Molecule Provides Clues about How Infection with Human Papillomavirus May Lead to Cancer

New research shows for the first time that certain types of human papillomavirus (HPV), which cause cervical and some other types of cancer, can inhibit the production of a tiny single-stranded RNA called microRNA 34a, or miR-34a. Because previous research had demonstrated that microRNAs regulate important functions of the cell, the new finding provides insight into the mechanisms by which HPV contributes to the development of cancer and may lead to the development of treatments to counter HPV infection. Currently, such treatments do not exist. The study, appearing online March 3, 2009, and in the April print edition of the journal RNA, was led by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health.

Besides causing cervical cancer, HPV is a major cause of penile, anal, and vaginal cancers. HPV inhibits natural tumor suppression by inactivating a cellular tumor suppressor protein called p53. The p53 protein regulates the expression of other genes that control the cell cycle, activates the repair of damaged DNA in cells, and, in cases of severe damage, initiates cell death. This protein also stimulates the expression of a group of microRNAs, including miR-34a.

MicroRNAs are short strands of RNA that regulate protein expression by binding to specific messenger RNA molecules and inhibiting them from their normal function, which is to direct the production of proteins. Dysregulation and abnormal expression of microRNA genes are common occurrences in many human cancers, but little is known about the role that microRNAs play in cancer development or the causes leading to their abnormal expression.

The research team, led by Zhi-Ming Zheng, M.D., Ph.D., at NCI’s Center for Cancer Research, first compared microRNA levels in cervical cancer cells and normal cervical cells and found that levels of miR-34a were much lower in the cancer cells than the normal cells.

During the early stages of HPV infection, the virus produces a protein known as E6. To gain an understanding of the mechanism by which E6 protein inhibits the expression of miR-34a during HPV infection, the researchers used a method known as RNA interference, which makes it possible to turn specific genes off and to observe the subsequent effects on cell activity. The team found that interfering with the expression of E6 in HPV-infected cervical cancer cells grown in the laboratory led to increased expression of both p53 protein and miR-34a. Most miR-34a accumulated during the early stages of cell division. The researchers also observed that induced expression of miR-34a suppressed cell growth and promoted cell death, which suggests that this microRNA also plays a role in tumor suppression.

"This study is the first compelling evidence to show tumor viruses are involved in the regulation of microRNA expression," said Zheng. "Our data imply that, in addition to HPV, other tumor viruses may also contribute to the abnormal expression of cellular microRNAs in virus-associated cancers."

The Zheng team is working to identify miR-34a targets in HPV-infected cells in order to understand the mechanism by which decreased expression of a microRNA favors tumor formation. In addition, they are studying several other microRNAs that are normally involved in cell growth regulation, yet increase their expression levels during HPV infection.

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