MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis

Abstract

MicroRNA-122 (miR-122), which accounts for 70% of the liver's total miRNAs, plays a pivotal role in the liver. However, its intrinsic physiological roles remain largely undetermined. We demonstrated that mice lacking the gene encoding miR-122a (Mir122a) are viable but develop temporally controlled steatohepatitis, fibrosis, and hepatocellular carcinoma (HCC). These mice exhibited a striking disparity in HCC incidence based on sex, with a male-to-female ratio of 3.9:1, which recapitulates the disease incidence in humans. Impaired expression of microsomal triglyceride transfer protein (MTTP) contributed to steatosis, which was reversed by in vivo restoration of Mttp expression. We found that hepatic fibrosis onset can be partially attributed to the action of a miR-122a target, the Klf6 transcript. In addition, Mir122a -/-livers exhibited disruptions in a range of pathways, many of which closely resemble the disruptions found in human HCC. Importantly, the reexpression of miR-122a reduced disease manifestation and tumor incidence in Mir122a -/-mice. This study demonstrates that mice with a targeted deletion of the Mir122a gene possess several key phenotypes of human liver diseases, which provides a rationale for the development of a unique therapy for the treatment of chronic liver disease and HCC.

MicroRNA-122 Promotes Proliferation, Invasion and Migration of Renal Cell Carcinoma Cells Through the PI3K/Akt Signaling Pathway

“…Recent studies found that miR-122 is frequently suppressed in hepatocellular carcinomas (Bai et al, 2009;Tsai et al, 2012) and breast cancer specimens (Wang et al, 2012). Overexpression of miR-122 could suppress proliferation and induce apoptosis and cell cycle arrest in cancer cells through reducing the expression of Bcl-W, CCNG1 (Ma et al, 2010), IGF1R/PI3K/Akt (Wang et al, 2012) and Wnt/beta-catenin signal pathways (Xu et al, 2012).…”

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma

“…Li et al (2013), Fan et al (2011) showed that low miR-122 levels stimulated HBV replication and overexpression of viral antigen with subsequent cellular damage, overgrowth and hepatocellular fibrosis. Indeed, low levels of miR-122 stimulated Klf6, a fibrosis activator (Tsai et al, 2012). Circulating levels of miR-122 are elevated with good diagnostic performance.…”

MicroRNAs in Liver Disease: Bench to Bedside

“…40,44,45 Serum/plasma levels of miR-122 correlate with hepatic necro-inflammation, liver damage, cell death and increased aminotransferase levels in acute and chronic liver diseases. 44,[46][47][48][49] Interestingly, hepatic and circulating miR-122 levels do not correlate in NAFLD 14,39,[50][51][52][53][54][55] or viral hepatitis 41,47,49,56 although both have been statistically associated with various measures of disease severity in these studies. Together these studies show that miR-122 may play a role in most liver diseases.…”

“…12,14 The targeted deletion of miR-122a in mice results in NASH, fibrosis and HCC. 54 In miR profile analysis of high fat fed rat liver, 14 miRs were up-regulated and six were down-regulated, that might represent a distinctive molecular signature in the transition of steatosis to steatohepatitis. 53 MiR-34a and miR146b were shown to be significantly over-expressed (99% and 80%, respectively) in human NASH.…”