Two less common human microRNAs miR-875 and miR-3144 target a conserved site of E6 oncogene in most high-risk human papillomavirus subtypes

Abstract

Human papillomaviruses (HPVs) including high-risk (HR) and low-risk (LR) subtypes have distinguishable variation on both genotypes and phenotypes. The coinfection of multiple HR-HPVs, headed by HPV16, is common in cervical cancer in female. Recently accumulating reports have focused on the interaction between virus and host, particularly the role of human microRNAs (miRNAs) in anti-viral defense by targeting viral genome. Here, we found a well-conserved target site of miRNAs in the genomes of most HR-HPVs, not LR-HPVs, by scanning all potential target sites of human miRNAs on 24 HPVs of unambiguous subtypes of risk. The site is targeted by two less common human miRNAs, miR-875 and miR-3144, and is located in E6 oncogene open reading frame (ORF) and overlap with the first alternative splice exon of viral early transcripts. In validation tests, miR-875 and miR-3144 were identified to suppress the target reporter activity markedly and inhibit the expression of both synthetically exogenous E6 and endogenous E6 oncogene. High level of two miRNAs can inhibit cell growth and promote apoptosis in HPV16-positive cervical cancer cells. This study provides a promising common target of miRNAs for most HR-HPVs and highlights the effects of two low expressed human miRNAs on tumour suppression.

Keywords

human papillomavirus / microRNA / E6 / miR-875 / miR-3144

References

[1] Alp Avci G (2012) Genomic organization and proteins of human papillomavirus. Mikrobiyol bul 46: 507-515

[2] Ambros V (2004) The functions of animal microRNAs. Nature 431: 350-355

[3] Bentwich I (2005) Prediction and validation of microRNAs and their targets. FEBS Lett 579: 5904-5910

[4] Bernard HU, Burk RD, Chen Z, van Doorslaer K, zur Hausen H, de Villiers EM(2010) Classification of papillomaviruses (PVs) basedon 189 PV types and proposal of taxonomic amendments. Virology 401: 70-79

[5] Chan LW, Wang FF, Cho WC (2012) Genomic sequence analysis of EGFR regulation by microRNAs in lung cancer. Curr Top Med Chem 12: 920-926

[6] de Freitas AC, Coimbra EC, Leitao Mda C (2014) Molecular targets of HPV oncoproteins: potential biomarkers for cervical carcinogenesis. Biochim Biophys Acta 1845: 91-103

[7] del Moral-Hernandez O, Lopez-Urrutia E, Bonilla-Moreno R, Martinez-Salazar M, Arechaga-Ocampo E, Berumen J, Villegas-Sepulveda N (2010) The HPV-16 E7 oncoprotein is expressed mainly from the unspliced E6/E7 transcript in cervical carcinoma C33-A cells. Arch Virol 155: 1959-1970

[8] Dreher A, Rossing M, Kaczkowski B, Andersen DK, Larsen TJ, Christophersen MK, Nielsen FC, Norrild B (2011) Differential expression of cellular microRNAs in HPV 11, -16, and-45 transfected cells. Biochem Biophys Res Commun 412: 20-25

[9] Filippova M, Johnson MM, Bautista M, Filippov V, Fodor N, Tungteakkhun SS, Williams K, Duerksen-Hughes PJ (2007) The large and small isoforms of human papillomavirus type 16 E6 bind to and differentially affect procaspase 8 stability and activity. J Virol 81: 4116-4129

[10] Forman JJ, Coller HA (2010) The code within the code: microRNAs target coding regions. Cell Cycle 9: 1533-1541

[11] Ghosh Z, Mallick B, Chakrabarti J (2009) Cellular versus viral microRNAs in host-virus interaction. Nucleic Acids Res 37: 1035-1048

[12] Greco D, Kivi N, Qian K, Leivonen SK, Auvinen P, Auvinen E (2011) Human papillomavirus 16 E5 modulates the expression of host microRNAs. PLoS One 6: e21646

[13] Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ (2008) miRBase: tools for microRNA genomics. Nucleic Acids Res 36: D154-D158

[14] Gunasekharan V, Laimins LA (2013) Human papillomaviruses modulate microRNA 145 expression to directly control genome amplification. J Virol 87: 6037-6043

[15] Hamfjord J, Stangeland AM, Hughes T, Skrede ML, Tveit KM, Ikdahl T, Kure EH (2012) Differential expression of miRNAs in colorectal cancer: comparison of paired tumor tissue and adjacent normal mucosa using high-throughput sequencing. PLoS One 7: e34150

[16] Hao J, Zhang S, Zhou Y, Hu X, Shao C (2011) MicroRNA 483-3p suppresses the expression of DPC4/Smad4 in pancreatic cancer. FEBS Lett 585: 207-213

[17] Harper DM, Demars LR (2014) Primary strategies for HPV infection and cervical cancer prevention. Clin Obstet Gynecol 57: 256-278

[18] Hayes J, Peruzzi PP, Lawler S (2014) MicroRNAs in cancer: biomarkers, functions and therapy. Trends Mol Med 20: 460-469

[19] Hernandez-Lopez HR, Graham SV (2012) Alternative splicing in human tumour viruses: a therapeutic target? Biochem J 445: 145-156

[20] Houzet L, Klase Z, Yeung ML, Wu A, Le SY, Quinones M, Jeang KT (2012) The extent of sequence complementarity correlates with the potency of cellular miRNA-mediated restriction of HIV-1. Nucleic Acids Res 40: 11684-11696

[21] Jimenez-Wences H, Peralta-Zaragoza O, Fernandez-Tilapa G (2014) Human papilloma virus, DNA methylation and microRNA expression in cervical cancer (Review). Oncol Rep 31: 2467-2476

[22] John B, Enright AJ, Aravin A, Tuschl T, Sander C, Marks DS (2004) Human microRNA targets. PLoS Biol 2: e363

[23] Juan Moran GR, Uribe-Boll Jimena, Cruz Alfredo, Jimenez Luis, Banales Jose-Luis, Romero Sandra, Hidalgo Alfredo, Bautista Edgar, Merino Enrique, Zuniga Joaquin (2014) Circulating microRNA profiles in patients with severe pneumonia associated to the A/H1N1 virus. Am J Respir Crit Care Med 189: A2694

[24] Jung HM, Phillips BL, Chan EK (2014) miR-375 activates p21 and suppresses telomerase activity by coordinately regulating HPV E6/E7, E6AP, CIP2A, and 14-3-3zeta. Mol Cancer 13: 80

[25] Kuhn DE, Martin MM, Feldman DS, Terry AV Jr, Nuovo GJ, Elton TS (2008) Experimental validation of miRNA targets. Methods 44: 47-54

[26] Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, Aravin A, Pfeffer S, Rice A, Kamphorst AO, Landthaler M (2007) A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129: 1401-1414

[27] Lecellier CH, Dunoyer P, Arar K, Lehmann-Che J, Eyquem S, Himber C, Saib A, Voinnet O (2005) A cellular microRNA mediates antiviral defense in human cells. Science 308: 557-560

[28] Li Y, Li Z, He Y, Kang Y, Zhang X, Cheng M, Zhong Y, Xu C (2009) Phylogeographic analysis of human papillomavirus 58. Sci China Ser C 52: 1164-1172

[29] Li YP, Gottwein JM, Scheel TK, Jensen TB, Bukh J (2011) MicroRNA-122 antagonism against hepatitis C virus genotypes 1-6 and reduced efficacy by host RNA insertion or mutations in the HCV 5′ UTR. Proc Natl Acad Sci U S Am 108: 4991-4996

[30] Li L, Chen HZ, Chen FF, Li F, Wang M, Wang L, Li YQ, Gao DS (2013) Global microRNA expression profiling reveals differential expression of target genes in 6-hydroxydopamine-injured MN9D cells. Neuromol Med 15: 593-604

[31] Mahajan VS, Drake A, Chen J (2009) Virus-specific host miRNAs: antiviral defenses or promoters of persistent infection? Trends Immunol 30: 1-7

[32] Martinez I, Gardiner AS, Board KF, Monzon FA, Edwards RP, Khan SA (2008) Human papillomavirus type 16 reduces the expression of microRNA-218 in cervical carcinoma cells. Oncogene 27: 2575-2582

[33] Mejlhede N, Pedersen BV, Frisch M, Fomsgaard A (2010) Multiple human papilloma virus types in cervical infections: competition or synergy? APMIS 118: 346-352

[34] Melar-New M, Laimins LA (2010) Human papillomaviruses modulate expression of microRNA 203 upon epithelial differentiation to control levels of p63 proteins. J Virol 84: 5212-5221

[35] Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV, Snijders PJ, Meijer CJ, International Agency for Research on Cancer Multicenter Cervical Cancer Study, G (2003) Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 348: 518-527

[36] Nguyen HC, Xie W, Yang M, Hsieh CL, Drouin S, Lee GS, Kantoff PW (2013) Expression differences of circulating microRNAs in metastatic castration resistant prostate cancer and low-risk, localized prostate cancer. Prostate 73: 346-354

[37] Nuovo GJ, Wu X, Volinia S, Yan F, di Leva G, Chin N, Nicol AF, Jiang J, Otterson G, Schmittgen TD (2010) Strong inverse correlation between microRNA-125b and human papillomavirus DNA in productive infection. Diagn Mol Pathol 19: 135-143

[38] Pedersen IM, Cheng G, Wieland S, Volinia S, Croce CM, Chisari FV, David M (2007) Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature 449: 919-922

[39] Pim D, Banks L (1999) HPV-18 E6*I protein modulates the E6-directed degradation of p53 by binding to full-length HPV-18 E6. Oncogene 18: 7403-7408

[40] Potenza N, Papa U, Mosca N, Zerbini F, Nobile V, Russo A (2011) Human microRNA hsa-miR-125a-5p interferes with expression of hepatitis B virus surface antigen. Nucleic Acids Res 39: 5157-5163

[41] Qian K, Pietila T, Ronty M, Michon F, Frilander MJ, Ritari J, Tarkkanen J, Paulin L, Auvinen P, Auvinen E (2013) Identification and validation of human papillomavirus encoded microRNAs. PLoS One 8: e70202

[42] Qingqing Cai X.Z, Zoufeng Li (2010) MiRNAs as promising phylogenetic markers for inferring deep metazoan phylogeny and in support of Olfactores hypothesis. Bioinformatics and Biomedicine (BIBM), 2010 IEEE International Conference on 18-21 Dec 2010, Hong Kong, 101-104

[43] Rosenberger S, De-Castro Arce J, Langbein L, Steenbergen RD, Rosl F (2010) Alternative splicing of human papillomavirus type- 16 E6/E6* early mRNA is coupled to EGF signaling via Erk1/2 activation. Proc Natl Acad Sci U S A 107: 7006-7011

[44] Russo A, Potenza N (2011) Antiviral effects of human microRNAs and conservation of their target sites. FEBS lett 585: 2551-2555

[45] Scaria V, Hariharan M, Maiti S, Pillai B, Brahmachari SK (2006) Host-virus interaction: a new role for microRNAs. Retrovirology 3: 68

[46] 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

[47] Shi M, Du L, Liu D, Qian L, Hu M, Yu M, Yang Z, Zhao M, Chen C, Guo L (2012) Glucocorticoid regulation of a novel HPV-E6- p53-miR-145 pathway modulates invasion and therapy resistance of cervical cancer cells. J Pathol 228: 148-157

[48] Song L, Liu H, Gao S, Jiang W, Huang W (2010) Cellular microRNAs inhibit replication of the H1N1 influenza A virus in infected cells. J Virol 84: 8849-8860

[49] Stacey SN, Jordan D, Snijders PJ, Mackett M, Walboomers JM, Arrand JR (1995) Translation of the human papillomavirus type 16 E7 oncoprotein from bicistronic mRNA is independent of splicing events within the E6 open reading frame. J Virol 69: 7023-7031

[50] Stark MS, Tyagi S, Nancarrow DJ, Boyle GM, Cook AL, Whiteman DC, Parsons PG, Schmidt C, Sturm RA, Hayward NK (2010) Characterization of the melanoma miRNAome by deep sequencing. PloS One 5: e9685

[51] Stewart BW, Wild CP (2014) World cancer report. IARC Scientific Publications, New Delhi

[52] Thorland EC, Myers SL, Persing DH, Sarkar G, McGovern RM, Gostout BS, Smith DI (2000) Human papillomavirus type 16 integrations in cervical tumors frequently occur in common fragile sites. Cancer Res 60: 5916-5921

[53] Weng L, Wu X, Gao H, Mu B, Li X, Wang JH, Guo C, Jin JM, Chen Z, Covarrubias M (2010) MicroRNA profiling of clear cell renal cell carcinoma by whole-genome small RNA deep sequencing of paired frozen and formalin-fixed, paraffin-embedded tissue specimens. J Pathol 222: 41-51

[54] Witten D, Tibshirani R, Gu SG, Fire A, Lui WO (2010) Ultra-high throughput sequencing-based small RNA discovery and discrete statistical biomarker analysis in a collection of cervical tumours and matched controls. BMC Biol 8: 58

[55] Zaravinos A, Lambrou GI, Mourmouras N, Katafygiotis P, Papagregoriou G, Giannikou K, Delakas D, Deltas C (2014) New miRNA profiles accurately distinguish renal cell carcinomas and upper tract urothelial carcinomas from the normal kidney. PLoS One 9: e91646

[56] Zhao X, Liu Q, Cai Q, Li Y, Xu C, Li Z, Zhang X (2012) Dr.VIS: a database of human disease-related viral integration sites. Nucleic Acids Res 40: D1041-D1046

[57] Zheng ZM, Baker CC (2006) Papillomavirus genome structure, expression, and post-transcriptional regulation. Front Biosci 11: 2286-2302

[58] Zheng ZM, Wang X (2011) Regulation of cellular miRNA expression by human papillomaviruses. Biochim Biophys Acta 1809: 668-677

[59] zur Hausen H (2002) Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2: 342-350

RIGHTS & PERMISSIONS

2014 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.