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In our report, we found that miR\u201034a specifically targets p18Ink4c, a CDK4 and CDK6 inhibitor induced by E2F transactivation. HPV18<jats:sup>+<\/jats:sup> HeLa cells with ectopic miR\u201034a expression or by E6 siRNA knockdown\u2010induced expression of endogenous miR\u201034a exhibited a substantial reduction of p18Ink4c in a dose\u2010dependent manner, but had no effect on p16Ink4a, another member of CDK4\/6 inhibitor family. In contrast, <jats:italic>de novo<\/jats:italic> infection by oncogenic HPVs of human keratinocyte\u2010derived raft tissues increased p18Ink4c expression. Suppression of endogenous miR\u201034a in cell lines with a miR\u201034a inhibitor also increased p18Ink4c. We found that miR\u201034a suppresses the expression of p18Ink4c by binding to a specific seed match in the 5\u2032 UTR of p18Ink4c. Further investigation found remarkable increase of p18Ink4c in cervical precancer lesions and cervical cancer. Immunohistochemical staining of cervical tissue arrays showed increased expression of p18Ink4c in 68% of cervical cancer, 8.3% of chronic cervical inflammation and 4.8% of normal cervix. Although p18Ink4c inhibits cell proliferation in general and regulates E2F1 expression in HCT116 cells, it appears not to function as a tumor suppressor in cervical cancer cells lacking an intact G1 checkpoint because of viral E7 degradation of pRB. In summary, our study demonstrates an intimate connection among oncogenic HPV E6, p53, miR\u201034a and p18Ink4c and identifies p18Ink4c as a possible biomarker for cervical cancer.<\/jats:p>","DOI":"10.1002\/ijc.25800","type":"journal-article","created":{"date-parts":[[2010,12,2]],"date-time":"2010-12-02T14:51:25Z","timestamp":1291301485000},"page":"1362-1372","source":"Crossref","is-referenced-by-count":71,"title":["Upregulation of p18Ink4c expression by oncogenic HPV E6 <i>via<\/i> p53\u2010miR\u201034a 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