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Discovery in liver cancer cells provides new target for drugs

23.03.2011
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, M.B.B.S., Ph.D., 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 cancer.

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, M.Ph., Ph.D., 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.

In addition to Fisher, other collaborators on this study included Lewis K. Pannell, Ph.D., professor of oncologic sciences in the Mitchell Cancer Institute of the University of South Alabama; Luni Emdad, M.B.B.S., Ph.D., assistant professor from Mount Sinai Medical Center; and Byoung Kwon Yoo, Ph.D., Prasanna K. Santhekadur, Ph.D., Rachel Gredler, B.S., Dong Chen, M.D., and Sujit Bhutia, Ph.D., all from the VCU School of Medicine.

Funding for this study was provided by grants from the National Institutes of Health, the James S. McDonnell Foundation and the Dana Foundation.

The full manuscript is available online at: http://onlinelibrary.wiley.com/doi/10.1002/hep.24216/abstract.

About VCU Massey Cancer Center

VCU Massey Cancer Center is one of only 66 National Cancer Institute-designated institutions in the country that leads and shapes America's cancer research efforts. Working with all kinds of cancers, the Center conducts basic, translational and clinical cancer research, provides state-of-the-art treatments and clinical trials, and promotes cancer prevention and education. Since 1974, Massey has served as an internationally recognized center of excellence. It has one of the largest offerings of clinical trials in Virginia and serves patients in Richmond and in four satellite locations. Its 1,000 researchers, clinicians and staff members are dedicated to improving the quality of human life by developing and delivering effective means to prevent, control and ultimately to cure cancer. Visit Massey online at www.massey.vcu.edu or call 877-4-MASSEY for more information.

About VCU and the VCU Medical Center

Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located on two downtown campuses in Richmond, VCU enrolls more than 32,000 students in 211 certificate and degree programs in the arts, sciences and humanities. Sixty-nine of the programs are unique in Virginia, many of them crossing the disciplines of VCU's 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation's leading academic medical centers. For more, see www.vcu.edu.

John Wallace | EurekAlert!
Further information:
http://www.vcu.edu

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