in Liver Cancer Cells Provides New Target for Drugs
Va. -- March 23, 2011 -- Researchers at Virginia Commonwealth
University Massey Cancer Center and VCU Institute of Molecular
Medicine (VIMM) have discovered a novel mechanism in gene regulation
that contributes to the development of a form of liver cancer
called hepatocellular carcinoma (HCC). Currently, there is virtually
no effective treatment for HCC, and this breakthrough identifies
a promising new target for therapeutic intervention.
In the journal Hepatology, Devanand Sarkar, MBBS, PhD,
Harrison Endowed Scholar in Cancer Research at VCU Massey Cancer
Center, a Blick scholar and assistant professor in the Department
of Human and Molecular Genetics and a member of the VIMM at
VCU School of Medicine, describes for the first time how RNA-induced
silencing complex (RISC) contributes to the development of liver
RISC is an important factor in post-transcriptional gene regulation,
which occurs between transcription (where DNA is converted to
RNA) and translation (where RNA is converted to protein). These
processes regulate functions such as cellular growth, division
and death. Sarkar and his team identified the proteins AEG-1
and SND1 as factors that increase RISC activity and lead to
the development of liver cancer.
For years, Sarkar has been studying the role of AEG-1 in cancer
with his collaborator on this research, Paul B. Fisher, MPh,
PhD, Thelma Newmeyer Corman Endowed Chair in Cancer Research
at VCU Massey, professor and chair of the Department of Human
and Molecular Genetics and director of the VIMM.
"AEG-1 works as a scaffold protein," says Sarkar.
"If you think about scaffolding outside of a biological
setting, its function is to help facilitate things like construction.
In this case, AEG-1 was found to work with another protein,
SND1, to provide the scaffold for the formation of RISC. Since
both AEG-1 and SND1 are increased in HCC, the net effect is
increased RISC activity."
The study clearly identifies SND1 as a novel regulator of liver
cancer. As SND1 is a molecule that can be inhibited by drugs,
Sarkar's findings open up a novel avenue for treating liver
cancer by targeting SND1.
"RISC works by degrading tumor-suppressor mRNAs, which
transmit genetic information in a cell that prevents the formation
of tumors. This allows other cancer-causing factors to go unchecked
and aid tumor growth," says Sarkar. "Since we've shown
that RISC activity is higher in cancer cells than normal, healthy
cells, we're hopeful that inhibiting SND1 to decrease RISC activity
will do little, if any, damage to healthy liver cells while
stopping cancer progression."
Sarkar's team is working hard to find the most clinically-relevant
SND1 inhibitors. Once these are found, the researchers will
need to prove their effectiveness in several more experiments.
The ultimate goal is to move these findings to Phase I clinical
trials for patients with liver cancer.
Investigator affiliations: Department of Human and Molecular
Genetics, Department of Pathology, VCU Institute of Molecular
Medicine, and Massey Cancer Center, Virginia Commonwealth University
School of Medicine, Richmond, VA; Department of Neurosurgery,
Mount Sinai Medical Center, New York, NY; University of South
Alabama, Mitchell Cancer Institute, Mobile, AL.
Funding for this study was provided by grants from the National
Institutes of Health, the James S. McDonnell Foundation and
the Dana Foundation.