2018JJ3314, 2017JJ2173, 2017JJ3189), Health and Family Planning Commission of Hunan Province (20201699), Changsha Science and Technology Board (kq1801110), Fundamental Research Funds for the Central Universities of Central South University (502211903). References [1] R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics, 2019, CA Cancer J. Clin. 69 (1) (2019) 7–34. [2] K.D. Miller, L. Nogueira, A.B. Mariotto, J.H. Rowland, K.R. Yabroff, C.M. Alfano, A. Jemal, J.L. Kramer, R.L. Siegel, Cancer treatment and survivorship statistics, 2019, CA Cancer J. Clin. (2019). [3] F. Bray, J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre, A. Jemal, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J. Clin. 68 (6) (2018) 394–424. [4] M. Su, Y. Xiao, J. Ma, D. Cao, Y. Zhou, H. Wang, Q. Liao, W. Wang, Long non-coding RNAs in esophageal cancer: molecular mechanisms, functions, and potential applications, J. Hematol. Oncol. 11 (1) (2018) 118. [5] M.K. Iyer, Y.S. Niknafs, R. Malik, U. Singhal, A. Sahu, Y. Hosono, T.R. Barrette, J.R. Prensner, J.R. Evans, S. Zhao, A. Poliakov, X. Cao, S.M. Dhanasekaran, Y.M. Wu, D.R. Robinson, D.G. Beer, F.Y. Feng, H.K. Iyer, A.M. Chinnaiyan, The landscape of long noncoding RNAs in the human transcriptome, Nat. Genet. 47 (3) (2015) 199–208. [6] Y. Devaux, J. Zangrando, B. Schroen, E.E. Creemers, T. Pedrazzini, C.P. Chang, G.W. Dorn 2nd, T. Thum, S. Heymans, Long noncoding RNAs in cardiac development and ageing, Nat. Rev. Cardiol. 12 (7) (2015) 415–425. [7] J. Ponjavic, C.P. Ponting, G. Lunter, Functionality or transcriptional noise? Evidence for selection within long noncoding RNAs, Genome Res. 17 (5) (2007) 556–565. [8] S. Geisler, J. Coller, RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts, Nat. Rev. Mol. Cell Biol. 14 (11) (2013) 699–712. [9] C. Jiang, X. Li, H. Zhao, H. Liu, Long non-coding RNAs: potential new biomarkers for predicting tumor invasion and metastasis, Mol. Cancer 15 (1) (2016) 62. [10] T. Ota, Y. Suzuki, T. Nishikawa, T. Otsuki, T. Sugiyama, R. Irie, A. Wakamatsu, K. Hayashi, H. Sato, K. Nagai, K. Kimura, H. Makita, M. Sekine, M. Obayashi, T. Nishi, T. Shibahara, T. Tanaka, S. Ishii, J. Yamamoto, K. Saito, Y. Kawai, Y. Isono, Y. Nakamura, K. Nagahari, K. Murakami, T. Yasuda, T. Iwayanagi, M. Wagatsuma, A. Shiratori, H. Sudo, T. Hosoiri, Y. Kaku, H. Kodaira, H. Kondo, M. Sugawara, M. Takahashi, K. Kanda, T. Yokoi, T. Furuya, E. Kikkawa, Y. Omura, K. Abe, K. Kamihara, N. Katsuta, K. Sato, M. Tanikawa, M. Yamazaki, K. Ninomiya, T. Ishibashi, H. Yamashita, K. Murakawa, K. Fujimori, H. Tanai, M. Kimata, M. Watanabe, S. Hiraoka, Y. Chiba, S. Ishida, Y. Ono, S. Takiguchi, S. Watanabe, M. Yosida, T. Hotuta, J. Kusano, K. Kanehori, A. Takahashi-Fujii, H. Hara, T.O. Tanase, Y. Nomura, S. Togiya, F. Komai, R. Hara, K. Takeuchi, M. Arita, N. Imose, K. Musashino, H. Yuuki, A. Oshima, N. Sasaki, S. Aotsuka, Y. Yoshikawa, H. Matsunawa, T. Ichihara, N. Shiohata, S. Sano, S. Moriya, H. Momiyama, N. Satoh, S. Takami, Y. Terashima, O. Suzuki, S. Nakagawa, A. Senoh, H. Mizoguchi, Y. Goto, F. Shimizu, H. Wakebe, H. Hishigaki, T. Watanabe, A. Sugiyama, M. Takemoto, B. Kawakami, K. Watanabe, A. Kumagai, S. Itakura, Y. Fukuzumi, Y. Fujimori, M. Komiyama, H. Tashiro, A. Tanigami, T. Fujiwara, T. Ono, K. Yamada, Y. Fujii, K. Ozaki, M. Hirao, Y. Ohmori, A. Kawabata, T. Hikiji, N. Kobatake, H. Inagaki, Y. Ikema, S. Okamoto, R. Okitani, T. Kawakami, S. Noguchi, T. Itoh, K. Shigeta, T. Senba, K. Matsumura, Y. Nakajima, T. Mizuno, M. Morinaga, M. Sasaki, T. Togashi, M. Oyama, H. Hata, T. Komatsu, J. MizushimaSugano, T. Satoh, Y. Shirai, Y. Takahashi, K. Nakagawa, K. Okumura, T. Nagase, N. Nomura, H. Kikuchi, Y. Masuho, R. Yamashita, K. Nakai, T. Yada, O. Ohara, T. Isogai, S. Sugano, Complete sequencing and characterization of 21,243 fulllength human cDNAs, Nat. Genet. 36 (1) (2004) 40–45. [11] M.A. Chaudhry, Expression pattern of small nucleolar RNA host genes and long noncoding RNA in X-rays-treated lymphoblastoid cells, Int. J. Mol. Sci. 14 (5) (2013) 9099–9110. [12] C. Xu, J. Zhou, Y. Wang, A. Wang, L. Su, S. Liu, X. Kang, Inhibition of malignant human bladder cancer phenotypes through the down-regulation of the long noncoding RNA SNHG7, J. Cancer 10 (2) (2019) 539–546. [13] Y. Chen, Y. Peng, Z. Xu, B. Ge, X. Xiang, T. Zhang, L. Gao, H. Shi, C. Wang, J. Huang, Knockdown of lncRNA SNHG7 inhibited cell proliferation and migration in bladder cancer through activating Wnt/beta-catenin pathway, Pathol. Res. Pract. 215 (2) (2019) 302–307.
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Review
SNHG7: A novel vital oncogenic lncRNA in human cancers a,1
a,1
a,b
a
b
T a
a
Yong Zhou , Bo Tian , Jinming Tang , Jie Wu , Hui Wang , Zhining Wu , Xu Li , Desong Yanga, Baihua Zhanga, Yuhang Xiaoc, Ying Wangb, Junliang Maa, Wenxiang Wanga,b,*, Min Sua,b,* a Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China b Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China c Department of Pharmacy, Xiangya Hospital of Xiangya School of Medicine, Central South University, Changsha, China
A R T I C LE I N FO
A B S T R A C T
Keywords: Long noncoding RNA SNHG7 Human cancers Functional role Molecular mechanism
Long noncoding RNAs (lncRNAs) are a group of RNAs that lack protein-coding ability, with lengths greater than 200 nucleotides. Increasing evidence has indicated that they mediate multiple physiological and pathological processes by regulating gene expression at the epigenetic, transcriptional, post-transcriptional, and translational levels. The deregulation of lncRNAs was demonstrated to have tumor suppressive or oncogenic effects, and thus, these molecules play vital regulatory roles in tumor initiation and progression. Small nucleolar RNA hostgene 7 (SNHG7) is a lncRNA located on chromosome 9q34.3. Different studies have explored the potential role of SNHG7 in the development and progression of multiple human malignancies such as bladder, breast, colorectal, esophageal, gastric, and prostate cancer, as well as osteosarcoma, among others, and high expression predicts poor prognosis and poor survival for such patients. Moreover, this molecule can promote proliferation and metastasis, while inhibiting apoptosis in cancer cells. The present review highlights the latest insights into the expression, functional roles, and molecular mechanisms of SNHG7 in different human malignancies.
1. Introduction Cancer is the leading cause of death worldwide and is a serious public health problem [1,2]. It comprises a group of malignant diseases involving uncontrolled cell growth, migration, and invasion. The cancer incidence and mortality rates have been rapidly growing in recent years. 2 In 2018, there was an estimated 18.1 million newly diagnosed cancer cases and 9.6 million cancer-related deaths [3]. Even though diagnostic and therapeutic approaches including surgical techniques, radiochemotherapy, and targeted drugs have continuously been developed in recent decades, most patients still have a dismal prognosis due to a lack of early diagnostic biomarkers and efficient treatment targets [1]. Hence, further research should be initiated to detect new biomarkers and therapeutic targets, which could provide a crucial theoretical basis for clinical cancer treatment. In recent years, researchers have focused on long noncoding RNAs (lncRNAs), which are defined as noncoding RNA molecules longer than 200 nucleotides lacking protein coding potential [4,5]. LncRNAs are
mainly transcribed by RNA polymerase II and are frequently spliced and polyadenylated [6]. Whereas they were once thought to be transcriptional noise, in the last few decades, an increasing number of studies has revealed that lncRNAs can contribute to the gene expression network through various mechanisms including sponging miRNAs, modifying histone and chromatin, and regulating translation, among others [7,8]. Currently, lncRNAs are known to play a critical role in various aspects of cell biology and potentially contribute to tumor occurrence and development by regulating cell proliferation, apoptosis, metastasis, stemness, and therapy resistance [4]. Notably, these molecules also potentially represent effective biomarkers or therapeutic targets for the diagnosis and management of tumors [9]. However, to date, only a small portion of lncRNAs have been identified, with the function of the majority of them remaining largely unclear; therefore, this requires further investigation. Small nucleolar RNA hostgene 7 (SNHG7) is an example of lncRNA that palys an important role in cancer. Herein, we summarize recent studies on the role of SNHG7 in cancers, including those focused on its aberrant expression, biological
⁎
Corresponding authors at: Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. E-mail addresses: [email protected] (W. Wang), [email protected] (M. Su). 1 Contributed equally. https://doi.org/10.1016/j.biopha.2020.109921 Received 6 September 2019; Received in revised form 30 December 2019; Accepted 30 December 2019 0753-3322/ © 2020 Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
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2.3. Colorectal cancer
functions, and associated clinical features, in addition to its regulatory network.
Li et al. [17] and Shan et al. [18] found that SNHG7 expression is expressed at high levels in colorectal cancer. SNHG7 expression is also significantly related to risk factors of disease such as tumor size, clinical stage, lymphatic metastasis, and distant metastasis, as well as poor DFS and OS, in colorectal cancer patients. Furthermore, in vitro studies showed that this molecule promotes cell proliferation, migration, and invasion in colorectal cancer cells, while accelerating apoptosis rates. Results also indicated that SNHG7 exhibits oncogenic properties as a competitive endogenous RNA (ceRNA) to regulate the miR-34a/ GALNT7 [17] and miR-216b/GALNT1 axis [18]. GALNT7 and GALNT1 are members of the family of acetylgalactosaminyl transferase, which are involved in O-linked oligosaccharide biosynthesis and play a pivotal role in malignancy [29,30]. These findings indicate that SNHG7 might serve as a pivotal carcinogenic lncRNA in colorectal cancer and could be a novel therapeutic target.
2. Deregulation and functional role of SNHG7 in human cancers SNHG7 is located on chromosome 9q34.3 with a length of 2157 bp [10]. It has been firstly reported in 2013 by Chaudhry [11] as being a small nucleolar RNA host gene that expressed in lymphoblastoid cell lines TK6 and WTK1. Further, it has been reported that this molecule is upregulated and plays important role in various cancers, including bladder cancer [12–14], breast cancer [15,16], colorectal cancer [17,18], esophageal cancer [19], gastric cancer [20], glioblastoma [21], hypopharyngeal cancer [22], lung cancer [23,24], osteosarcoma [25,26], pancreatic cancer [27] and prostate cancer [28]. The highest expression of SNHG7 was reported in breast cancer cell line SKBR3 by Luo et al. [15], which is about 20–25 fold higher than that in the normal mammary epithelial cell line MCF-10A. However, in another study conducted by Sun et.al [16], the fold change of SNHG7 expression in SKBR3 cells was only 1.5–2.0 compared to that in MCF-10A. The discrepancy between the two studies cannot be explained by differences in cell lines or methodology and need further investigation. Beyond that, SNHG7 expression was much higher in bladder cancer cell line T24 and glioblastoma cell line U87, compared to that in relative normal cells [13,21]. All together the expression of SNHG7 was upregulated in tumor tissues and cancer cells. In addition, SNHG7 has been demonstrated to act as an oncogene in tumors and positively related to clinicopathological characteristics and poor prognosis of patients. The involvement of SNHG7 in biology of various cancers will be discussed in this section (Table 1 and Fig. 1).
2.4. Esophageal cancer One study from Xu et al. [19] revealed that the expression of SNHG7 in esophageal cancer clinical specimens and representative cells is significantly upregulated and positively associated with lymph node metastasis. In vitro experiments further showed that after SNHG7 expression was inhibited, the proliferation of EC cells was suppressed, apoptosis rate was increased, and cell cycle was blocked in the G1-G0 phase. Mechanistically, SNHG7 knockdown significantly upregulated the expression of p15 and p16 [19], two well-known tumor suppressors that are often suppressed in malignancy [31]. However, how p15 and p16 are regulated by SNHG7 is unclear and this requires further investigation. Taken together, SNHG7 plays a crucial role in the development of esophageal cancer and might act as a prognostic biomarker.
2.1. Bladder cancer Several studies have shown than SNHG7 is highly expressed in bladder cancer tissues compared to levels in adjacent normal tissues; further, the expression of SNHG7 was found to be higher in invasive tumors than in non-invasive tumors [12–14]. Its expression is also strongly related to tumor range, pathological stage, lymph node metastasis, and poor overall survival (OS) [12–14]. Accordingly, the knockdown of SNHG7 was determined to suppress cell viability, proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT), while inducing apoptosis in bladder cancer cell lines [12–14]. Several proteins were found to be regulated after SNHG7 knockdown; for example, the levels of Bax and p21 were increased [12], while the levels of β-catenin and its target molecules c-myc and cyclin D1 were reduced [13]. In addition, rescue assays performed in SNHG7 knockdown cells showed that the re-activation of Wnt/β-catenin signaling could partly restore the effects of SNHG7 on the biological behaviors of bladder cancer cells, indicating that this pathway might be a potential downstream target of SNHG7 [13]. However, the underlying signaling mechanisms still need to be further investigated. Taken together, these results revealed that SNHG7 acts as an oncogenic lncRNA and might provide a potential therapeutic target for bladder cancer.
2.5. Gastric cancer Wang et al. [20] found that SNHG7 is overexpressed in gastric cancer tissues and cell lines. After si-SNHG7 intervention, the proliferation of gastric cancer cells was inhibited, which was associated with an increase in apoptotic rate and arrest of the cell cycle at the G1/ G0 phase. In terms of the underlying mechanism, p15 and p16 comprise potential targets of SNHG7. These two proteins have been reported to act as tumor-suppressor genes in a variety of cancer. In conclusion, these results suggest that SNHG7 might serve as an oncogene and a therapeutic target for gastric cancer. 2.6. Glioblastoma A study performed by Ren et al. [21] demonstrated that SNHG7 is significantly overexpressed in glioblastoma tissues and cell lines. Further, clinical data showed that high levels of SNHG7 is related to poorer prognosis and shorter OS. Accordingly, the knockdown of SNHG7 markedly was found to markedly inhibit proliferation, migration, and invasion and promote apoptosis in glioblastoma cells. Further mechanistic studies revealed that SNHG7 directly inhibits miR-5095 and thus regulates its target CTNNB1 [21], which encodes a vital protein of the Wnt/b-catenin signaling pathway, ultimately resulting in activation of this pathway [32]. These findings suggest that SNHG7 might act as a cancer-promoting gene and a promising therapeutic target for glioblastoma.
2.2. Breast cancer The relative expression of SNHG7 was shown to be upregulated in breast cancer tissues and cells in comparison to that in normal tissues [15,16]. Further, high SNHG7 expression is strongly related to tumor stage, distant metastasis, lymph node metastasis, and OS in breast cancer patients [15]. si-SNHG7 intervention led to inhibited proliferation, invasion, and EMT in breast cancer cells [15,16]. Further mechanistic studies revealed that SNHG7 could act as an miRNA sponge to regulate the miR-34a/Notch-1 axis [16], as well as miR-186 [15] in breast cancer cells. Thus, SNHG7 acts as a crucial tumor-promoting lncRNA, suggesting its potential value as a novel therapeutic target for breast cancer treatment.
2.7. Hypopharyngeal cancer Wu and colleagues [22] showed that the expression of SNHG7 was much higher in taxol-resistant patients than in taxol-sensitive patients, and was positively related to advanced tumor stage and OS for hypopharyngeal cancer patients. This indicates that SNHG7 overexpression 2
3
up
up
up
pancreatic cancer
prostate cancer
up
up
TNM stage, lymph node metastasis
up up
hypopharyngeal cancer lung cancer
Osteosarcoma
tumor stage, OS –
up
glioblastoma
OS
OS
Enneking stage, distant metastasis, and OS tumor stage
OS
up
gastric cancer
tumor size, tumor stage, lymphatic metastasis, distant metastasis, DFS and OS clinical stage, lymph node metastasis, distant metastasis and OS lymph node metastasis –
up
up
up
esophageal cancer
colorectal cancer
up
tumor stage, lymph node metastasis, distant metastasis, OS –
tumor size, metastasis and stage.
up
up
OS
up
breast cancer
tumor grade
up
bladder cancer
Associated clinical features
Expression in tissues
Cancer type
Table 1 Functional characterization of SNHG7 in various tumors.
WPMY1
HPDE6-C7
–
–
BEAS-2B
– –
HEB
GES-1
HEEC
FHC
FHC
MCF-10A
MCF-10A
SV-HUC-1
SV-HUC-1
–
Relative normal cell lines
BxPC-3 (∼2-3), AsPC-1 (∼3-4), AW1990 (∼3-4), PANC-1 (∼4-5), PaCa-2 (∼4-5) LNCaP (∼4-6), VCaP(∼2-4), 22RV1(∼2-4), DU145(∼4-6), PC-3(∼2-4)
H125 (∼2-3), 95D (∼2-3), A594 (∼3-4)
SW620 (∼4-5), SW480 (∼1-2), LOVO (∼3-4), HCT-116 (∼1-2) Eca109 (∼5-6), EC9706 (∼4-5), TE-10 (∼3-4), TE-11 (∼2-3) BGC823 (∼4-5), MGC803 (∼4-5), SGC7901 (∼6-7), N87 (∼3-4), AGS (∼6-7) A172 (∼4-6), U87 (∼6-8), T98 G (∼4-6), SHG44 (∼2-4)
MDA-MB-231 (∼5-10), MCF-7 (∼10-15), SKBR3 (∼20–25) MCF-7 (∼2-2.5), MDA-MB-231 (∼1.5-2), MDA-MB-157 (∼1.5-), MDA-MB-435 (∼1.5-), T47D (∼1-1.5), SK-BR-3 (∼1.5-2) caco2 (∼1-2), SW620 (∼3-4), SW480 (∼1-2), Hct116 (∼1-2), LoVo (∼3-4)
T24 (∼7-8), 5637 (∼5-6), 253 J (∼2-3), TCC (∼3-4), J82 (∼3-4), EJ (∼3-4) T24 (∼2-4), J82 (∼4-6), SW780 (∼6-8)
Expression in cancer cell lines and relative fold change
promote cell proliferation, migration, invasion and EMT promote cell proliferation, inhibit cell apoptosis promote cell proliferation, inhibit cell apoptosis promote cell proliferation, migration, invasion promote chemo- and radio- therapy promote cell proliferation, migration, invasion, inhibit apoptosis promote cell proliferation, migration, invasion, inhibit apoptosis promote cell vitality, migration, invasion, inhibit apoptosis promote cell proliferation, inhibit apoptosis promote cell proliferation, migration, invasion promote cell proliferation
promote cell proliferation, metastasis, inhibit apoptosis
promote cell proliferation, invasion, inhibit cell apoptosis promote cell proliferation, migretion and invasion promote cell proliferation, invasion and EMT
promote cell proliferation, metastasis, inhibit apoptosis promote cell migration
Associated cell process
[14] [15] [16]
E-cadherin, N-cadherin, vimentin and snail miR-186 miR-34a/Notch-1
miR-503/cyclin D1
miR-342-3p/ID4
p53
[28]
[27]
[26]
[25]
[24]
miR-193b/FAIM2
miR-34a
[22] [23]
[21]
miR-5095/CTNNB1 – FAIM2
[20]
[19]
[18]
p15, p16
p15, p16
miR-216b/GALNT1
[17]
[13]
β-catenin pathway
miR-34a/GALNT7
[12]
Ref.
Bax, p21, E-cadherin
Targets
Y. Zhou, et al.
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Fig. 1. The different regulatory mechanisms of SNHG7 in multiple human cancers.
vitality, migration, invasion, and EMT induced by TGF-b, in addition to accelerating apoptosis and inducing G1/S arrest. Mechanistically, SNHG7 inhibition induced the restoration of miR-34, a classic tumorsuppressive miRNA that is implicated in tumor proliferation, cell cycle, EMT, and apoptosis. Subsequently, the targets of miR-34a could be upregulated by SNHG7, including proliferation-related Notch1, apoptosis-related BCL-2, cell cycle-related CDK6, and EMT-related SMAD4 [25]. In addition, SNHG7 was also found to inhibit p53 expression by binding DNMT1 and recruiting it to the promoter of p53 [26]. Taken together, SNHG7 might act as an oncogene in osteosarcoma, with both epigenetic and genetic regulatory mechanisms affecting gene expression.
is involved in hypopharyngeal cancer chemotherapy resistance. Further, patients with high SNHG7 exhibit poor OS. Moreover, the expression of this molecule was also found to be upregulated in hypopharyngeal cancer cells and could remarkably promote cell viability and inhibit apoptosis mediated by metformin treatment. In conclusion, these findings present evidence that SNHG7 has potential value as a candidate prognostic marker and therapeutic target for hypopharyngeal cancer. 2.8. Lung cancer She et al. reported that the expression levels of SNHG7 are obviously increased in lung cancer tissues [23,24]. Loss-of-function assays also revealed that SNHG7 silencing by siRNA inhibits cell proliferation, migration, and invasion, while inducing apoptosis in lung cancer cells in vitro. Subsequent mechanistic studies demonstrated that this molecule directly inhibits miR-193b and subsequently upregulates its target FAIM2 [24], an anti-apoptotic protein [33]. These findings strongly indicate that SNHG7 might function as a potential therapeutic target for lung cancer.
2.10. Pancreatic cancer Chen et al. [27] showed that the expression level of SNHG7 is high in pancreatic cancer tissues and was positively correlates with poor OS. It was also found to be upregulated in pancreatic cancer cell lines. Lossof-function assays confirmed that SNHG7 knockdown suppresses PC cell proliferation, migration and invasion. In addition, this molecule was found to act as a ceRNA to sponge miR-342-3p and regulate its target ID4 [27], a member of the dominant-negative regulators of the basic helix-loop-helix transcription factor family that functions as a tumor suppressor [34]. Consequently, SNHG7 can effectively promote pancreatic cancer carcinogenesis and might serve as a potential biomarker for prognosis and treatment.
2.9. Osteosarcoma SNHG7 was found to be highly expressed in osteosarcoma and correlate with high Enneking stage, distant metastasis, and short patient OS [25,26]. Further, its knockdown markedly impairs the cell 4
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Fig. 2. Upstream regulatory and downstream molecular mechanisms underlying SNHG7 in human cancers.
regulate their target genes, such as the miR-34a/GALNT7 [17], miR216b/GALNT1 [18], miR-5095/CTNNB1 [21], miR-193b/FAIM2 [24], miR-342-3p/ID4 [27], and miR-503/cyclin D1 [28] axes.
2.11. Prostate cancer Qi et al. [28] found that SNHG7 was significantly overexpressed in prostate cancer tissues and cell lines. Further, its upregulation is closely related to tumor stage and OS for prostate cancer patients. Further in vitro assays using prostate cancer cell lines showed that SNHG7 knockdown markedly suppresses cell proliferation and induces cell cycle arrest at the G0/G1 phase. Mechanistically, SNHG7 was found to mediate the expression of Cyclin D1 by sponging miR-503. These results suggest that SNHG7 might play a vital role in prostate cancer development and could be used as a therapeutic target for this disease.
3.3. SNHG7 regulates various genes SNHG7 was also reported to be localized to the cell nucleus [26]. Here, it was found to directly bind DNMT1, which in turn binds the p53 promoter region, thus inhibiting its expression at the epigenetic level [26]. In addition, several proteins can be regulated by SNHG7, including Bax and p21 [12], p15 and p16 [19,20], and β-catenin pathway members [13], but the underlying mechanisms require further elucidation (Fig. 2).
3. Regulatory network of SNHG7 3.1. SNHG7 is regulated by methylation
4. Conclusions
Metformin, a typical hypoglycemic agent with potential anti-tumor activity, has been demonstrated to reduce the risk of cancer by promoting global DNA methylation and activating S-adenosylhomocysteine (SAHH), rather than altering its expression, in cancer cells [35,36]. Wu et al. [22] reported that in hypopharyngeal cancer cells, metformin increases SAHH activity and upregulates DNMT1 expression, subsequently leading to hypermethylation of the SNHG7 promotor and decreasing its expression. In addition, the downregulation of NMT1 was found to diminish hypermethylation of the SNHG7 promoter, indicating that the expression of SNHG7 can be regulated by methylation.
Based on the literature discussed above, it is clear that SNHG7 is upregulated and can promote the progression of multiple tumors. Studies have demonstrated that SNHG7 influences cancer cell proliferation, apoptosis, migration and invasion via the regulation of miRNAs, and the modulation of protein levels. In addition, SNHG7 expression was positively related to the prognosis of patients with various tumors. Many authors have concluded the high levels of SNHG7 can be used as a potential prognostic biomarker for various cancers. Although targeting SNHG7 may serve as a potential strategy for the treatment of a variety of cancers. Further studies are necessary to better investigate the involvement of SNHG7 in cancer and verify the clinical value of SNHG7.
3.2. SNHG7 functions as a competitive endogenous RNA It is well known that subcellular location can dictate the function of lncRNAs [37]. LncRNAs that are enriched in the cytoplasm typically interact with miRNAs to regulate gene expression at the post-transcriptional level, whereas those in the nucleus exert regulatory effects at the transcriptional level [37]. SNHG7 is reported to localize to the cell cytoplasm [18], and thus, itcould act as a ceRNA to sponge miRNAs and
Declaration of Competing Interest The authors declare that there is no conflict of interest regarding the publication of this article. 5
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Acknowledgements
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