Infection by human papillomavirus (HPV) can cause cervical intraepithelial neoplasia (CIN) and cancer. Down-regulation of E6 and E7 expression may be responsible for the positive clinical outcomes observed with IFN treatment, but the molecular basis has not been well determined. As miRNAs play an important role in HPV induced cervical carcinogenesis, we hypothesize that IFN-β can regulate the expressions of specific miRNAs in cervical cancer cells, and that these miRNAs can mediate E6 and E7 expression, thus modulate their oncogenic potential. In this study, we found that miR-129-5p to be a candidate IFN-β inducible miRNA. MiR-129-5p levels gradually decrease with the development of cervical intraepithelial lesions. Manipulation of miR-129-5p expression in Hela cells modulates HPV-18 E6 and E7 viral gene expression. Exogenous miR-129-5p inhibits cell proliferation in Hela cells, promotes apoptosis and blocks cell cycle progression in Hela cells. SP1 is a direct target of miR-129-5p in Hela cells. This study is the first report of a cellular miRNA with anti-HPV activity and provides new insights into regulatory mechanisms between the HPV and the IFN system in host cells at the miRNA level.
References
[1]
Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM, et al. (1995) Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst 87: 796–802.
[2]
Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM (1990) The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63: 1129–1136.
[3]
Scheffner M, Huibregtse JM, Vierstra RD, Howley PM (1993) The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75: 495–505.
[4]
Werness BA, Levine AJ, Howley PM (1990) Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248: 76–79.
[5]
Dyson N, Howley PM, Munger K, Harlow E (1989) The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243: 934–937.
[6]
Cowland JB, Hother C, Gronbaek K (2007) MicroRNAs and cancer. APMIS 115: 1090–1106.
[7]
Li Y, Liu J, Yuan C, Cui B, Zou X, et al. (2010) High-risk human papillomavirus reduces the expression of microRNA-218 in women with cervical intraepithelial neoplasia. J Int Med Res 38: 1730–1736.
[8]
Martinez I, Gardiner AS, Board KF, Monzon FA, Edwards RP, et al. (2008) Human papillomavirus type 16 reduces the expression of microRNA-218 in cervical carcinoma cells. Oncogene 27: 2575–2582.
[9]
Wang X, Meyers C, Guo M, Zheng ZM (2011) Upregulation of p18Ink4c expression by oncogenic HPV E6 via p53-miR-34a pathway. Int J Cancer 129: 1362–1372.
[10]
Yao Q, Xu H, Zhang QQ, Zhou H, Qu LH (2009) MicroRNA-21 promotes cell proliferation and down-regulates the expression of programmed cell death 4 (PDCD4) in HeLa cervical carcinoma cells. Biochem Biophys Res Commun 388: 539–542.
[11]
Tanaka T, Sugaya S, Kita K, Arai M, Kanda T, et al. (2012) Inhibition of cell viability by human IFN-beta is mediated by microRNA-431. Int J Oncol 40: 1470–1476.
[12]
Pedersen IM, Cheng G, Wieland S, Volinia S, Croce CM, et al. (2007) Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature 449: 919–922.
[13]
Ren C, Cheng X, Lu B, Yang G (2013) Activation of interleukin-6/signal transducer and activator of transcription 3 by human papillomavirus early proteins 6 induces fibroblast senescence to promote cervical tumourigenesis through autocrine and paracrine pathways in tumour microenvironment. Eur J Cancer: in press.
[14]
Qin R, Chen Z, Ding Y, Hao J, Hu J, et al. (2013) Long non-coding RNA MEG3 inhibits the proliferation of cervical carcinoma cells through the induction of cell cycle arrest and apoptosis. Neoplasma 60: 486–92.
[15]
Shen R, Pan S, Qi S, Lin X, Cheng S (2010) Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 in gastric cancer. Biochem Biophys Res Commun 394: 1047–1052.
[16]
Huang YW, Liu JC, Deatherage DE, Luo J, Mutch DG, et al. (2009) Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 oncogene in endometrial cancer. Cancer Res 69: 9038–9046.
[17]
Dyrskjot L, Ostenfeld MS, Bramsen JB, Silahtaroglu AN, Lamy P, et al. (2009) Genomic profiling of microRNAs in bladder cancer: miR-129 is associated with poor outcome and promotes cell death in vitro. Cancer Res 69: 4851–4860.
[18]
Liu Y, Hei Y, Shu Q, Dong J, Gao Y, et al. (2012) VCP/p97, Down-Regulated by microRNA-129-5p, Could Regulate the Progression of Hepatocellular Carcinoma. PLoS One 7: e35800.
[19]
Wu J, Qian J, Li C, Kwok L, Cheng F, et al. (2010) miR-129 regulates cell proliferation by downregulating Cdk6 expression. Cell Cycle 9: 1809–1818.
[20]
Hoppe-Seyler F, Butz K (1992) Activation of human papillomavirus type 18 E6-E7 oncogene expression by transcription factor Sp1. Nucleic Acids Res 20: 6701–6706.
[21]
Demeret C, Desaintes C, Yaniv M, Thierry F (1997) Different mechanisms contribute to the E2-mediated transcriptional repression of human papillomavirus type 18 viral oncogenes. J Virol 71: 9343–9349.
[22]
Demeret C, Le Moal M, Yaniv M, Thierry F (1995) Control of HPV 18 DNA replication by cellular and viral transcription factors. Nucleic Acids Res 23: 4777–4784.
[23]
Dreher A, Rossing M, Kaczkowski B, Andersen DK, Larsen TJ, et al. (2011) Differential expression of cellular microRNAs in HPV 11, -16, and -45 transfected cells. Biochem Biophys Res Commun 412: 20–25.
