miR‑498 inhibits the growth and metastasis of liver cancer by targeting ZEB2

Zhang,Xu; Xu,Xueying; Ge,Guohong; Zang,Xueyan; Shao,Meng; Zou,Shengqiang; Zhang,Yu; Mao,Zheying; Zhang,Jiayin; Mao,Fei; Qian,Hui; Xu,Wenrong

doi:10.3892/or.2018.6948

miR‑498 inhibits the growth and metastasis of liver cancer by targeting ZEB2

Authors:
- Xu Zhang
- Xueying Xu
- Guohong Ge
- Xueyan Zang
- Meng Shao
- Shengqiang Zou
- Yu Zhang
- Zheying Mao
- Jiayin Zhang
- Fei Mao
- Hui Qian
- Wenrong Xu
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Affiliations: Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China, Liver Disease and Cancer Institute, The Affiliated Zhenjiang Third Hospital of Jiangsu University, Zhenjiang, Jiangsu 212021, P.R. China
Published online on: December 21, 2018 https://doi.org/10.3892/or.2018.6948
Pages: 1638-1648
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

MicroRNAs (miRNAs) play critical roles in the growth, metastasis and therapeutic resistance of liver cancer. Accumulating evidence suggests that miR‑498 is aberrantly expressed in several human malignancies. However, the role and underlying mechanism of miR‑498 in liver cancer remain unclear. In the present study, we investigated the potential roles and clinical value of miR‑498 in liver cancer. We found that the miR‑498 expression level was significantly lower in liver cancer patient tissues than that in healthy control tissues. The expression of miR‑498 was also decreased in liver cancer cell lines compared to that noted in a normal human normal liver cell line. miR‑498 overexpression markedly inhibited liver cancer cell proliferation, migration and invasion. miR‑498 overexpression induced cell cycle arrest and apoptosis while it suppressed epithelial‑mesenchymal transition (EMT) in liver cancer cells. Bioinformatic analysis and luciferase reporter assay further identified zinc finger E‑box binding homeobox 2 (ZEB2) as a novel target of miR‑498. Furthermore, ZEB2 knockdown recapitulated the inhibitory effects of miR‑498 overexpression in liver cancer cells. ZEB2 overexpression rescued the inhibition of liver cancer cell proliferation, migration, and invasion by miR‑498, indicating that ZEB2 acts as a downstream effector of miR‑498 in liver cancer cells. Thus, we demonstrated that miR‑498 suppresses the growth and metastasis of liver cancer cells, partly at least, by directly targeting ZEB2, suggesting that miR‑498 may serve as a potential biomarker for the diagnosis and therapy of liver cancer.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. CA Cancer J Clin. 68:7–30. 2018. View Article : Google Scholar : PubMed/NCBI
2	Singal AG and El-Serag HB: Hepatocellular carcinoma from epidemiology to prevention: Translating knowledge into practice. Clin Gastroenterol Hepatol. 13:2140–2151. 2015. View Article : Google Scholar : PubMed/NCBI
3	Mizuguchi Y, Takizawa T, Yoshida H and Uchida E: Dysregulated miRNA in progression of hepatocellular carcinoma: A systematic review. Hepatol Res. 46:391–406. 2016. View Article : Google Scholar : PubMed/NCBI
4	Morishita A and Masaki T: miRNA in hepatocellular carcinoma. Hepatol Res. 45:128–141. 2015. View Article : Google Scholar : PubMed/NCBI
5	Chang RM, Xiao S, Lei X, Yang H, Fang F and Yang LY: miRNA-487a promotes proliferation and metastasis in hepatocellular carcinoma. Clin Cancer Res. 23:2593–2604. 2017. View Article : Google Scholar : PubMed/NCBI
6	Dietrich P, Koch A, Fritz V, Hartmann A, Bosserhoff AK and Hellerbrand C: Wild type Kirsten rat sarcoma is a novel microRNA-622-regulated therapeutic target for hepatocellular carcinoma and contributes to sorafenib resistance. Gut. 67:1328–1341. 2018. View Article : Google Scholar : PubMed/NCBI
7	Kabir TD, Ganda C, Brown RM, Beveridge DJ, Richardson KL, Chaturvedi V, Candy P, Epis M, Wintle L, Kalinowski F, et al: A microRNA-7/growth arrest specific 6/TYRO3 axis regulates the growth and invasiveness of sorafenib-resistant cells in human hepatocellular carcinoma. Hepatology. 67:216–231. 2018. View Article : Google Scholar : PubMed/NCBI
8	Wang M, Zhang Q, Wang J and Zhai Y: MicroRNA-498 is downregulated in non-small cell lung cancer and correlates with tumor progression. J Cancer Res Ther. 11 Suppl 1:C107–C111. 2015. View Article : Google Scholar : PubMed/NCBI
9	Cong J, Liu R, Wang X, Wang J, Wang H and Hou J: Low miR-498 expression levels are associated with poor prognosis in ovarian cancer. Eur Rev Med Pharmacol Sci. 19:4762–4765. 2015.PubMed/NCBI
10	Islam F, Gopalan V, Law S, Tang JC, Chan KW and Lam AK: MiR-498 in esophageal squamous cell carcinoma: Clinicopathological impacts and functional interactions. Hum Pathol. 62:141–151. 2017. View Article : Google Scholar : PubMed/NCBI
11	Gopalan V, Smith RA and Lam AK: Downregulation of microRNA-498 in colorectal cancers and its cellular effects. Exp Cell Res. 330:423–428. 2015. View Article : Google Scholar : PubMed/NCBI
12	Kasiappan R, Shen Z, Tse AK, Jinwal U, Tang J, Lungchukiet P, Sun Y, Kruk P, Nicosia SV, Zhang X, et al: 1,25-Dihydroxyvitamin D3 suppresses telomerase expression and human cancer growth through microRNA-498. J Biol Chem. 287:41297–41309. 2012. View Article : Google Scholar : PubMed/NCBI
13	Liu R, Liu F, Li L, Sun M and Chen K: MiR-498 regulated FOXO3 expression and inhibited the proliferation of human ovarian cancer cells. Biomed Pharmacother. 72:52–57. 2015. View Article : Google Scholar : PubMed/NCBI
14	Kojima M, Sudo H, Kawauchi J, Takizawa S, Kondou S, Nobumasa H and Ochiai A: MicroRNA markers for the diagnosis of pancreatic and biliary-tract cancers. PLoS One. 10:e01182202015. View Article : Google Scholar : PubMed/NCBI
15	Tao ZH, Wan JL, Zeng LY, Xie L, Sun HC, Qin LX, Wang L, Zhou J, Ren ZG, Li YX, et al: miR-612 suppresses the invasive-metastatic cascade in hepatocellular carcinoma. J Exp Med. 210:789–803. 2013. View Article : Google Scholar : PubMed/NCBI
16	Fu M, Huang Z, Zang X, Pan L, Liang W, Chen J, Qian H, Xu W, Jiang P and Zhang X: Long noncoding RNA LINC00978 promotes cancer growth and acts as a diagnostic biomarker in gastric cancer. Cell Prolif. 5:2017.doi: 10.1111/cpr.12425.
17	Zhang Z, Zhang Y, Sun XX, Ma X and Chen ZN: microRNA-146a inhibits cancer metastasis by downregulating VEGF through dual pathways in hepatocellular carcinoma. Mol Cancer. 14:52015. View Article : Google Scholar : PubMed/NCBI
18	Wu G, Zheng K, Xia S, Wang Y, Meng X, Qin X and Cheng Y: MicroRNA-655-3p functions as a tumor suppressor by regulating ADAM10 and β-catenin pathway in hepatocellular carcinoma. J Exp Clin Cancer Res. 35:892016. View Article : Google Scholar : PubMed/NCBI
19	Yu S, Jing L, Yin XR, Wang MC, Chen YM, Guo Y, Nan KJ and Han LL: MiR-195 suppresses the metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by inhibiting YAP. Oncotarget. 8:99757–99771. 2017.PubMed/NCBI
20	Yang L, Wei N, Wang L, Wang X and Liu QH: miR-498 promotes cell proliferation and inhibits cell apoptosis in retinoblastoma by directly targeting CCPG1. Childs Nerv Syst. 34:417–422. 2018. View Article : Google Scholar : PubMed/NCBI
21	Matamala N, Vargas MT, González-Cámpora R, Arias JI, Menéndez P, Andrés-León E, Yanowsky K, Llaneza-Folgueras A, Miñambres R, Martínez-Delgado B, et al: MicroRNA deregulation in triple negative breast cancer reveals a role of miR-498 in regulating BRCA1 expression. Oncotarget. 7:20068–20079. 2016. View Article : Google Scholar : PubMed/NCBI
22	Chai C, Wu H, Wang B, Eisenstat DD and Leng RP: MicroRNA- 498 promotes proliferation and migration by targeting the tumor suppressor PTEN in breast cancer cells. Carcinogenesis. 39:1185–1196. 2018. View Article : Google Scholar : PubMed/NCBI
23	Dai YH, Tang YP, Zhu HY, Lv L, Chu Y, Zhou YQ and Huo JR: ZEB2 promotes the metastasis of gastric cancer and modulates epithelial mesenchymal transition of gastric cancer cells. Dig Dis Sci. 57:1253–1260. 2012. View Article : Google Scholar : PubMed/NCBI
24	Li MZ, Wang JJ, Yang SB, Li WF, Xiao LB, He YL and Song XM: ZEB2 promotes tumor metastasis and correlates with poor prognosis of human colorectal cancer. Am J Transl Res. 9:2838–2851. 2017.PubMed/NCBI
25	Chen Z, Zhang J, Zhang Z, Feng Z, Wei J, Lu J, Fang Y, Liang Y, Cen J, Pan Y, et al: The putative tumor suppressor microRNA-30a-5p modulates clear cell renal cell carcinoma aggressiveness through repression of ZEB2. Cell Death Dis. 8:e28592017. View Article : Google Scholar : PubMed/NCBI
26	Kan Q, Su Y and Yang H: MicroRNA-335 is downregulated in papillary thyroid cancer and suppresses cancer cell growth, migration and invasion by directly targeting ZEB2. Oncol Lett. 14:7622–7628. 2017.PubMed/NCBI
27	Pang X, Huang K, Zhang Q, Zhang Y and Niu J: miR-154 targeting ZEB2 in hepatocellular carcinoma functions as a potential tumor suppressor. Oncol Rep. 34:3272–3279. 2015. View Article : Google Scholar : PubMed/NCBI
28	Hu B, Sun M, Liu J, Hong G and Lin Q: MicroRNA-204 suppressed proliferation and motility capacity of human hepatocellular carcinoma via directly targeting zinc finger E-box binding homeobox 2. Oncol Lett. 13:3823–3830. 2017. View Article : Google Scholar : PubMed/NCBI
29	Qi S, Song Y, Peng Y, Wang H, Long H, Yu X, Li Z, Fang L, Wu A, Luo W, et al: ZEB2 mediates multiple pathways regulating cell proliferation, migration, invasion, and apoptosis in glioma. PLoS One. 7:e388422012. View Article : Google Scholar : PubMed/NCBI
30	Zhou DD, Wang X, Wang Y, Xiang XJ, Liang ZC, Zhou Y, Xu A, Bi CH and Zhang L: MicroRNA-145 inhibits hepatic stellate cell activation and proliferation by targeting ZEB2 through Wnt/β-catenin pathway. Mol Immunol. 75:151–160. 2016. View Article : Google Scholar : PubMed/NCBI
31	Vasuri F, Visani M, Acquaviva G, Brand T, Fiorentino M, Pession A, Tallini G, D'Errico A and de Biase D: Role of microRNAs in the main molecular pathways of hepatocellular carcinoma. World J Gastroenterol. 24:2647–2660. 2018. View Article : Google Scholar : PubMed/NCBI