The absence of a tiny, abundant liver-specific microRNA (miRNA) molecule may lead to liver cancer, say researchers who tested the idea in mice and write about their findings in a paper published online this week in the Journal of Clinical Investigation. They suggest their findings show it may be possible to develop a treatment that restores the molecule, miR-122, in some patients with liver cancer, an often fatal disease for which there are few treatments.
Some genes do not produce proteins, instead they make hundreds of very small RNA molecules comprizing around two dozen nucleotides, called microRNAs or miRNAs for short. Each of these tiny molecules is thought to interact with hundreds of other genes, for instance swithching them on and off, in a complex pattern of genome regulation in humans, and other complex organisms.
An increasing body of evidence is starting to show absent or malfunctioning miRNAs are linked to a growing list of diseases like cancer, diabetes and even virus infections.
In this new animal study, a team led by researchers from the Ohio State University Comprehensive Cancer Center (USUCCC) in the US, investigated miR-122, an abundant liver-specific miRNA that regulates cholesterol metabolism and promotes hepatitis C virus (HCV) replication.
They already knew from previous research that reduced expression of miR-122 in hepatocellular carcinoma (HCC), the most common form of liver cancer, is linked to disease spread (metastasis) and poor survival.
But what had not yet been investigated, was what happened when there was a permanent absence of miR-122 in a live animal (in vivo)?
In their study, they found mice bred lacking the miR-122 gene developed fatty deposits in their livers, got hepatitis, and grew tumors that resembled HCC.
On further examination, they found these disease signs were accompanied by over-active cancer signalling pathways, and that the livers were full of inflammatory cells that produce tumor-generating molecules called cytokines, including two well-known to cancer researchers, IL-6 and TNF.
To test their theory further, the researchers used another group of mice that spontaneously develops liver cancer due to overexpression of a cancer-causing gene called MYC (pronounced “mick”). They delivered miR-122 artificially into some of the MYC-mice’s livers during tumor development, and found three weeks later, that those treated with the molecule had smaller and fewer tumors.
The tumors in the treated liver cancer mice only covered 8% of the liver surface, compared with 40% in liver cancer mice that were not treated with miR-122 (the controls).
Study leader Kalpana Ghoshal, is an associate professor of pathology at OSUCCC and a member of the Experimental Therapeutics Program run by OSUCCC – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James). She told the press:
“These findings reveal miR-122 has a critical tumor-suppressor role in the healthy liver, and they highlight the possible therapeutic value of miR-122 replacement for some patients with liver cancer.”
“Because our findings demonstrate what happens when miR-122 is lost in liver cells, they might help improve the safety of new drugs that treat hepatitis C virus infection by blocking miR-122,” she added.
Liver cancer is the third leading cancer killer in the world, and new treatments are urgently needed. It can be cured if caught early, but unfortunately most cases aren’t found until the disease is quite advanced.
In the US, estimates for 2012 suggest there will be more than 28,700 new cases of HCC, and the disease will kill 20,550 Americans.
Major risk factors for HCC include hepatitis B and C, and liver damage through alcohol use.
Funding for the study came from NIH/National Cancer Institute and NIH/ National Institute of Diabetes and Digestive and Kidney Diseases grants, a Pelotonia idea grant, a Pelotonia predoctoral fellowship. The Cancer Prevention and Research Institute of Texas also supported the research.
Written by Catharine Paddock PhD