HCV core protein-induced upregulation of microRNA-196a promotes aberrant proliferation in hepatocellular carcinoma by targeting FOXO1

Xu,Hao; Li,Guangming; Yue,Zhanyi; Li,Chengzhong

doi:10.3892/mmr.2016.5159

HCV core protein-induced upregulation of microRNA-196a promotes aberrant proliferation in hepatocellular carcinoma by targeting FOXO1

Authors:
- Hao Xu
- Guangming Li
- Zhanyi Yue
- Chengzhong Li
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Affiliations: Department of Infectious Diseases, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China, Department of Hepatology, The 6th People's Hospital of Zhengzhou, Zhengzhou, Henan 450000, P.R. China, Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China
Published online on: April 22, 2016 https://doi.org/10.3892/mmr.2016.5159
Pages: 5223-5229

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Abstract

The hepatitis C virus (HCV) core protein is critical in the development of hepatocellular carcinoma (HCC). Investigations on HCC have previously focused on microRNAs, a class of small non‑coding RNAs, which are crucial in cancer development and progression. The present study aimed to investigate whether microRNA (miR)‑196a is aberrantly regulated by the HCV core protein, and whether miR‑196a is involved in the regulation of the aberrant proliferation of HCV‑HCC cells. In the study, miRNA expression was detected by quantitative polymerase chain reaction analysis. An Ad‑HCV core adenovirus was constructed and cell proliferation was measured using a Cell Counting Kit-8 assay and a cell cycle assay following infection. The results of the present study demonstrated that the HCV core protein increased the expression of miR‑196a, and that overexpression of miR‑196a in the HepG2 and Huh‑7 HCC cell lines promoted cell proliferation by inducing the G1‑S transition. Furthermore, the present study demonstrated that forkhead box O1 (FOXO1) was directly regulated by miR‑196a, and was essential in mediating the biological effects of miR‑196a in HCC. The overexpression of FOXO1 markedly reversed the effect of miR‑196a in HCC cell proliferation. Taken together, the data obtained in the present study provided compelling evidence that elevated expression levels of miR‑196a by the HCV core protein can function as an onco‑microRNA during HCV‑induced cell proliferation by downregulating the expression of FOXO1, indicating a potential novel therapeutic target for HCV-related HCC.

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1	Berasain C, Perugorria MJ, Latasa MU, Castillo J, Goñi S, Santamaría M, Prieto J and Avila MA: The epidermal growth factor receptor: A link between inflammation and liver cancer. Exp Biol Med (Maywood). 234:713–725. 2009. View Article : Google Scholar
2	Sherman M: Hepatocellular carcinoma: Epidemiology, risk factors and screening. Semin Liver Dis. 25:143–154. 2005. View Article : Google Scholar
3	El-Serag HB and Rudolph KL: Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology. 132:2557–2576. 2007. View Article : Google Scholar : PubMed/NCBI
4	Kremsdorf D, Soussan P, Paterlini-Brechot P and Brechot C: Hepatitis B virus-related hepatocellular carcinoma: Paradigms for viral-related human carcinogenesis. Oncogene. 25:3823–3833. 2006. View Article : Google Scholar : PubMed/NCBI
5	Lupberger J and Hildt E: Hepatitis B virus-induced oncogenesis. World J Gastroenterol. 13:74–81. 2007. View Article : Google Scholar : PubMed/NCBI
6	Brody H: Hepatitis C. Nature. 474:S12011. View Article : Google Scholar : PubMed/NCBI
7	Gravitz L: Introduction: A smouldering public-health crisis. Nature. 474:S2–S4. 2011. View Article : Google Scholar : PubMed/NCBI
8	Thomas DL: Global control of hepatitis C: Where challenge meets opportunity. Nat Med. 19:850–858. 2013. View Article : Google Scholar : PubMed/NCBI
9	Moradpour D and Penin F: Hepatitis C virus proteins: from structure to function. Curr Top Microbiol Immunol. 369:113–142. 2013.PubMed/NCBI
10	Zhang Y, Li RQ, Feng XD, Zhang YH and Wang L: Down-regulation of PTEN by HCV core protein through activating nuclear factor-κB. Int J Clin Exp Pathol. 7:7351–7359. 2014.
11	Watashi K and Shimotohno K: The roles of hepatitis C virus proteins in modulation of cellular functions: A novel action mechanism of the HCV core protein on gene regulation by nuclear hormone receptors. Cancer Sci. 94:937–943. 2003. View Article : Google Scholar : PubMed/NCBI
12	Siavoshian S, Abraham JD, Kieny MP and Schuster C: HCV core, NS3, NS5A and NS5B proteins modulate cell proliferation independently from p53 expression in hepatocarcinoma cell lines. Arch Virol. 149:323–336. 2004. View Article : Google Scholar : PubMed/NCBI
13	Farh KK, Grimson A, Jan C, Lewis BP, Johnston WK, Lim LP, Burge CB and Bartel DP: The widespread impact of mammalian MicroRNAs on mRNA repression and evolution. Science. 310:1817–1821. 2005. View Article : Google Scholar : PubMed/NCBI
14	Ell B and Kang Y: MicroRNAs as regulators of bone homeostasis and bone metastasis. Bonekey Rep. 3:5492014. View Article : Google Scholar : PubMed/NCBI
15	Huang S, Xie Y, Yang P, Chen P and Zhang L: HCV core protein-induced down-regulation of microRNA-152 promoted aberrant proliferation by regulating Wnt1 in HepG2 cells. PLoS One. 9:e817302014. View Article : Google Scholar : PubMed/NCBI
16	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2^−ΔΔCt method. Methods. 25:402–408. 2001. View Article : Google Scholar
17	Hou T, Ou J, Zhao X, Huang X, Huang Y and Zhang Y: MicroRNA-196a promotes cervical cancer proliferation through the regulation of FOXO1 and p27Kip1. Br J Cancer. 110:1260–1268. 2014. View Article : Google Scholar : PubMed/NCBI
18	Eckman MH, Talal AH, Gordon SC, Schiff E and Sherman KE: Cost-effectiveness of screening for chronic hepatitis C infection in the United States. Clin Infect Dis. 56:1382–1393. 2013. View Article : Google Scholar : PubMed/NCBI
19	Akamatsu S, Hayes CN, Tsuge M, Miki D, Akiyama R, Abe H, Ochi H, Hiraga N, Imamura M, Takahashi S, et al: Differences in serum microRNA profiles in hepatitis B and C virus infection. J Infect. 70:273–287. 2015. View Article : Google Scholar
20	Liu CJ, Tsai MM, Tu HF, Lui MT, Cheng HW and Lin SC: miR-196a overexpression and miR-196a2 gene polymorphism are prognostic predictors of oral carcinomas. Ann Surg Oncol. 20(Suppl 3): S406–S414. 2013. View Article : Google Scholar
21	Liu P, Xin F and Ma CF: Clinical significance of serum miR-196a in cervical intraepithelial neoplasia and cervical cancer. Genetics and molecular research: GMR. 14:17995–18002. 2015. View Article : Google Scholar
22	Li JH, Luo N, Zhong MZ, Xiao ZQ, Wang JX, Yao XY, Peng Y and Cao J: Inhibition of microRNA-196a might reverse cisplatin resistance of A549/DDP non-small-cell lung cancer cell line. Tumour Biol. Sept 16–2015.Epub ahead of print.
23	Li SC, Shi H, Khan M, Caplin M, Meyer T, Öberg K and Giandomenico V: Roles of miR-196a on gene regulation of neuroendocrine tumor cells. Mol Cell Endocrinol. 412:131–139. 2015. View Article : Google Scholar : PubMed/NCBI
24	Ge J, Chen Z, Li R, Lu T and Xiao G: Upregulation of microRNA-196a and microRNA-196b cooperatively correlate with aggressive progression and unfavorable prognosis in patients with colorectal cancer. Cancer Cell Int. 14:1282014. View Article : Google Scholar : PubMed/NCBI
25	Liu XH, Lu KH, Wang KM, Sun M, Zhang EB, Yang JS, Yin DD, Liu ZL, Zhou J, Liu ZJ, et al: MicroRNA-196a promotes non-small cell lung cancer cell proliferation and invasion through targeting HOXA5. BMC Cancer. 12:3482012. View Article : Google Scholar : PubMed/NCBI
26	Tsai MM, Wang CS, Tsai CY, Chen CY, Chi HC, Tseng YH, Chung PJ, Lin YH, Chung IH, Chen CY and Lin KH: MicroRNA-196a/-196b promote cell metastasis via negative regulation of radixin in human gastric cancer. Cancer Lett. 351:222–231. 2014. View Article : Google Scholar : PubMed/NCBI
27	Zhang C, Yao C, Li H, Wang G and He X: Combined elevation of microRNA-196a and microRNA-196b in sera predicts unfavorable prognosis in patients with osteosarcomas. Int J Mol Sci. 15:6544–6555. 2014. View Article : Google Scholar : PubMed/NCBI
28	Liu B, Xiang Y and Zhang HS: Circulating microRNA-196a as a candidate diagnostic biomarker for chronic hepatitis C. Mol Med Rep. 12:105–110. 2015.PubMed/NCBI
29	Mukherjee A, Di Bisceglie AM and Ray RB: Hepatitis C virus-mediated enhancement of microRNA miR-373 impairs the JAK/STAT signaling pathway. J Virol. 89:3356–3365. 2015. View Article : Google Scholar : PubMed/NCBI
30	Shang Y, Wang LQ, Guo QY and Shi TL: MicroRNA-196a overexpression promotes cell proliferation and inhibits cell apoptosis through PTEN/Akt/FOXO1 pathway. Int J Clin Exp Pathol. 8:2461–2472. 2015.PubMed/NCBI
31	Greer EL and Brunet A: FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene. 24:7410–7425. 2005. View Article : Google Scholar : PubMed/NCBI
32	Calnan DR and Brunet A: The FoxO code. Oncogene. 27:2276–2288. 2008. View Article : Google Scholar : PubMed/NCBI
33	Myatt SS and Lam EW: The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer. 7:847–859. 2007. View Article : Google Scholar : PubMed/NCBI
34	Paik JH, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z, Miao L, Tothova Z, Horner JW, Carrasco DR, et al: FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell. 128:309–323. 2007. View Article : Google Scholar : PubMed/NCBI
35	Yang XW, Shen GZ, Cao LQ, Jiang XF, Peng HP, Shen G, Chen D and Xue P: MicroRNA-1269 promotes proliferation in human hepatocellular carcinoma via downregulation of FOXO1. BMC Cancer. 14:9092014. View Article : Google Scholar : PubMed/NCBI
36	Lee SY, Lee GR, Woo DH, Park NH, Cha HJ, Moon YH and Han IS: Depletion of Aurora A leads to upregulation of FoxO1 to induce cell cycle arrest in hepatocellular carcinoma cells. Cell Cycle. 12:67–75. 2013. View Article : Google Scholar :