Upregulation of p18Ink4c expression by oncogenic HPV E6 via p53-miR-34a pathway

Xiaohong Wang, Craig Meyers, Ming Guo, Zhi Ming Zheng

Research output: Contribution to journalArticle

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Abstract

Binding of p53 to miR-34a promoter activates the expression of tumor-suppressive miR-34a. Oncogenic human papillomavirus (HPV) infection downregulates miR-34a expression through viral E6 degradation of p53. In our report, we found that miR-34a specifically targets p18Ink4c, a CDK4 and CDK6 inhibitor induced by E2F transactivation. HPV18+ HeLa cells with ectopic miR-34a expression or by E6 siRNA knockdown-induced expression of endogenous miR-34a exhibited a substantial reduction of p18Ink4c in a dose-dependent manner, but had no effect on p16Ink4a, another member of CDK4/6 inhibitor family. In contrast, de novo infection by oncogenic HPVs of human keratinocyte-derived raft tissues increased p18Ink4c expression. Suppression of endogenous miR-34a in cell lines with a miR-34a inhibitor also increased p18Ink4c. We found that miR-34a suppresses the expression of p18Ink4c by binding to a specific seed match in the 5′ 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-34a and p18Ink4c and identifies p18Ink4c as a possible biomarker for cervical cancer.

Original languageEnglish (US)
Pages (from-to)1362-1372
Number of pages11
JournalInternational Journal of Cancer
Volume129
Issue number6
DOIs
StatePublished - Sep 15 2011

Fingerprint

Uterine Cervical Neoplasms
Up-Regulation
HCT116 Cells
Papillomavirus Infections
5' Untranslated Regions
Keratinocytes
HeLa Cells
Cervix Uteri
Small Interfering RNA
Transcriptional Activation
Neoplasms
Seeds
Down-Regulation
Biomarkers
Cell Proliferation
Staining and Labeling
Inflammation
Cell Line
Infection

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Wang, Xiaohong ; Meyers, Craig ; Guo, Ming ; Zheng, Zhi Ming. / Upregulation of p18Ink4c expression by oncogenic HPV E6 via p53-miR-34a pathway. In: International Journal of Cancer. 2011 ; Vol. 129, No. 6. pp. 1362-1372.
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abstract = "Binding of p53 to miR-34a promoter activates the expression of tumor-suppressive miR-34a. Oncogenic human papillomavirus (HPV) infection downregulates miR-34a expression through viral E6 degradation of p53. In our report, we found that miR-34a specifically targets p18Ink4c, a CDK4 and CDK6 inhibitor induced by E2F transactivation. HPV18+ HeLa cells with ectopic miR-34a expression or by E6 siRNA knockdown-induced expression of endogenous miR-34a exhibited a substantial reduction of p18Ink4c in a dose-dependent manner, but had no effect on p16Ink4a, another member of CDK4/6 inhibitor family. In contrast, de novo infection by oncogenic HPVs of human keratinocyte-derived raft tissues increased p18Ink4c expression. Suppression of endogenous miR-34a in cell lines with a miR-34a inhibitor also increased p18Ink4c. We found that miR-34a suppresses the expression of p18Ink4c by binding to a specific seed match in the 5′ 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-34a and p18Ink4c and identifies p18Ink4c as a possible biomarker for cervical cancer.",
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Upregulation of p18Ink4c expression by oncogenic HPV E6 via p53-miR-34a pathway. / Wang, Xiaohong; Meyers, Craig; Guo, Ming; Zheng, Zhi Ming.

In: International Journal of Cancer, Vol. 129, No. 6, 15.09.2011, p. 1362-1372.

Research output: Contribution to journalArticle

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