MicroRNA-616 promotes the migration, invasion and epithelial-mesenchymal transition of HCC by targeting PTEN

Zhang,Di; Zhou,Peihua; Wang,Wei; Wang,Xiaolong; Li,Junhui; Sun,Xuejun; Zhang,Li

doi:10.3892/or.2015.4334

MicroRNA-616 promotes the migration, invasion and epithelial-mesenchymal transition of HCC by targeting PTEN

Authors:
- Di Zhang
- Peihua Zhou
- Wei Wang
- Xiaolong Wang
- Junhui Li
- Xuejun Sun
- Li Zhang
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Affiliations: Department of General Surgery, The Second Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China, Department of General Surgery, The First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
Published online on: October 16, 2015 https://doi.org/10.3892/or.2015.4334
Pages: 366-374

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Abstract

MicroRNAs, which can post-transcriptionally regulate gene expression by binding to the 3'-untranslated regions of the mRNAs, have been found to be the critical regulators of the development and progression of hepatocellular carcinoma (HCC). The present study demonstrated for the first time that microRNA-616 (miR-616) was markedly upregulated in HCC tissues, and was associated with the recurrence and metastasis of HCC. Elevated level of miR-616 was correlated with adverse clinicopathological features and poor prognosis of HCC patients. Gain- and loss-of-function studies revealed that miR-616 could potentiate the migration, invasion and the epithelial-mesenchymal transtion (EMT) phenotype of HCC cells. Phosphatase and tensin homolog (PTEN), the predicted target of miR-616 by bioinformatics analysis, was confirmed as a direct downstream target of miR-616 through western blotting, luciferase reporter and immunohistochemical assays. Furthermore, we demonstrated that miR-616 exerted the promoting effects on EMT and metastatic ability of HCC cells through suppressing PTEN expression. Based on these results, we conclude that miR-616 is a promising prognostic biomarker of HCC and targeting miR-616 may be a potential option to prevent the progression of HCC.

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1	Bosch FX, Ribes J, Díaz M and Cléries R: Primary liver cancer: Worldwide incidence and trends. Gastroenterology. 127(Suppl 1): S5–S16. 2004. View Article : Google Scholar : PubMed/NCBI
2	Karaman B, Battal B, Sari S and Verim S: Hepatocellular carcinoma review: Current treatment, and evidence-based medicine. World J Gastroenterol. 20:18059–18060. 2014.PubMed/NCBI
3	El-Serag HB and Rudolph KL: Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastro-enterology. 132:2557–2576. 2007. View Article : Google Scholar
4	Roberts LR: Sorafenib in liver cancer - just the beginning. N Engl J Med. 359:420–422. 2008. View Article : Google Scholar : PubMed/NCBI
5	Rosa A and Brivanlou AH: MicroRNAs in early vertebrate development. Cell Cycle. 8:3513–3520. 2009. View Article : Google Scholar : PubMed/NCBI
6	Yates LA, Norbury CJ and Gilbert RJ: The long and short of microRNA. Cell. 153:516–519. 2013. View Article : Google Scholar : PubMed/NCBI
7	Calin GA and Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 6:857–866. 2006. View Article : Google Scholar : PubMed/NCBI
8	Chang RM, Yang H, Fang F, Xu JF and Yang LY: MicroRNA-331-3p promotes proliferation and metastasis of hepatocellular carcinoma by targeting PH domain and leucine-rich repeat protein phosphatase. Hepatology. 60:1251–1263. 2014. View Article : Google Scholar : PubMed/NCBI
9	Budhu A, Jia HL, Forgues M, Liu CG, Goldstein D, Lam A, Zanetti KA, Ye QH, Qin LX, Croce CM, et al: Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology. 47:897–907. 2008. View Article : Google Scholar : PubMed/NCBI
10	Garzon R, Calin GA and Croce CM: MicroRNAs in Cancer. Annu Rev Med. 60:167–179. 2009. View Article : Google Scholar : PubMed/NCBI
11	Jansson MD and Lund AH: MicroRNA and cancer. Mol Oncol. 6:590–610. 2012. View Article : Google Scholar : PubMed/NCBI
12	Ladeiro Y, Couchy G, Balabaud C, Bioulac-Sage P, Pelletier L, Rebouissou S and Zucman-Rossi J: MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology. 47:1955–1963. 2008. View Article : Google Scholar : PubMed/NCBI
13	Giordano S and Columbano A: MicroRNAs: New tools for diagnosis, prognosis, and therapy in hepatocellular carcinoma? Hepatology. 57:840–847. 2013. View Article : Google Scholar
14	Cho WC: MicroRNAs: Potential biomarkers for cancer diagnosis, prognosis and targets for therapy. Int J Biochem Cell Biol. 42:1273–1281. 2010. View Article : Google Scholar
15	Yao Y, Suo AL, Li ZF, Liu LY, Tian T, Ni L, Zhang WG, Nan KJ, Song TS and Huang C: MicroRNA profiling of human gastric cancer. Mol Med Rep. 2:963–970. 2009.PubMed/NCBI
16	Rani S, Gately K, Crown J, O'Byrne K and O'Driscoll L: Global analysis of serum microRNAs as potential biomarkers for lung adenocarcinoma. Cancer Biol Ther. 14:1104–1112. 2013. View Article : Google Scholar : PubMed/NCBI
17	Ma S, Chan YP, Kwan PS, Lee TK, Yan M, Tang KH, Ling MT, Vielkind JR, Guan XY and Chan KW: MicroRNA-616 induces androgen-independent growth of prostate cancer cells by suppressing expression of tissue factor pathway inhibitor TFPI-2. Cancer Res. 71:583–592. 2011. View Article : Google Scholar : PubMed/NCBI
18	Książkiewicz M, Markiewicz A and Zaczek AJ: Epithelial-mesenchymal transition: A hallmark in metastasis formation linking circulating tumor cells and cancer stem cells. Pathobiology. 79:195–208. 2012. View Article : Google Scholar
19	Reichl P, Haider C, Grubinger M and Mikulits W: TGF-β in epithelial to mesenchymal transition and metastasis of liver carcinoma. Curr Pharm Des. 18:4135–4147. 2012. View Article : Google Scholar
20	Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST and Patel T: MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 133:647–658. 2007. View Article : Google Scholar : PubMed/NCBI
21	Xia H, Ooi LL and Hui KM: MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer. Hepatology. 58:629–641. 2013. View Article : Google Scholar : PubMed/NCBI
22	Song MS, Salmena L and Pandolfi PP: The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol. 13:283–296. 2012.PubMed/NCBI
23	Roberts LR and Gores GJ: Hepatocellular carcinoma: Molecular pathways and new therapeutic targets. Semin Liver Dis. 25:212–225. 2005. View Article : Google Scholar : PubMed/NCBI
24	Aravalli RN, Steer CJ and Cressman EN: Molecular mechanisms of hepatocellular carcinoma. Hepatology. 48:2047–2063. 2008. View Article : Google Scholar : PubMed/NCBI
25	Jiang J, Gusev Y, Aderca I, Mettler TA, Nagorney DM, Brackett DJ, Roberts LR and Schmittgen TD: Association of microRNA expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival. Clin Cancer Res. 14:419–427. 2008. View Article : Google Scholar : PubMed/NCBI
26	Murakami Y, Yasuda T, Saigo K, Urashima T, Toyoda H, Okanoue T and Shimotohno K: Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene. 25:2537–2545. 2006. View Article : Google Scholar
27	Haldrup C, Kosaka N, Ochiya T, Borre M, Høyer S, Orntoft TF and Sorensen KD: Profiling of circulating microRNAs for prostate cancer biomarker discovery. Drug Deliv Transl Res. 4:19–30. 2014. View Article : Google Scholar
28	Thiery JP and Sleeman JP: Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 7:131–142. 2006. View Article : Google Scholar : PubMed/NCBI
29	Choi SS and Diehl AM: Epithelial-to-mesenchymal transitions in the liver. Hepatology. 50:2007–2013. 2009. View Article : Google Scholar : PubMed/NCBI
30	Bullock MD, Sayan AE, Packham GK and Mirnezami AH: MicroRNAs: Critical regulators of epithelial to mesenchymal (EMT) and mesenchymal to epithelial transition (MET) in cancer progression. Biol Cell. 104:3–12. 2012. View Article : Google Scholar
31	Lee JM, Dedhar S, Kalluri R and Thompson EW: The epithelial-mesenchymal transition: New insights in signaling, development, and disease. J Cell Biol. 172:973–981. 2006. View Article : Google Scholar : PubMed/NCBI
32	Wan XW, Jiang M, Cao HF, He YQ, Liu SQ, Qiu XH, Wu MC and Wang HY: The alteration of PTEN tumor suppressor expression and its association with the histopathological features of human primary hepatocellular carcinoma. J Cancer Res Clin Oncol. 129:100–106. 2003.PubMed/NCBI
33	Bao L, Yan Y, Xu C, Ji W, Shen S, Xu G, Zeng Y, Sun B, Qian H, Chen L, et al: MicroRNA-21 suppresses PTEN and hSulf-1 expression and promotes hepatocellular carcinoma progression through AKT/ERK pathways. Cancer Lett. 337:226–236. 2013. View Article : Google Scholar : PubMed/NCBI
34	Garofalo M, Di Leva G, Romano G, Nuovo G, Suh SS, Ngankeu A, Taccioli C, Pichiorri F, Alder H, Secchiero P, et al: miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell. 16:498–509. 2009. View Article : Google Scholar : PubMed/NCBI
35	Kong G, Zhang J, Zhang S, Shan C, Ye L and Zhang X: Upregulated microRNA-29a by hepatitis B virus X protein enhances hepatoma cell migration by targeting PTEN in cell culture model. PLoS One. 6:e195182011. View Article : Google Scholar : PubMed/NCBI
36	Wu W, Yang J, Feng X, Wang H, Ye S, Yang P, Tan W, Wei G and Zhou Y: MicroRNA-32 (miR-32) regulates phosphatase and tensin homologue (PTEN) expression and promotes growth, migration, and invasion in colorectal carcinoma cells. Mol Cancer. 12:302013. View Article : Google Scholar : PubMed/NCBI
37	Hers I, Vincent EE and Tavaré JM: Akt signalling in health and disease. Cell Signal. 23:1515–1527. 2011. View Article : Google Scholar : PubMed/NCBI
38	Dasari VR, Kaur K, Velpula KK, Gujrati M, Fassett D, Klopfenstein JD, Dinh DH and Rao JS: Upregulation of PTEN in glioma cells by cord blood mesenchymal stem cells inhibits migration via downregulation of the PI3K/Akt pathway. PLoS One. 5:e103502010. View Article : Google Scholar : PubMed/NCBI