Medical College of Wisconsin
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Oncogenic HPV infection interrupts the expression of tumor-suppressive miR-34a through viral oncoprotein E6. RNA 2009 Apr;15(4):637-47

Date

03/05/2009

Pubmed ID

19258450

Pubmed Central ID

PMC2661824

DOI

10.1261/rna.1442309

Scopus ID

2-s2.0-62549156668 (requires institutional sign-in at Scopus site)   202 Citations

Abstract

MicroRNAs (miRNA) play pivotal roles in controlling cell proliferation and differentiation. Aberrant miRNA expression in human is becoming recognized as a new molecular mechanism of carcinogenesis. However, the causes for alterations in miRNA expression remain largely unknown. Infection with oncogenic human papillomavirus types 16 (HPV16) and 18 (HPV18) can lead to cervical and other ano-genital cancers. Here, we have demonstrated that cervical cancer tissues and cervical cancer-derived cell lines containing oncogenic HPVs display reduced expression of tumor-suppressive miR-34a. The reduction of miR-34a expression in organotypic tissues derived from HPV-containing primary human keratinocytes correlates with the early productive phase and is attributed to the expression of viral E6, which destabilizes the tumor suppressor p53, a known miR-34a transactivator. Knockdown of viral E6 expression in HPV16(+) and HPV18(+) cervical cancer cell lines by siRNAs leads to an increased expression of p53 and miR-34a and accumulation of miR-34a in G(0)/G(1) phase cells. Ectopic expression of miR-34a in HPV18(+) HeLa cells and HPV(-) HCT116 cells results in a substantial induction of cell growth retardation and a moderate cell apoptosis. Together, this is the first time a viral oncoprotein has been shown to regulate cellular miRNA expression. Our data have provided new insights into mechanisms by which high-risk HPVs contribute to the development of cervical cancer.

Author List

Wang X, Wang HK, McCoy JP, Banerjee NS, Rader JS, Broker TR, Meyers C, Chow LT, Zheng ZM

Author

Janet Sue Rader MD Chair, Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adult
Cell Line, Tumor
DNA-Binding Proteins
Female
Gene Knockdown Techniques
Human papillomavirus 16
Human papillomavirus 18
Humans
MicroRNAs
Middle Aged
Oncogene Proteins, Viral
Papillomavirus Infections
Repressor Proteins