December 10, 2011
Researchers Identify A Novel Therapeutic Approach For Liver Cancer
Scientists use a micro-RNA tool to block a cancer-causing molecular circuit in liver cells
Cancer of the liver — rare in the United States but the third-leading cause of cancer death worldwide — can result from environmental exposures or infections like chronic hepatitis, but the link is poorly understood.
Now, researchers at Dana-Farber Cancer Institute have identified a mechanism in mice that triggers inflammation in the liver and transforms normal cells into cancerous ones. In addition, they demonstrated in a mouse model that a particular micro-RNA (miR-124) - a member of a recently discovered class of molecular regulators — could be harnessed to treat or even prevent liver cancer.
"In this study we are describing for the first time a micro-RNA that is able to prevent and treat liver cancer," said Dimitrios Iliopoulos, of Dana-Farber's Department of Cancer Immunology and AIDS. The findings are being published today in the journal Cell.
The authors said they plan to start a phase I clinical trial using miR-124 in liver cancer patients in 2012.
Iliopoulos and his colleagues found that in mice given a carcinogenic chemical, DEN, liver cancer is initiated by the activation of a molecular circuit that sets up an inflammatory state in the cells, leading to cancer. Once this inflammatory circuit is turned on even for a few days, it becomes permanent, sustaining its activity through a never-ending feedback loop — a "snowball effect," as Iliopoulos termed it.
Iliopoulos previously identified a similar feedback circuit implicated in the development of breast cancer.
One element of the circuit is a micro-RNA called miR-124, the Dana-Farber team reported.
Micro-RNAs are extremely short lengths of RNA — a messenger molecule that helps the cell build proteins according to DNA instructions - which are not translated into proteins. MiRNAs have been recently implicated in the pathogenesis of human diseases including different types of cancer. The Dana-Farber team found that miR-124 and another key controller of the feedback circuit, HNF4Î±, showed reduced activity in the cancer cells.
HFN4Î± is an essential factor in formation of liver cells and their proper function. When HNF4Î± is suppressed, said Iliopoulos, 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," he said.
Because HNF4Î± and miR-124 interact with each other, the scientists hypothesized that boosting activity of miR-124 might restore normal activity in HNF4Î±, halting the runaway inflammatory cycle and causing tumors to stop growing.
To test this notion they administered systemically miR-124 once a week for four weeks to mice that had developed liver cancer by exposure to DEN. "We found that miR-124 suppressed more than 80 per cent of tumor growth and size" by causing the cancer cells to self-destruct, the scientists wrote. They observed no toxic effects in other essential organs, such as the kidneys, spleen, heart and lungs.
Further, they showed that giving miR-124 to mice exposed to DEN actually prevented the development of liver tumors.
"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" said Iliopoulos.
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