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 NCIís 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.
For more information on Dr. Zhengís research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5572.
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through research into prevention and cancer biology, the development of new interventions,
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Reference: Wang X, Wang HK, McCoy JP, Banerjee NS, Rader JS, Broker TR, Meyers
C, Chow LT, and Zheng ZM. Oncogenic HPV infection interrupts the expression of
tumor-suppressive miR-34a through viral oncoprotein E6. RNA. Online March 3,