Register for Molecule Provides Clues about How Infection with Human Papillomavirus May Lead to Cancer
Tuesday, March 3, 2009
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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.
For more information on Dr. Zheng’s research, please go to
http://ccr.cancer.gov/staff/staff.asp?profileid=5572
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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,
2009.
