miR-125b regulates the Lin-28/IGF-II axis during hepatocellular carcinogenesis

Background: MicroRNA (miRNA), involved in posttranscriptional regulation of gene expression, play an important role in cell proliferation and differentiation. Previous data have shown that miR-125b expression was shown to be involved in liver carcinogenesis. Here, we focused on the role of miR-125b in development of hepatocellular carcinoma (HCC).

Methodology: A Cre-expressing adenoviral vector was applied to Alb-SV40 T-Ag transgenic mice in order to induce liver carcinogenesis. Expression levels of miR-125b were determined at different time points of murine tumorogenesis and in human hepatoma cell lines. Putative miR-125b binding sites were fused to the luciferase reporter and reporter assays were carried out with miR-125b treated hepatoma cells.

Principal Findings: During development of mouse HCC, the expression of miR-125b progressively decreased. In agreement miR-125b was reduced in human hepatoma cells in comparison to normal liver. Overexpression of miR-125b in Hep3B and Pop10 cells resulted in a pronounced reduction of cell growth. Screening of putative miR-125b target transcripts by various algorithm calculations identified various pathways involved in proliferation and apoptosis. Reporter assays of 3'-UTR-regions of the putative targets identified miR-125b binding sites in lin-28 mRNA. Since lin28 is known to effect synthesis of the mitogen IGF-II, the miR-125b/lin28 axis is suggested to be involved in HCC pathogenesis by IGF-II mediated regulation of cell growth.

Conclusions: Expression of miR-125b is down-regulated during progression of hepatocarcinogenesis leading to up-regulation of lin-28 that in turn triggers enhanced cell growth and proliferation.