2013/07/08

MicroRNAs regulate methionine adenosyltransferase 1A expression in hepatocellular carcinoma: basis for a novel therapeutic approach.

MAT1A is the main gene involved in the hepatic synthesis of S-adenosylmethionine (SAMe), the principal biological methyl donor and a precursor of polyamines and glutathione synthesis. We have previously shown that the disruption of MAT1A in mice induces a reduction in hepatic SAMe content, the spontaneous development of nonalcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC) (Mato & Lu. Phys Rev 2012; 92:1515-42). We have also shown that MAT1A expression is dysregulated in human cirrhotics, which are at risk to develop liver cancer, and in HCC (Avila et al. J Hepatol 2000; 33:907-14); and that SAMe treatment increases survival in patients with alcoholic liver cirrhosis (Mato et al. J Hepatol 1999; 30:1081-9). The molecular mechanisms leading to MAT1A down regulation during the development of cirrhosis and carcinogenesis are however not completely understood. Now, in a new study published in the Journal of Clinical Investigation, José Mato in collaboration with the group of Shelly Lu, from the Keck School of Medicine of the University of Southern California, have identified three microRNAs (miR-664, miR-485-3p, and miR-495) that negatively regulate MAT1A expression during HCC development. The expression of this miRNAs trio is increased in HCC. Individual silencing of each of these three miRNAs in liver cancer cells (Hep3B and HepG2) induces the expression of MAT1A, reduces cell proliferation and produces apoptosis, whereas the combined reduction of these miRNAs increased the effect on all these parameters. The injection of Hep3B cells over expressing each of these three miRNAs induces tumorigenesis and metastasis, and the down regulation of this trio of miRNAs with siRNAs prevents these effects. In summary, this work 1) explains the mechanism by which MAT1A is silenced and SAMe content decreases during carcinogenesis, 2) demonstrates that MAT1A is a therapeutic target, and 3) identifies the basis for a new therapeutic approach.

See free full-text http://www.ncbi.nlm.nih.gov/pubmed/23241961

and comment http://www.ncbi.nlm.nih.gov/pubmed/23468134

Figure legend. Effect of varying miR-664, miR-485-3p, and miR-495 expression on tumorigenesis in an orthotopic liver cancer model. HepG2 cells were injected into the left hepatic lobe, and lentiviral vectors containing miRNA siRNA or scramble siRNA (SC) were injected into the spleen at the time of HepG2 cell injection. Two weeks later, lentiviral siRNA was injected into the tail vein, and this was repeated every 2 weeks until sacrifice at 8 weeks. Arrows point to tumor at the site of injection, and tumor volumes are shown below each image.