Function of miRNAs in murine liver carcinogenesis

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Its progression is a multistage process that typically arises in the context of liver fibrosis. Liver fibrosis is a consequence of an exaggerated wound healing response to reoc- curring or chronic liver injury, characterized by excessive accumulation of ECM. This process ultimately results in scarring and thickening of affected tissue, which inter- feres with normal liver function and facilitates HCC tumorigenesis. Although, liver fibrosis and HCC pose a major threat to human health, regulatory networks governing the events leading to their development are insufficiently understood. Accumulating data support a regulatory role of microRNAs (miRNAs) in control of gene expression programs that underline different normal and pathologic processes, including cancer. In this study, the SRF-VP16iHep HCC model was used as starting point to investigate the role of miRNAs in regulation of HCC and associated microenvironment develop- ment. The resulting analysis identified a miRNA network composed of 8 miRNA hubs and 54 target genes. Collectively, let-7 and miR-30 families, miR-29c, miR-335 and miR-338 (termed anti-fibrotic microRNAs, AF-miRNAs) downregulate key structural, signaling and remodeling components of the extracellular matrix. During fibrogenic transition, these miRNAs are transcriptionally regulated by the transcription factors Pparg and Egr1. Thus, this study identified a new role of Pparg and Egr1 as regulator of a functionally related class of AF-miRNAs. The miRNA network is active in human HCC, breast and lung carcinomas, as well as in two independent mouse fibrosis mod- els. Therefore, identified miRNA:mRNA network regulates fibrosis of tumorous and non-tumorous organs, the liver in particular, in mice and humans.