MicroRNA-615-5p targets insulin-like growth factor 2 and exerts tumor-suppressing functions in human esophageal squamous cell carcinoma

Yang,Bingyin; Xie,Rui; Wu,Shang-Nong; Gao,Cheng-Cheng; Yang,Xiao-Zhong; Zhou,Jing-Fang

doi:10.3892/or.2017.6079

MicroRNA-615-5p targets insulin-like growth factor 2 and exerts tumor-suppressing functions in human esophageal squamous cell carcinoma

Authors:
- Bingyin Yang
- Rui Xie
- Shang-Nong Wu
- Cheng-Cheng Gao
- Xiao-Zhong Yang
- Jing-Fang Zhou
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Affiliations: Department of Gastroenterology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
Published online on: November 6, 2017 https://doi.org/10.3892/or.2017.6079
Pages: 255-263

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Abstract

To investigate the expression pattern, clinical significance and functional roles of microRNA (miR)-615-5p in human esophageal squamous cell carcinoma (ESCC), , quantitative real-time PCR was performed to detect expression levels of miR‑615‑5p in ESCC tissues and cell lines. Associations between miR‑615‑5p expression and various clinicopathological features of ESCC patients were also statistically evaluated. The candidate targets of miR‑615‑5p were identified by integrating bioinformatics miRNA target prediction, western blot analysis and luciferase reporter assay. Moreover, the functions of miR‑615‑5p in ESCC cell migration and invasion were determined using the transfection of miRNA mimics, or co-transfected with miRNA mimics and the expression vector of its target gene. As a result, miR‑615‑5p expression in ESCC tissues and cells were markedly lower than those in non-cancerous esophageal mucosa and human normal esophageal cells, respectively (both P<0.001). miR‑615‑5p downregulation was significantly associated with advanced tumor-node-metastasis stage, positive lymph node metastasis and moderate-poor differentiation. Functionally, the re-expression of miR‑615‑5p suppressed the invasion and migration of ESCC cells in vitro. Interestingly, insulin-like growth factor 2 (IGF2) was identified as a direct target gene of miR‑615‑5p, and the inhibitory effects of miR‑615‑5p in ESCC cell motility were reversed by the restoration of IGF2 expression. In conclusion, miR‑615‑5p downregulation may be an underlying molecular mechanism of development and progression of ESCC, and may function as a potential therapeutic target of this malignancy. Also, we illustrate that the miR‑615‑5p/IGF2 axis may bring important contributions to cell motility of human ESCC.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Enzinger PC and Mayer RJ: Esophageal cancer. N Engl J Med. 349:2241–2252. 2003. View Article : Google Scholar : PubMed/NCBI
3	Tan C, Qian X, Guan Z, Yang B, Ge Y, Wang F and Cai J: Potential biomarkers for esophageal cancer. Springerplus. 5:4672016. View Article : Google Scholar : PubMed/NCBI
4	Ohashi S, Miyamoto S, Kikuchi O, Goto T, Amanuma Y and Muto M: Recent advances from basic and clinical studies of esophageal squamous cell carcinoma. Gastroenterology. 149:1700–1715. 2015. View Article : Google Scholar : PubMed/NCBI
5	Kang X, Chen K, Li Y, Li J, D'Amico TA and Chen X: Personalized targeted therapy for esophageal squamous cell carcinoma. World J Gastroenterol. 21:7648–7658. 2015. View Article : Google Scholar : PubMed/NCBI
6	Makarova JA, Shkurnikov MU, Wicklein D, Lange T, Samatov TR, Turchinovich AA and Tonevitsky AG: Intracellular and extracellular microRNA: An update on localization and biological role. Prog Histochem Cytochem. 51:33–49. 2016. View Article : Google Scholar : PubMed/NCBI
7	Yan X, Xu H and Yan Z: Functional perspective and implications of gene expression by noncoding RNAs. Cancer Transl Med. 1:137–152. 2015. View Article : Google Scholar
8	Svoronos AA, Engelman DM and Slack FJ: OncomiR or tumor suppressor? The duplicity of microRNAs in cancer. Cancer Res. 76:3666–3670. 2016. View Article : Google Scholar : PubMed/NCBI
9	Rupaimoole R, Calin GA, Lopez-Berestein G and Sood AK: miRNA deregulation in cancer cells and the tumor microenvironment. Cancer Discov. 6:235–246. 2016. View Article : Google Scholar : PubMed/NCBI
10	Liu W, Li M, Chen X, Zhang D, Wei L, Zhang Z, Wang S, Meng L, Zhu S and Li B: MicroRNA-373 promotes migration and invasion in human esophageal squamous cell carcinoma by inhibiting TIMP3 expression. Am J Cancer Res. 6:1–14. 2015.PubMed/NCBI
11	Nie J, Ge X, Geng Y, Cao H, Zhu W, Jiao Y, Wu J, Zhou J and Cao J: miR-34a inhibits the migration and invasion of esophageal squamous cell carcinoma by targeting Yin Yang-1. Oncol Rep. 34:311–317. 2015. View Article : Google Scholar : PubMed/NCBI
12	Mao Y, Liu J, Zhang D and Li B: MiR-1290 promotes cancer progression by targeting nuclear factor I/X(NFIX) in esophageal squamous cell carcinoma (ESCC). Biomed Pharmacother. 76:82–93. 2015. View Article : Google Scholar : PubMed/NCBI
13	Jiang Y, Zhang Y, Li F, Du X and Zhang J: CDX2 inhibits pancreatic adenocarcinoma cell proliferation via promoting tumor suppressor miR-615-5p. Tumour Biol. 37:1041–1049. 2016. View Article : Google Scholar : PubMed/NCBI
14	Gao W, Gu Y, Li Z, Cai H, Peng Q, Tu M, Kondo Y, Shinjo K, Zhu Y, Zhang J, et al: miR-615-5p is epigenetically inactivated and functions as a tumor suppressor in pancreatic ductal adenocarcinoma. Oncogene. 34:1629–1640. 2015. View Article : Google Scholar : PubMed/NCBI
15	Song LJ, Zhang WJ, Chang ZW, Pan YF, Zong H, Fan QX and Wang LXPU: PU.1 is identified as a novel metastasis suppressor in hepatocellular carcinoma regulating the miR-615-5p/IGF2 axis. Asian Pac J Cancer Prev. 16:3667–3671. 2015. View Article : Google Scholar : PubMed/NCBI
16	Zhao ZG, Jin JY, Zhang AM, Zhang LP, Wang XX, Sun JG and Chen ZT: MicroRNA profile of tumorigenic cells during carcinogenesis of lung adenocarcinoma. J Cell Biochem. 116:458–466. 2015. View Article : Google Scholar : PubMed/NCBI
17	Chou CH, Chang NW, Shrestha S, Hsu SD, Lin YL, Lee WH, Yang CD, Hong HC, Wei TY, Tu SJ, et al: miRTarBase 2016: Updates to the experimentally validated miRNA-target interactions database. Nucleic Acids Res. 44(D1): D239–D247. 2016. View Article : Google Scholar : PubMed/NCBI
18	El Tayebi HM, Hosny KA, Esmat G, Breuhahn K and Abdelaziz AI: miR-615-5p is restrictedly expressed in cirrhotic and cancerous liver tissues and its overexpression alleviates the tumorigenic effects in hepatocellular carcinoma. FEBS Lett. 586:3309–3316. 2012. View Article : Google Scholar : PubMed/NCBI
19	Gulyaeva LF and Kushlinskiy NE: Regulatory mechanisms of microRNA expression. J Transl Med. 14:1432016. View Article : Google Scholar : PubMed/NCBI
20	Harada K, Baba Y, Ishimoto T, Shigaki H, Kosumi K, Yoshida N, Watanabe M and Baba H: The role of microRNA in esophageal squamous cell carcinoma. J Gastroenterol. 51:520–530. 2016. View Article : Google Scholar : PubMed/NCBI
21	Arora A, Singh S, Bhatt AN, Pandey S, Sandhir R and Dwarakanath BS: Interplay between metabolism and oncogenic process: Role of microRNAs. Transl Oncogenomics. 7:11–27. 2015.PubMed/NCBI
22	Sun Y, Zhang T, Wang C, Jin X, Jia C, Yu S and Chen J: MiRNA-615-5p functions as a tumor suppressor in pancreatic ductal adenocarcinoma by targeting AKT2. PLoS One. 10:e01197832015. View Article : Google Scholar : PubMed/NCBI
23	Bai Y, Li J, Li J, Liu Y and Zhang B: MiR-615 inhibited cell proliferation and cell cycle of human breast cancer cells by suppressing of AKT2 expression. Int J Clin Exp Med. 8:3801–3808. 2015.PubMed/NCBI
24	Wu X, Deng L, Tang D, Ying G, Yao X, Liu F and Liang G: miR-615-5p prevents proliferation and migration through negatively regulating serine hydromethyltransferase 2 (SHMT2) in hepatocellular carcinoma. Tumour Biol. 37:6813–6821. 2016. View Article : Google Scholar : PubMed/NCBI
25	Brouwer-Visser J and Huang GS: IGF2 signaling and regulation in cancer. Cytokine Growth Factor Rev. 26:371–377. 2015. View Article : Google Scholar : PubMed/NCBI
26	Bruchim I, Sarfstein R and Werner H: The IGF Hormonal Network in Endometrial Cancer: Functions, regulation, and targeting approaches. Front Endocrinol (Lausanne). 5:762014.PubMed/NCBI
27	Chao W and D'Amore PA: IGF2: Epigenetic regulation and role in development and disease. Cytokine Growth Factor Rev. 19:111–120. 2008. View Article : Google Scholar : PubMed/NCBI
28	Mu Q, Wang L, Yu F, Gao H, Lei T, Li P, Liu P, Zheng X, Hu X, Chen Y, et al: Imp2 regulates GBM progression by activating IGF2/PI3K/Akt pathway. Cancer Biol Ther. 16:623–633. 2015. View Article : Google Scholar : PubMed/NCBI
29	Chava S, Mohan V, Shetty PJ, Manolla Ml, Vaidya S, Khan IA, Waseem GL, Boddala P, Ahuja YR and Hasan Q: Immunohistochemical evaluation of p53, FHIT, and IGF2 gene expression in esophageal cancer. Dis Esophagus. 25:81–87. 2012. View Article : Google Scholar : PubMed/NCBI
30	Gao T, He B, Pan Y, Xu Y, Li R, Deng Q, Sun H and Wang S: Long non-coding RNA 91H contributes to the occurrence and progression of esophageal squamous cell carcinoma by inhibiting IGF2 expression. Mol Carcinog. 54:359–367. 2015. View Article : Google Scholar : PubMed/NCBI