HBx protein-induced upregulation of microRNA-221 promotes aberrant proliferation in HBV‑related hepatocellular carcinoma by targeting estrogen receptor-α

Chen,Juan-Juan; Tang,Yi-Shu; Huang,Shi-Feng; Ai,Jian-Gang; Wang,Hai-Xia; Zhang,Li-Ping

doi:10.3892/or.2014.3647

HBx protein-induced upregulation of microRNA-221 promotes aberrant proliferation in HBV‑related hepatocellular carcinoma by targeting estrogen receptor-α

Authors:
- Juan-Juan Chen
- Yi-Shu Tang
- Shi-Feng Huang
- Jian-Gang Ai
- Hai-Xia Wang
- Li-Ping Zhang
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Affiliations: Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China
Published online on: December 4, 2014 https://doi.org/10.3892/or.2014.3647
Pages: 792-798

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Abstract

Hepatitis B virus X protein (HBx) plays an important role in the development of hepatocellular carcinoma (HCC). Emerging evidence has shown the association between aberrantly expressed miR-221 and cancer development; however, little is known concerning its potential role in hepatitis B virus (HBV)-related HCC. In the present study, functional studies demonstrated that HBx leads to the promotion of cell proliferation and cell growth viability. Obviously overexpressed miR-221 was found in HBx-transfected cells compared with the mock counterparts. Suppression of miR-221 significantly inhibited HCC cell proliferation. Western blot analysis indicated that estrogen receptor-α (ERα) was downregulated in HCC tissues and cell lines. Bioinformatic analysis combined with validation experiments identified ERα as a direct target of miR-221. The present study suggests that miR-221 modulates HCC cancer cell proliferation by suppressing ERα, functioning as a tumor promoter. Moreover, our data imply that miR-221 has potential as an miRNA-based therapeutic target for HBV-related HCC.

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1	Sangiovanni A, Del Ninno E, Fasani P, et al: Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance. Gastroenterology. 126:1005–1014. 2004. View Article : Google Scholar : PubMed/NCBI
2	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar : PubMed/NCBI
3	Han Z: Recent progress in genomic [corrected] research of liver cancer. Sci China C Life Sci. 52:24–30. 2009. View Article : Google Scholar : PubMed/NCBI
4	Lavanchy D: Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat. 11:97–107. 2004. View Article : Google Scholar : PubMed/NCBI
5	Neuveut C, Wei Y and Buendia MA: Mechanisms of HBV-related hepatocarcinogenesis. J Hepatol. 52:594–604. 2010. View Article : Google Scholar : PubMed/NCBI
6	Ng SA and Lee C: Hepatitis B virus X gene and hepatocarcinogenesis. J Gastroenterol. 46:974–990. 2011. View Article : Google Scholar : PubMed/NCBI
7	Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
8	Brenneck J, Hipfner DR, Stark A, et al: bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell. 113:25–36. 2003. View Article : Google Scholar
9	Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI
10	Shi XB, Tepper CG and deVere White RW: Cancerous miRNAs and their regulation. Cell Cycle. 7:1529–1538. 2008. View Article : Google Scholar : PubMed/NCBI
11	Santhekadur PK, Das SK, Gredler R, et al: Multifunction protein staphylococcal nuclease domain containing 1 (SND1) promotes tumor angiogenesis in human hepatocellular carcinoma through novel pathway that involves nuclear factor κB and miR-221. J Biol Chem. 287:13952–13958. 2012. View Article : Google Scholar : PubMed/NCBI
12	Park JK, Koqure T, Nuovo GJ, et al: miR-221 silencing blocks hepatocellular carcinoma and promotes survival. Cancer Res. 71:7608–7616. 2011. View Article : Google Scholar : PubMed/NCBI
13	Ogawa T, Enomoto M, Fujii H, et al: MicroRNA-221/222 upregulation indicates the activation of stellate cells and the progression of liver fibrosis. Gut. 61:1600–1609. 2012. View Article : Google Scholar : PubMed/NCBI
14	Naugler WE, Sakurai T, Kim S, et al: Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 317:121–124. 2007. View Article : Google Scholar : PubMed/NCBI
15	Zhao JJ, Lin J, Yang H, et al: MicroRNA-221/222 negatively regulates estrogen receptor α and is associated with tamoxifen resistance in breast cancer. J Biol Chem. 283:31079–31086. 2008. View Article : Google Scholar : PubMed/NCBI
16	Acs G, Sells MA, Purcell RH, et al: Hepatitis B virus produced by transfected HepG2 cells causes hepatitis in chimpanzees. Proc Natl Acad Sci USA. 84:4641–4644. 1987. View Article : Google Scholar
17	Sells MA, Chen ML and Acs G: Production of hepatitis B virus particles in HepG2 cells transfected with cloned hepatitis B virus DNA. Proc Natl Acad Sci USA. 84:1005–1009. 1987. View Article : Google Scholar
18	Mott JL, Kobayashi S, Bronk SF and Gores GJ: miR-29 regulates Mcl-1 protein expression and apoptosis. Oncogene. 26:6133–6140. 2007. View Article : Google Scholar : PubMed/NCBI
19	Roderburq C, Urban GW, Bettermann K, et al: Micro-RNA profiling reveals a role of miR-29 in human and murine liver fibrosis. Hepatology. 53:209–218. 2011. View Article : Google Scholar
20	Pineau P, Volinia S, McJunkin K, et al: miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci USA. 107:264–269. 2010. View Article : Google Scholar :
21	Gramantieri L, Ferracin M, Formari F, et al: Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma. Cancer Res. 67:6092–6099. 2007. View Article : Google Scholar : PubMed/NCBI
22	le Sage C, Nagel R, Egan DA, et al: Regulation of the p27^Kip1 tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. EMBO J. 26:3699–3708. 2007. View Article : Google Scholar : PubMed/NCBI
23	Medina R, Zaidi SK, Liu CG, et al: MicroRNAs 221 and 222 bypass quiescence and compromise cell suvival. Cancer Res. 68:2773–2780. 2008. View Article : Google Scholar : PubMed/NCBI
24	Rehman SK, Li SH, Wyszomierski SL, et al: 14-3-3ζ orchestrates mammary tumor onset and progression via miR-221-mediated cell proliferation. Cancer Res. 74:363–373. 2014. View Article : Google Scholar :
25	Su A, He S, Tian B, et al: MicroRNA-221 mediates the effects of PDGF-BB on migration, proliferation, and the epithelial-mesenchymal transition in pancreatic cancer cells. PLoS One. 8:e713092013. View Article : Google Scholar : PubMed/NCBI
26	Rommer A, Steinleitner K, Hackl H, et al: Overexpression of primary microRNA 221/222 in acute myeloid leukemia. BMC Cancer. 13:3642013. View Article : Google Scholar : PubMed/NCBI
27	Yu MW, Chang HC, Chang SC, et al: Role of reproductive factors in hepatocellular carcinoma: impact on hepatitis B- and C-related risk. Hepatology. 38:1393–1400. 2003.PubMed/NCBI
28	Vesselinovitch SD, Itze L, Mihailovich N and Rao KV: Modifying role of partial hepatectomy and gonadectomy in ethylnitrosourea-induced hepatocarcinogenesis. Cancer Res. 40:1538–1542. 1980.PubMed/NCBI
29	Nakatani T, Roy G, Fujimoto N, et al: Sex hormone dependency of diethylnitrosamine-induced liver tumors in mice and chemoprevention by leuprorelin. Jpn J Cancer Res. 92:249–256. 2001. View Article : Google Scholar : PubMed/NCBI
30	Ng IO, Ng M and Fan ST: Better survival in woman with respected hepatocellular carcinoma is not related to tumor proliferation or expression of hormone receptors. Am J Gastroenterol. 92:1355–1358. 1997.PubMed/NCBI
31	Jonas S, Bechstein WO, Heinze T, et al: Female sex hormone receptor status in advanced hepatocellular carcinoma and outcome after surgical resection. Surgery. 121:456–461. 1997. View Article : Google Scholar : PubMed/NCBI
32	Nagasue N, Kohno H, Chang YC, et al: Clinicopathologic comparisons between estrogen receptor-positive and -negative hepatocellular carcinomas. Ann Surg. 212:150–154. 2009. View Article : Google Scholar
33	Liu WH, Yeh SH, Lu CC, et al: MicroRNA-18a prevents estrogen receptor-α expression, promoting proliferation of hepatocellular carcinoma cells. Gastroenterology. 136:683–693. 2009. View Article : Google Scholar
34	Shen L, Ahuja N, Shen Y, et al: DNA methylation and environmental exposures in human hepatocellular carcinoma. J Natl Cancer Inst. 94:755–761. 2002. View Article : Google Scholar : PubMed/NCBI
35	Pike MC and Spicer DV: Hormonal contraception and chemoprevention of female cancers. Endocr Relat Cancer. 7:73–83. 2000. View Article : Google Scholar : PubMed/NCBI
36	Dutertre M and Smith CL: Molecular mechanisms of selective estrogen receptor modulator (SERM) action. J Pharmacol Exp Ther. 295:431–437. 2000.PubMed/NCBI