July 25, 2012

Possible Liver Cancer Cause

By: Erika Dunayer, Ivanhoe Health Correspondent

(Ivanhoe Newswire) -- Liver cancer is the third leading cancer killer worldwide. Now, researchers are working to crack the code to see what is causing it.

Studies show that loss of a small RNA molecule in liver cells might cause liver cancer and that restoring the molecule might slow tumor growth and offer a new way to treat the disease.

"In previous studies the microRNA-122 was very high in a normal liver but in a tumor it went down tremendously, that is what prompted our research," Dr. Kalpana Ghoshal, associate professor of pathology and a member of the OSUCCC — James Experimental Therapeutics Program, told Ivanhoe.

The scientists examined what happens when liver cells lack a molecule called microRNA-122 (miR-122). They found that when the molecule is missing, the liver develops fat deposits, inflammation and tumors that resemble hepatocellular carcinoma (HCC), the most common form of liver cancer.

When the researchers artificially restored miR-122 to nearly normal levels by delivering the miR-122 gene into liver cells, it dramatically reduced the size and number of tumors, with tumors making up 8 percent on average of liver surface area in treated animals versus 40 percent in control animals.

"I decided to generate mice because we wanted to study the biological role of microRNA in-vivo. We disrupted the genes in mice stem cells and generated conditional knockout mice, meaning that you can delete the cell type in any condition," Dr. Goshal said.

MiR-122 is found mainly in liver cells — it is the most abundant microRNA in those cells — and it plays a major role in regulating cholesterol in the body.

For this study, Ghoshal and her colleagues developed a strain of mice that lacks miR-122 and develops HCC through the progression of events that begins with fatty liver deposits followed by inflammation and liver cancer.

The researchers then used a second strain of mice that spontaneously develops liver cancer due to overexpression of a cancer-causing gene called MYC (pronounced "mick"). The researchers delivered miR-122 into the animals' livers during tumor development. Three weeks later, those treated with the molecule had smaller and fewer tumors.

"This means that miR-122 is a very important micron in the liver and that its loss of function, or if it reaches low levels even in humans it may compromise liver function. Liver cancer is the end stage of this disease but in early stages we saw a mild level of hepatitis and also fatty liver which can ultimately lead to liver cancer," Dr. Goshal said.

"Our studies show that the reason that humans are developing liver cancer is because mir-122 is down. We have to maintain mir-122 at some optimal level to have a healthy liver," Dr. Goshal continued.

"To see that these mice progressively developed liver disease and ultimately liver cancer was kind of unexpected because the micron is very tiny. It is hard to believe that such a tiny molecule could have such a profound effect on the liver biology. It was very fascinating to me," Dr. Goshal concluded.

Source: Interview with Dr. Kalpana Ghoshal, associate professor of pathology and a member of the OSUCCC — James Experimental Therapeutics Program, July 23, 2012.