Investigators at the Dana-Farber Cancer Institute (Boston, MA, USA) centered their study on the protein HNF4alpha (hepatocyte nuclear factor 4alpha), which is essential for liver development and hepatocyte function. They examined the activity of this protein in a mouse model in which some animals were exposed to a carcinogenic chemical that causes liver cancer.
The investigators reported in the December 9, 2011, issue of the journal Cell that disruption of HNF4alpha enabled the activation of a molecular pathway comprising micro RNAs (miRNAs), interleukins, and signaling proteins. The specific molecules involved were miR-124, IL6R, STAT3, miR-24, and miR-629. Once established, this pathway became a self-sustaining inflammatory feedback loop that maintained suppression of HNF4alpha and encouraged oncogenesis.
To break the feedback loop the investigators systematically treated the animals with miR-124. This microRNA modulated inflammatory signaling with the result that is prevented, and suppressed hepatocellular carcinogenesis by inducing tumor-specific apoptosis. Treatment with miR-124 caused no toxic effects in other essential organs, such as the kidneys, spleen, heart, and lungs.
“In this study we are describing for the first time a micro-RNA that is able to prevent and treat liver cancer,” said senior author Dr. Dimitrios Iliopoulos, professor of cancer immunology at the Dana-Farber Cancer Institute. “When HNF4alpha is suppressed, it creates a temporary state of inflammation in the cell – a forerunner of cancer. After only a few days, this transient inflammatory response is converted into a chronic inflammatory response by this feedback circuit that is continuously amplified.”
“We found that miR-124 suppressed more than 80% of tumor growth and size by causing the cancer cells to self-destruct,” said Dr. Iliopoulos. “Our hope is that miR-124 potentially could be used as a preventive in patients at high risk of liver cancer because they have chronic hepatitis C or as a therapeutic agent in patients with liver cancer.”
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Dana-Farber Cancer Institute
