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Epigenetics and cervical cancer: from pathogenesis to therapy

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Tumor Biology

Abstract

Although human papillomavirus (HPV) infection has been found in most of the cervical cancer cases, additional genetic and epigenetic changes are required for disease progression. Previously, it was thought that only genetic mutation plays a key role in cervical cancer development. But recent advances in the biology of cervical cancer revealed that epigenetic alteration is common in cervical carcinogenesis and metastasis. Epigenetic alteration due to aberrant DNA methylation and histone modification has been extensively studied in cervical cancer. Recent research strategies keep insight into noncoding RNAs, especially miRNA and lncRNA. At the same time, interest has been grown to study the utility of these changes as biomarkers to determine disease progression as well as use them as the therapeutic targets. This study has been aimed to review the recent progress of epigenetic study for cervical cancer research including role of these epigenetic changes in disease progression, their prognostic values, and their use in targeted therapy.

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References

  1. Satterwhite CL, Torrone E, Meites E, Dunne EF, Mahajan R, Ocfemia MC, et al. Sexually transmitted infections among U.S. women and men: prevalence and incidence estimates, 2008. Sex Transm Dis. 2013;40:187–93.

    PubMed  Google Scholar 

  2. Munoz N, Castellsague X, de Gonzalez AB, Gissmann L. Chapter 1. HPV in the etiology of human cancer. Vaccine. 2006;24:1–10.

    Google Scholar 

  3. Saavedra KP, Brebi PM, Roa JC. Epigenetic alterations in preneoplastic and neoplastic lesions of the cervix. Clin Epigenetics. 2012;4:13.

    PubMed Central  CAS  PubMed  Google Scholar 

  4. Momparler RL. Cancer epigenetics. Oncogene. 2003;22:6479–83.

    CAS  PubMed  Google Scholar 

  5. Costello JF, Frühwald MC, Smiraglia DJ, Rush LJ, et al. Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat Genet. 2000;24:132–8.

    CAS  PubMed  Google Scholar 

  6. Kouzarides T. Chromatin modifications and their function. Cell. 2007;128:693–705.

    CAS  PubMed  Google Scholar 

  7. Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009;10:155–9.

    CAS  PubMed  Google Scholar 

  8. Huang T, Alvarez A, Hu B, Cheng SY. Noncoding RNAs in cancer and cancer stem cells. Chin J Cancer. 2013;32:582–93.

    PubMed Central  CAS  PubMed  Google Scholar 

  9. Burd EM. Human papillomavirus and cervical cancer. Clin Microbiol Rev. 2003;16:1–17.

    PubMed Central  CAS  PubMed  Google Scholar 

  10. Yugawa T, Kiyono T. Molecular mechanisms of cervical carcinogenesis by high-risk human papillomaviruses: novel functions of E6 and E7 oncoproteins. Rev Med Virol. 2009;19:97–113.

    CAS  PubMed  Google Scholar 

  11. Shukla S, Bharti AC, Mahata S, Hussain S, Kumar R, Hedau S, et al. Infection of human papillomaviruses in cancers of different human organ sites. Indian J Med Res. 2009;130:222–33.

    CAS  PubMed  Google Scholar 

  12. Nour NM. Cervical cancer: a preventable death. Rev Obstet Gynecol. 2009;2:240–4.

    PubMed Central  PubMed  Google Scholar 

  13. Grm HS, Bergant M, Banks L. Human papillomavirus infection, cancer & therapy. Indian J Med Res. 2009;130:277–85.

    PubMed  Google Scholar 

  14. Fernandez AF, Esteller M. Viral epigenomes in human tumorigenesis. Oncogene. 2010;29:1405–20.

    CAS  PubMed  Google Scholar 

  15. Moody CA, Laimins LA. Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer. 2010;10:550–60.

    CAS  PubMed  Google Scholar 

  16. Zheng ZM, Baker CC. Papillomavirus genome structure, expression, and post-transcriptional regulation. Front Biosci. 2006;11:2286–302.

    PubMed Central  CAS  PubMed  Google Scholar 

  17. Narisawa-Saito M, Kiyono T. Basic mechanisms of high-risk human papillomavirus-induced carcinogenesis: roles of E6 and E7 proteins. Cancer Sci. 2007;98:1505–11.

    CAS  PubMed  Google Scholar 

  18. Nguyen DX, Massague J. Genetic determinants of cancer metastasis. Nat Rev Genet. 2007;8:341–52.

    CAS  PubMed  Google Scholar 

  19. Szalmas A, Konya J. Epigenetic alterations in cervical carcinogenesis. Semin Cancer Biol. 2009;19:144–52.

    CAS  PubMed  Google Scholar 

  20. Balch C, Matei DE, Huang TH, Nephew KP. Role of epigenomics in ovarian and endometrial cancers. Epigenomics. 2010;2:419–47.

    CAS  PubMed  Google Scholar 

  21. Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358:1148–59.

    CAS  PubMed  Google Scholar 

  22. Duenas-Gonzalez A, Lizano M, Candelaria M, Cetina L, Arce C, Cervera E. Epigenetics of cervical cancer. An overview and therapeutic perspectives. Mol Cancer. 2005;4:38.

    PubMed Central  PubMed  Google Scholar 

  23. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683–92.

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Nehls K, Vinokurova S, Schmidt D, Kommoss F, Reuschenbach M, Kisseljov F, et al. p16 methylation does not affect protein expression in cervical carcinogenesis. Eur J Cancer. 2008;44:2496–505.

    CAS  PubMed  Google Scholar 

  25. Huang LW, Pan HS, Lin YH, Seow KM, Chen HJ, Hwang JL. P16 methylation is an early event in cervical carcinogenesis. Int J Gynecol Cancer. 2011;21:452–56.

    PubMed  Google Scholar 

  26. Munger K, Howley PM. Human papillomavirus immortalization and transformation functions. Virus Res. 2002;89:213–28.

    CAS  PubMed  Google Scholar 

  27. Missaoui N, Trabelsi A, Hmissa S, Fontanière B, Yacoubi MT, Mokni M, et al. p16INK4A overexpression in precancerous and cancerous lesions of the uterine cervix in Tunisian women. Pathol Res Pract. 2010;206:550–5.

    CAS  PubMed  Google Scholar 

  28. McLaughlin-Drubin ME, Crum CP, Münger K. Human papillomavirus E7 oncoprotein induces KDM6A and KDM6B histone demethylase expression and causes epigenetic reprogramming. Proc Natl Acad Sci U S A. 2011;108:2130–35.

    PubMed Central  CAS  PubMed  Google Scholar 

  29. McLaughlin-Drubin ME, Park D, Munger K. Tumor suppressor p16INK4A is necessary for survival of cervical carcinoma cell lines. Proc Natl Acad Sci U S A. 2013;110:16175–80.

    PubMed Central  CAS  PubMed  Google Scholar 

  30. Neyaz MK, Hussain S, Hassan MI, Das BC, Husain SA, Bharadwaj M. Novel missense mutation in FHIT gene: interpreting the effect in HPV-mediated cervical cancer in Indian women. Mol Cell Biochem. 2010;335:53–8.

    CAS  PubMed  Google Scholar 

  31. Choi CH, Lee KM, Choi JJ, Kim TJ, Kim WY, Lee JW, et al. Hypermethylation and loss of heterozygosity of tumor suppressor genes on chromosome 3p in cervical cancer. Cancer Lett. 2007;255:26–33.

    CAS  PubMed  Google Scholar 

  32. Ki KD, Lee SK, Tong SY, Lee JM, Song DH, Chi SG. Role of 5′-CpG island hypermethylation of the FHIT gene in cervical carcinoma. J Gynecol Oncol. 2008;19:117–22.

    PubMed Central  CAS  PubMed  Google Scholar 

  33. Yang R, Müller C, Huynh V, Fung YK, Yee AS, Koeffler HP. Functions of cyclin A1 in the cell cycle and its interactions with transcription factor E2F-1 and the Rb family of proteins. Mol Cell Biol. 1999;19:2400–7.

    PubMed Central  CAS  PubMed  Google Scholar 

  34. Yanatatsaneejit P, Mutirangura A, Kitkumthorn N. Human papillomavirus's physical state and cyclin A1 promoter methylation in cervical cancer. Int J Gynecol Cancer. 2011;21:902–6.

    PubMed  Google Scholar 

  35. Kitkumthorn N, Yanatatsanajit P, Kiatpongsan S, Phokaew C, Triratanachat S, Trivijitsilp P, et al. Cyclin A1 promoter hypermethylation in human papillomavirus-associated cervical cancer. BMC Cancer. 2006;6:55.

    PubMed Central  PubMed  Google Scholar 

  36. Michie AM, McCaig AM, Nakagawa R, Vukovic M. Death-associated protein kinase (DAPK) and signal transduction: regulation in cancer. FEBS J. 2010;277:74–80.

    CAS  PubMed  Google Scholar 

  37. Kim JH, Choi YD, Lee JS, Lee JH, Nam JH, Choi C. Assessment of DNA methylation for the detection of cervical neoplasia in liquid-based cytology specimens. Gynecol Oncol. 2010;116:99–104.

    CAS  PubMed  Google Scholar 

  38. Yang N, Nijhuis ER, Volders HH, Eijsink JJ, Lendvai A, Zhang B, et al. Gene promoter methylation patterns throughout the process of cervical carcinogenesis. Cell Oncol. 2010;32:131–43.

    CAS  PubMed  Google Scholar 

  39. Hesson LB, Cooper WN, Latif F. The role of RASSF1A methylation in cancer. Dis Markers. 2007;23:73–87.

    PubMed Central  CAS  PubMed  Google Scholar 

  40. Yang HJ, Liu VW, Wang Y, Chan KY, Tsang PC, Khoo US, et al. Detection of hypermethylated genes in tumor and plasma of cervical cancer patients. Gynecol Oncol. 2004;93:435–40.

    CAS  PubMed  Google Scholar 

  41. Cohen Y, Singer G, Lavie O, Dong SM, Beller U, Sidransky D. The RASSF1A tumor suppressor gene is commonly inactivated in adenocarcinoma of the uterine cervix. Clin Cancer Res. 2003;9:2981–4.

    CAS  PubMed  Google Scholar 

  42. Kuzmin I, Liu L, Dammann R, Geil L, Stanbridge EJ, Wilczynski SP, et al. Inactivation of RAS association domain family 1A gene in cervical carcinomas and the role of human papillomavirus infection. Cancer Res. 2003;63:1888–93.

    CAS  PubMed  Google Scholar 

  43. Wentzensen N, Sherman ME, Schiffman M, Wang SS. Utility of methylation markers in cervical cancer early detection: appraisal of the state-of-the-science. Gynecol Oncol. 2009;112:293–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  44. Lin Z, Gao M, Zhang X, Kim YS, Lee ES, Kim HK, et al. The hypermethylation and protein expression of p16 INK4A and DNA repair gene O6-methylguanine-DNA methyltransferase in various uterine cervical lesions. J Cancer Res Clin Oncol. 2005;131:364–70.

    CAS  PubMed  Google Scholar 

  45. Iliopoulos D, Oikonomou P, Messinis I, Tsezou A. Correlation of promoter hypermethylation in hTERT, DAPK and MGMT genes with cervical oncogenesis progression. Oncol Rep. 2009;22:199–204.

    CAS  PubMed  Google Scholar 

  46. Aoki K, Taketo MM. Adenomatous polyposis coli (APC): a multi-functional tumor suppressor gene. J Cell Sci. 2007;120:3327–35.

    CAS  PubMed  Google Scholar 

  47. Yang HJ, Liu VW, Wang Y, Tsang PC, Ngan HY. Differential DNA methylation profiles in gynecological cancers and correlation with clinico-pathological data. BMC Cancer. 2006;6:212.

    PubMed Central  PubMed  Google Scholar 

  48. Henken FE, Wilting SM, Overmeer RM, van Rietschoten JG, Nygren AO, Errami A, et al. Sequential gene promoter methylation during HPV-induced cervical carcinogenesis. Br J Cancer. 2007;97:1457–64.

    PubMed Central  CAS  PubMed  Google Scholar 

  49. Dong SM, Kim HS, Rha SH, Sidransky D. Promoter hypermethylation of multiple genes in carcinoma of the uterine cervix. Clin Cancer Res. 2001;7:1982–6.

    CAS  PubMed  Google Scholar 

  50. Kang S, Kim JW, Kang GH, Lee S, Park NH, Song YS, et al. Comparison of DNA hypermethylation patterns in different types of uterine cancer: cervical squamous cell carcinoma, cervical adenocarcinoma and endometrial adenocarcinoma. Int J Cancer. 2006;118:2168–71.

    CAS  PubMed  Google Scholar 

  51. Yang Q, Sakurai T, Kakudo K. Retinoid, retinoic acid receptor beta and breast cancer. Breast Cancer Res Treat. 2002;76:167–73.

    CAS  PubMed  Google Scholar 

  52. Ivanova T, Petrenko A, Gritsko T, Vinokourova S, Eshilev E, Kobzeva V, et al. Methylation and silencing of the retinoic acid receptor-beta 2 gene in cervical cancer. BMC Cancer. 2002;2:4.

    PubMed Central  PubMed  Google Scholar 

  53. Zhang Z, Joh K, Yatsuki H, Zhao W, Soejima H, Higashimoto K, et al. Retinoic acid receptor beta2 is epigenetically silenced either by DNA methylation or repressive histone modifications at the promoter in cervical cancer cells. Cancer Lett. 2007;247:318–27.

    CAS  PubMed  Google Scholar 

  54. Cheung TH, Lo KW, Yim SF, Chan LK, Heung MS, Chan CS, et al. Epigenetic and genetic alternation of PTEN in cervical neoplasm. Gynecol Oncol. 2004;93:621–27.

    CAS  PubMed  Google Scholar 

  55. Zhang Z, Huettner PC, Nguyen L, Bidder M, Funk MC, Li J, et al. Aberrant promoter methylation and silencing of the POU2F3 gene in cervical cancer. Oncogene. 2006;25:5436–45.

    CAS  PubMed  Google Scholar 

  56. Overmeer RM, Henken FE, Snijders PJ, Claassen-Kramer D, Berkhof J, Helmerhorst TJ, et al. Association between dense CADM1 promoter methylation and reduced protein expression in high-grade CIN and cervical SCC. J Pathol. 2008;215:388–97.

    CAS  PubMed  Google Scholar 

  57. Mazumder Indra D, Mitra S, Roy A, Mondal RK, Basu PS, Roychoudhury S, et al. Alterations of ATM and CADM1 in chromosomal 11q22.3-23.2 region are associated with the development of invasive cervical carcinoma. Hum Genet. 2011;130:735–48.

    CAS  PubMed  Google Scholar 

  58. Narayan G, Arias-Pulido H, Koul S, Vargas H, Zhang FF, Villella J, et al. Frequent promoter methylation of CDH1, DAPK, RARB, and HIC1 genes in carcinoma of cervix uteri: its relationship to clinical outcome. Mol Cancer. 2003;2:24.

    PubMed Central  PubMed  Google Scholar 

  59. Li J, Zhang Z, Bidder M, Funk MC, Nguyen L, Goodfellow PJ, et al. IGSF4 promoter methylation and expression silencing in human cervical cancer. Gynecol Oncol. 2005;96:150–8.

    CAS  PubMed  Google Scholar 

  60. Steenbergen RD, Kramer D, Braakhuis BJ, Stern PL, Verheijen RH, Meijer CJ, et al. TSLC1 gene silencing in cervical cancer cell lines and cervical neoplasia. J Natl Cancer Inst. 2004;96:294–305.

    CAS  PubMed  Google Scholar 

  61. Liu SS, Leung RC, Chan KY, Chiu PM, Cheung AN, Tam KF, et al. p73 expression is associated with the cellular radiosensitivity in cervical cancer after radiotherapy. Clin Cancer Res. 2004;10:3309–16.

    CAS  PubMed  Google Scholar 

  62. Sova P, Feng Q, Geiss G, Wood T, Strauss R, Rudolf V, et al. Discovery of novel methylation biomarkers in cervical carcinoma by global demethylation and microarray analysis. Cancer Epidemiol Biomarkers Prev. 2006;15:114–23.

    CAS  PubMed  Google Scholar 

  63. Wisman GB, Nijhuis ER, Hoque MO, Reesink-Peters N, Koning AJ, Volders HH, et al. Assessment of gene promoter hypermethylation for detection of cervical neoplasia. Int J Cancer. 2006;119:1908–14.

    CAS  PubMed  Google Scholar 

  64. Cho S, Cinghu S, Yu JR, Park WY. Helicase-like transcription factor confers radiation resistance in cervical cancer through enhancing the DNA damage repair capacity. J Cancer Res Clin Oncol. 2011;137:629–37.

    CAS  PubMed  Google Scholar 

  65. Huang BH, Laban M, Leung CH, Lee L, Lee CK, Salto-Tellez M, et al. Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1. Cell Death Differ. 2005;12:395–404.

    CAS  PubMed  Google Scholar 

  66. Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293:1074–80.

    CAS  PubMed  Google Scholar 

  67. Danam RP, Howell SR, Brent TP, Harris LC. Epigenetic regulation of O6-methylguanine-DNA methyltransferase gene expression by histone acetylation and methyl-CpG binding proteins. Mol Cancer Ther. 2005;4:61–9.

    CAS  PubMed  Google Scholar 

  68. Jaehyouk L, Young Soo Y, Jae Hoon C. Epigenetic silencing of the WNT antagonist DICKKOPF-1 in cervical cancer cell lines. Gynecol Oncol. 2008;109:270–4.

    Google Scholar 

  69. Bardos JI, Ashcroft M. Negative and positive regulation of HIF-1: a complex network. Biochim Biophys Acta. 2005;1755:107–20.

    CAS  PubMed  Google Scholar 

  70. Bodily JM, Mehta KP, Laimins LA. Human papillomavirus e7 enhances hypoxia-inducible factor 1 mediated transcription by inhibiting binding of histone deacetylases. Cancer Res. 2011;71:1187–95.

    PubMed Central  CAS  PubMed  Google Scholar 

  71. Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet. 1998;19:187–91.

    CAS  PubMed  Google Scholar 

  72. Lu TY, Kao CF, Lin CT, Huang DY, Chiu CY, Huang YS, et al. DNA methylation and histone modification regulate silencing of OPG during tumor progression. J Cell Biochem. 2009;108:315–25.

    CAS  PubMed  Google Scholar 

  73. Liu D, Zhou P, Zhang L, Gong W, Huang G, Zheng Y, et al. HDAC1/DNMT3A-containing complex is associated with suppression of Oct4 in cervical cancer cells. Biochemistry (Mosc). 2012;77:934–40.

    CAS  Google Scholar 

  74. Friedman JM, Jones PA. MicroRNAs: critical mediators of differentiation, development and disease. Swiss Med Wkly. 2009;139:466–72.

    PubMed Central  CAS  PubMed  Google Scholar 

  75. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33.

    PubMed Central  CAS  PubMed  Google Scholar 

  76. Asli NS, Pitulescu ME, Kessel M. MicroRNAs in organogenesis and disease. Curr Mol Med. 2008;8:698–710.

    CAS  PubMed  Google Scholar 

  77. Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet. 2007;39:673–7.

    CAS  PubMed  Google Scholar 

  78. Kent OA, Mendell JT. A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes. Oncogene. 2006;25:6188–96.

    CAS  PubMed  Google Scholar 

  79. Wang X, Tang S, Le SY, Lu R, Rader JS, Meyers C, et al. Aberrant expression of oncogenic and tumor-suppressive microRNAs in cervical cancer is required for cancer cell growth. PLoS One. 2008;3:e2557.

    PubMed Central  PubMed  Google Scholar 

  80. Ma D, Zhang YY, Guo YL, Li ZJ, Geng L. Profiling of microRNA-mRNA reveals roles of microRNAs in cervical cancer. Chin Med J (Engl). 2012;125:4270–6.

    CAS  Google Scholar 

  81. Wu X, Xi X, Yan Q, Zhang Z, Cai B, Lu W, et al. MicroRNA-361-5p facilitates cervical cancer progression through mediation of epithelial-to-mesenchymal transition. Med Oncol. 2013;30:751.

    PubMed  Google Scholar 

  82. Yamamoto N, Kinoshita T, Nohata N, Yoshino H, Itesako T, Fujimura L, et al. Tumor-suppressive microRNA-29a inhibits cancer cell migration and invasion via targeting HSP47 in cervical squamous cell carcinoma. Int J Oncol. 2013;43:1855–63.

    PubMed Central  CAS  PubMed  Google Scholar 

  83. Xin JX, Yue Z, Zhang S, Jiang ZH, Wang PY, Li YJ, et al. miR-99 inhibits cervical carcinoma cell proliferation by targeting TRIB2. Oncol Lett. 2013;6:1025–30.

    PubMed Central  CAS  PubMed  Google Scholar 

  84. Zhang J, Zheng F, Yu G, Yin Y, Lu Q. miR-196a targets netrin 4 and regulates cell proliferation and migration of cervical cancer cells. Biochem Biophys Res Commun. 2013;440:582–8.

    CAS  PubMed  Google Scholar 

  85. Huang TH, Chu TY. Repression of miR-126 and upregulation of adrenomedullin in the stromal endothelium by cancer-stromal cross talks confers angiogenesis of cervical cancer. Oncogene. 2013.

  86. Wang YD, Cai N, Wu XL, Cao HZ, Xie LL, Zheng PS. OCT4 promotes tumorigenesis and inhibits apoptosis of cervical cancer cells by miR-125b/BAK1 pathway. Cell Death Dis. 2013;4:e760.

    PubMed Central  CAS  PubMed  Google Scholar 

  87. Cui F, Li X, Zhu X, Huang L, Huang Y, Mao C, et al. MiR-125b inhibits tumor growth and promotes apoptosis of cervical cancer cells by targeting phosphoinositide 3-kinase catalytic subunit delta. Cell Physiol Biochem. 2012;30:1310–8.

    CAS  PubMed  Google Scholar 

  88. Zhu X, Er K, Mao C, Yan Q, Xu H, Zhang Y, et al. miR-203 suppresses tumor growth and angiogenesis by targeting VEGFA in cervical cancer. Cell Physiol Biochem. 2013;32:64–73.

    CAS  PubMed  Google Scholar 

  89. How C, Hui AB, Alajez NM, Shi W, Boutros PC, Clarke BA, et al. MicroRNA-196b regulates the homeobox B7-vascular endothelial growth factor axis in cervical cancer. PLoS One. 2013;8:e67846.

    PubMed Central  CAS  PubMed  Google Scholar 

  90. Zhao S, Yao D, Chen J, Ding N. Circulating miRNA-20a and miRNA-203 for screening lymph node metastasis in early stage cervical cancer. Genet Test Mol Biomarkers. 2013;17:631–36.

    CAS  PubMed  Google Scholar 

  91. Kang HW, Wang F, Wei Q, Zhao YF, Liu M, Li X, et al. miR-20a promotes migration and invasion by regulating TNKS2 in human cervical cancer cells. FEBS Lett. 2012;586:897–904.

    CAS  PubMed  Google Scholar 

  92. Wang F, Li Y, Zhou J, Xu J, Peng C, Ye F, et al. miR-375 is down-regulated in squamous cervical cancer and inhibits cell migration and invasion via targeting transcription factor SP1. Am J Pathol. 2011;179:2580–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  93. Liu S, Zhang P, Chen Z, Liu M, Li X, Tang H. MicroRNA-7 downregulates XIAP expression to suppress cell growth and promote apoptosis in cervical cancer cells. FEBS Lett. 2013;587:2247–53.

    CAS  PubMed  Google Scholar 

  94. Shen SN, Wang LF, Jia YF, Hao YQ, Zhang L, Wang H. Upregulation of microRNA-224 is associated with aggressive progression and poor prognosis in human cervical cancer. Diagn Pathol. 2013;8:69.

    PubMed Central  CAS  PubMed  Google Scholar 

  95. Yamamoto N, Kinoshita T, Nohata N, Itesako T, Yoshino H, Enokida H, et al. Tumor suppressive microRNA-218 inhibits cancer cell migration and invasion by targeting focal adhesion pathways in cervical squamous cell carcinoma. Int J Oncol. 2013;42:1523–32.

    PubMed Central  CAS  PubMed  Google Scholar 

  96. Li Y, Liu J, Yuan C, Cui B, Zou X, Qiao Y. High-risk human papillomavirus reduces the expression of microRNA-218 in women with cervical intraepithelial neoplasia. J Int Med Res. 2010;38:1730–6.

    CAS  PubMed  Google Scholar 

  97. Luo M, Shen D, Zhou X, Chen X. Wang WMicroRNA-497 is a potential prognostic marker in human cervical cancer and functions as a tumor suppressor by targeting the insulin-like growth factor 1 receptor. Surgery. 2013;153:836–47.

    PubMed  Google Scholar 

  98. Druz A, Chen YC, Guha R, Betenbaugh M, Martin SE. Shiloach JLarge-scale screening identifies a novel microRNA, miR-15a-3p, which induces apoptosis in human cancer cell lines. RNA Biol. 2013;10:287–300.

    PubMed Central  CAS  PubMed  Google Scholar 

  99. Wang F, Liu M, Li X, Tang H. MiR-214 reduces cell survival and enhances cisplatin-induced cytotoxicity via down-regulation of Bcl2l2 in cervical cancer cells. FEBS Lett. 2013;587:488–95.

    CAS  PubMed  Google Scholar 

  100. Peng RQ, Wan HY, Li HF, Liu M, Li X, Tang H. MicroRNA-214 suppresses growth and invasiveness of cervical cancer cells by targeting UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 7. J Biol Chem. 2012;287:14301–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Tang T, Wong HK, Gu W, Yu MY, To KF, Wang CC, et al. MicroRNA-182 plays an onco-miRNA role in cervical cancer. Gynecol Oncol. 2013;129:199–208.

    CAS  PubMed  Google Scholar 

  102. Xie H, Zhao Y, Caramuta S, Larsson C, Lui W. OmiR-205 expression promotes cell proliferation and migration of human cervical cancer cells. PLoS One. 2012;7:e46990.

    PubMed Central  CAS  PubMed  Google Scholar 

  103. Wei Q, Li YX, Liu M, Li X, Tang H. MiR-17-5p targets TP53INP1 and regulates cell proliferation and apoptosis of cervical cancer cells. IUBMB Life. 2012;64:697–704.

    CAS  PubMed  Google Scholar 

  104. Long MJ, Wu FX, Li P, Liu M, Li X, Tang H. MicroRNA-10a targets CHL1 and promotes cell growth, migration and invasion in human cervical cancer cells. Cancer Lett. 2012;324:186–96.

    CAS  PubMed  Google Scholar 

  105. Xu XM, Wang XB, Chen MM, Liu T, Li YX, Jia WH, et al. MicroRNA-19a and -19b regulate cervical carcinoma cell proliferation and invasion by targeting CUL5. Cancer Lett. 2012;322:148–58.

    CAS  PubMed  Google Scholar 

  106. Xu J, Li Y, Wang F, Wang X, Cheng B, Ye F, et al. Suppressed miR-424 expression via upregulation of target gene Chk1 contributes to the progression of cervical cancer. Oncogene. 2013;32:976–87.

    CAS  PubMed  Google Scholar 

  107. Shi M, Du L, Liu D, Qian L, Hu M, Yu M, et al. Glucocorticoid regulation of a novel HPV-E6-p53-miR-145 pathway modulates invasion and therapy resistance of cervical cancer cells. Pathol. 2012;228:148–57.

    CAS  Google Scholar 

  108. Qin W, Dong P, Ma C, Mitchelson K, Deng T, Zhang L, et al. MicroRNA-133b is a key promoter of cervical carcinoma development through the activation of the ERK and AKT1 pathways. Oncogene. 2012;31:4067–75.

    CAS  PubMed  Google Scholar 

  109. Liu L, Yu X, Guo X, Tian Z, Su M, Long Y, et al. miR-143 is downregulated in cervical cancer and promotes apoptosis and inhibits tumor formation by targeting Bcl-2. Mol Med Rep. 2012;5:753–60.

    CAS  PubMed  Google Scholar 

  110. Yao T, Lin Z. MiR-21 is involved in cervical squamous cell tumorigenesis and regulates CCL20. Biochim Biophys Acta. 1822;2012:248–60.

    Google Scholar 

  111. Yao Q, Xu H, Zhang QQ, Zhou H, Qu LH. 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. 2009;388:539–42.

    CAS  PubMed  Google Scholar 

  112. Tian RQ, Wang XH, Hou LJ, Jia WH, Yang Q, Li YX, et al. MicroRNA-372 is down-regulated and targets cyclin-dependent kinase 2 (CDK2) and cyclin A1 in human cervical cancer, which may contribute to tumorigenesis. J Biol Chem. 2011;286:25556–63.

    PubMed Central  CAS  PubMed  Google Scholar 

  113. Li BH, Zhou JS, Ye F, Cheng XD, Zhou CY, Lu WG, et al. Reduced miR-100 expression in cervical cancer and precursors and its carcinogenic effect through targeting PLK1 protein. Eur J Cancer. 2011;47:2166–74.

    CAS  PubMed  Google Scholar 

  114. Wang X, Meyers C, Guo M, Zheng ZM. Upregulation of p18Ink4c expression by oncogenic HPV E6 via p53-miR-34a pathway. Int J Cancer. 2011;129:1362–72.

    PubMed Central  CAS  PubMed  Google Scholar 

  115. Pang RT, Leung CO, Ye TM, Liu W, Chiu PC, Lam KK, et al. MicroRNA-34a suppresses invasion through downregulation of Notch1 and Jagged1 in cervical carcinoma and choriocarcinoma cells. Carcinogenesis. 2010;31:1037–44.

    CAS  PubMed  Google Scholar 

  116. Li JH, Xiao X, Zhang YN, Wang YM, Feng LM, Wu YM, et al. MicroRNA miR-886-5p inhibits apoptosis by down-regulating Bax expression in human cervical carcinoma cells. Gynecol Oncol. 2011;120:145–51.

    CAS  PubMed  Google Scholar 

  117. Wilting SM, van Boerdonk RA, Henken FE, Meijer CJ, Diosdado B, Meijer GA, et al. Methylation-mediated silencing and tumour suppressive function of hsa-miR-124 in cervical cancer. Mol Cancer. 2010;9:167.

    PubMed Central  PubMed  Google Scholar 

  118. Wilting SM, Verlaat W, Jaspers A, Makazaji NA, Agami R, Meijer CJ, et al. Methylation-mediated transcriptional repression of microRNAs during cervical carcinogenesis. Epigenetics. 2013;8:220–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  119. Yao T, Rao Q, Liu L, Zheng C, Xie Q, Liang J, et al. Exploration of tumor-suppressive microRNAs silenced by DNA hypermethylation in cervical cancer. Virol J. 2013;10:175.

    PubMed Central  CAS  PubMed  Google Scholar 

  120. Muralidhar B, Winder D, Murray M, Palmer R, Barbosa-Morais N, Saini H, et al. Functional evidence that Drosha overexpression in cervical squamous cell carcinoma affects cell phenotype and microRNA profiles. J Pathol. 2011;224:496–507.

    CAS  PubMed  Google Scholar 

  121. Muralidhar B, Goldstein LD, Ng G, Winder DM, Palmer RD, Gooding EL, et al. Global microRNA profiles in cervical squamous cell carcinoma depend on Drosha expression levels. J Pathol. 2007;212:368–77.

    CAS  PubMed  Google Scholar 

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

    PubMed Central  CAS  PubMed  Google Scholar 

  123. Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs. Cell. 2009;136:629–41.

    CAS  PubMed  Google Scholar 

  124. Wilusz JE, Sunwoo H, Spector DL. Long noncoding RNAs: functional surprises from the RNA world. Genes Dev. 2009;23:1494–504.

    PubMed Central  CAS  PubMed  Google Scholar 

  125. Maruyama R, Suzuki H. Long noncoding RNA involvement in cancer. BMB Rep. 2012;45:604–11.

    PubMed Central  CAS  PubMed  Google Scholar 

  126. Yang F, Zhang L, Huo XS, Yuan JH, Xu D, Yuan SX, et al. Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans. Hepatology. 2011;54:1679–89.

    CAS  PubMed  Google Scholar 

  127. Kim K, Jutooru I, Chadalapaka G, Johnson G, Frank J, Burghardt R, et al. HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene. 2013;32:1616–25.

    PubMed Central  CAS  PubMed  Google Scholar 

  128. Yuan SX, Yang F, Yang Y, Tao QF, Zhang J, Huang G, et al. Long non-coding RNA-MVIH promotes angiogenesis and serves as a predictor for HCC patients’ poor recurrence-free survival after hepatectomy. Hepatology. 2012;56:2231–41.

    CAS  PubMed  Google Scholar 

  129. Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature. 2009;458:223–27.

    PubMed Central  CAS  PubMed  Google Scholar 

  130. Gibb EA, Becker-Santos DD, Enfield KS, Guillaud M, Niekerk D, Matisic JP, et al. Aberrant expression of long noncoding RNAs in cervical intraepithelial neoplasia. Int J Gynecol Cancer. 2012;22:1557–63.

    PubMed  Google Scholar 

  131. Qin R, Chen Z, Ding Y, Hao J, Hu J, Guo F. Long non-coding RNA MEG3 inhibits the proliferation of cervical carcinoma cells through the induction of cell cycle arrest and apoptosis. Neoplasma. 2013;60:486–92.

    CAS  PubMed  Google Scholar 

  132. Yang HJ. Aberrant DNA, methylation in cervical carcinogenesis. Chin J Cancer. 2013;32:42–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  133. Arbyn M, Bergeron C, Klinkhamer P, Martin-Hirsch P, Siebers AG, Bulten J. Liquid compared with conventional cervical cytology: a systematic review and meta-analysis. Obstet Gynecol. 2008;111:167–77.

    PubMed  Google Scholar 

  134. Lim EH, Ng SL, Li JL, Chang AR, Ng J, Ilancheran A, et al. Cervical dysplasia: assessing methylation status (Methylight) of CCNA1, DAPK1, HS3ST2, PAX1 and TFPI2 to improve diagnostic accuracy. Gynecol Oncol. 2010;119:225–31.

    CAS  PubMed  Google Scholar 

  135. Carestiato FN, Afonso LA, Moysés N, Almeida Filho GL, Velarde LG. Cavalcanti SMAn upward trend in DNA p16ink4a methylation pattern and high risk HPV infection according to the severity of the cervical lesion. Rev Inst Med Trop Sao Paulo. 2013;55:329–34.

    PubMed Central  PubMed  Google Scholar 

  136. Zhong ZJ, Yang JX, Cao DY, Sun Y, Sun LL, Cheng XM, et al. Promoter methylation of DAPK1, RAR-β and MGMT in exfoliated cervical cytology and its clinical application. Zhonghua Fu Chan Ke Za Zhi. 2012;47:196–200.

    CAS  PubMed  Google Scholar 

  137. Mitra S, Mazumder Indra D, Basu PS, Mondal RK, Roy A, Roychoudhury S, et al. Alterations of RASSF1A in premalignant cervical lesions: clinical and prognostic significance. Mol Carcinog. 2012;51:723–33.

    CAS  PubMed  Google Scholar 

  138. Bierkens M, Hesselink AT, Meijer CJ, Heideman DA, Wisman GB, van der Zee AG, et al. CADM1 and MAL promoter methylation levels in hrHPV-positive cervical scrapes increase proportional to degree and duration of underlying cervical disease. Int J Cancer. 2013;133:1293–9.

    CAS  PubMed  Google Scholar 

  139. Shivapurkar N, Sherman ME, Stastny V, Echebiri C, Rader JS, Nayar R, et al. Evaluation of candidate methylation markers to detect cervical neoplasia. Gynecol Oncol. 2007;107:549–53.

    PubMed Central  CAS  PubMed  Google Scholar 

  140. Widschwendter A, Ivarsson L, Blassnig A, Müller HM, Fiegl H, Wiedemair A, et al. CDH1 and CDH13 methylation in serum is an independent prognostic marker in cervical cancer patients. Int J Cancer. 2004;109:163–6.

    CAS  PubMed  Google Scholar 

  141. Wang L, Wang Q, Li HL, Han LY. Expression of MiR200a, miR93, metastasis-related gene RECK and MMP2/MMP9 in human cervical carcinoma—relationship with prognosis. Asian Pac J Cancer Prev. 2013;14:2113–8.

    PubMed  Google Scholar 

  142. Deftereos G, Corrie SR, Feng Q, Morihara J, Stern J, Hawes SE, et al. Expression of mir-21 and mir-143 in cervical specimens ranging from histologically normal through to invasive cervical cancer. PLoS One. 2011;6:e28423.

    PubMed Central  CAS  PubMed  Google Scholar 

  143. Li B, Hu Y, Ye F, Li Y, Lv W, Xie X. Reduced miR-34a expression in normal cervical tissues and cervical lesions with high-risk human papillomavirus infection. Int J Gynecol Cancer. 2010;20:597–604.

    PubMed  Google Scholar 

  144. Lin CJ, Lai HC, Wang KH, Hsiung CA, Liu HW, Ding DC, et al. Testing for methylated PCDH10 or WT1 is superior to the HPV test in detecting severe neoplasms (CIN3 or greater) in the triage of ASC-US smear results. Am J Obstet Gynecol. 2011;204:21.e1–7.

    Google Scholar 

  145. Chao TK, Ke FY, Liao YP, Wang HC, Yu CP, Lai HC. Triage of cervical cytological diagnoses of atypical squamous cells by DNA methylation of paired boxed gene 1 (PAX1). Diagn Cytopathol. 2013;41:41–6.

    PubMed  Google Scholar 

  146. Kahn SL, Ronnett BM, Gravitt PE, Gustafson KS. Quantitative methylation-specific PCR for the detection of aberrant DNA methylation in liquid-based Pap tests. Cancer. 2008;114:57–64.

    PubMed Central  CAS  PubMed  Google Scholar 

  147. Feng Q, Balasubramanian A, Hawes SE, Toure P, Sow PS, Dem A, et al. Detection of hypermethylated genes in women with and without cervical neoplasia. J Natl Cancer Inst. 2005;97:273–82.

    CAS  PubMed  Google Scholar 

  148. Song Y, Zhang C. Hydralazine inhibits human cervical cancer cell growth in vitro in association with APC demethylation and re-expression. Cancer Chemother Pharmacol. 2009;63:605–13.

    CAS  PubMed  Google Scholar 

  149. Zambrano P, Segura-Pacheco B, Perez-Cardenas E, Cetina L, Revilla-Vazquez A, Taja-Chayeb L, et al. A phase I study of hydralazine to demethylate and reactivate the expression of tumor suppressor genes. BMC Cancer. 2005;5:44.

    PubMed Central  PubMed  Google Scholar 

  150. Segura-Pacheco B, Trejo-Becerril C, Perez-Cardenas E, Taja-Chayeb L, Mariscal I, Chavez A, et al. Reactivation of tumor suppressor genes by the cardiovascular drugs hydralazine and procainamide and their potential use in cancer therapy. Clin Cancer Res. 2003;9:1596–603.

    CAS  PubMed  Google Scholar 

  151. Huang Y, Song H, Hu H, Cui L, You C, Huang L. Trichosanthin inhibits DNA methyltransferase and restores methylation-silenced gene expression in human cervical cancer cells. Mol Med Rep. 2013;6:872–8.

    Google Scholar 

  152. de la Cruz-Hernández E, Pérez-Cárdenas E, Contreras-Paredes A, Cantú D, Mohar A, Lizano M, et al. The effects of DNA methylation and histone deacetylase inhibitors on human papillomavirus early gene expression in cervical cancer, an in vitro and clinical study. Virol J. 2007;4:18.

    PubMed Central  PubMed  Google Scholar 

  153. Chen J, Ghazawi FM, Bakkar W, Li Q. Valproic acid and butyrate induce apoptosis in human cancer cells through inhibition of gene expression of Akt/protein kinase B. Mol Cancer. 2006;5:71.

    PubMed Central  CAS  PubMed  Google Scholar 

  154. You JS, Kang JK, Lee EK, Lee JC, Lee SH, Jeon YJ, et al. Histone deacetylase inhibitor apicidin downregulates DNA methyltransferase 1 expression and induces repressive histone modifications via recruitment of corepressor complex to promoter region in human cervix cancer cells. Oncogene. 2008;27:1376–86.

    CAS  PubMed  Google Scholar 

  155. Liu N, Zhao LJ, Li XP, Wang JL, Chai GL, Wei LH. Histone deacetylase inhibitors inducing human cervical cancer cell apoptosis by decreasing DNA-methyltransferase 3B. Chin Med J (Engl). 2012;125:3273–8.

    CAS  Google Scholar 

  156. Jiang Y, Wang Y, Su Z, Yang L, Guo W, Liu W, et al. Synergistic induction of apoptosis in HeLa cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitor SAHA. Mol Med Rep. 2010;3:613–9.

    CAS  PubMed  Google Scholar 

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Fang, J., Zhang, H. & Jin, S. Epigenetics and cervical cancer: from pathogenesis to therapy. Tumor Biol. 35, 5083–5093 (2014). https://doi.org/10.1007/s13277-014-1737-z

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