Enzyme Complex Will Be Targeted by Liver Cancer Drugs

An enzyme complex that promotes growth and spread of a form of liver cancer called hepatocellular carcinoma (HCC) may prove to be a drug target for treatment of this disease, which at this time is virtually untreatable.

Investigators at Virginia Commonwealth University (Richmond, USA) have been working for several years to unravel and understand the blend of enzymes that comprise the RNA-Induced Silencing Complex, (RISC), an amalgam of proteins that also incorporates one strand of a small interfering RNA (siRNA) or micro RNA (miRNA). RISC uses the siRNA or miRNA as a template for recognizing complementary mRNA. When it finds a complementary strand, it activates the enzyme RNase and cleaves the RNA, resulting in substantially decreased levels of protein translation and effectively turning off the gene. This process is important both in gene regulation by microRNAs and in defense against viral infections, which often use double-stranded RNA as an infectious vector.

In the current study, the investigators identified the proteins AEG-1 (astrocyte elevated gene-1) and SND1 (staphylococcal nuclease domain containing 1) as components that increase RISC activity and lead to the development of HCC. They reported in the February 10, 2011, online edition of the journal Hepatology that SND1 was overexpressed in about 74% of 109 human HCC samples as compared to normal liver cells. Higher RISC activity was observed in human HCC cells compared to cultures of immortal normal hepatocytes. Increased RISC activity, conferred by AEG-1 or SND1, resulted in increased degradation of tumor suppressor mRNAs, while inhibition of enzymatic activity of SND1 significantly slowed proliferation of human HCC cells.

"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,” said senior author Dr. Devanand Sarkar, assistant professor of human and molecular genetics. "Since we have shown that RISC activity is higher in cancer cells than normal, healthy cells, we are hopeful that inhibiting SND1 to decrease RISC activity will do little, if any, damage to healthy liver cells while stopping cancer progression.”

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