Antitumor function of microRNA-122 against hepatocellular carcinoma

• Published in: Journal of gastroenterology Vol. 49; no. 4; pp. 589 - 593
• Main Authors: Nakao, Kazuhiko, Miyaaki, Hisamitsu, Ichikawa, Tatsuki
• Format: Journal Article
• Language: English
• Published: Tokyo Springer Japan 01.04.2014; Springer; Springer Nature B.V
• Subjects: Abdominal Surgery; Animals; Carcinoma, Hepatocellular - chemistry; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Cell Transformation, Neoplastic - genetics; Colorectal Surgery; DNA binding proteins; Down-Regulation; Epigenetic inheritance; Gastroenterology; Gene Expression; Gene Expression Regulation, Neoplastic; Genes; Hepatology; Hepatoma; Humans; Liver; Liver Neoplasms - chemistry; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Medicine; Medicine & Public Health; Mice; MicroRNA; MicroRNAs - analysis; MicroRNAs - genetics; MicroRNAs - therapeutic use; Prognosis; Protein binding; Review; Stem cells; Surgical Oncology; Steatohepatitis; Hepatocellular carcinoma (HCC); MicroRNA-122 (miR-122)
• ISSN: 0944-1174; 1435-5922
• DOI: 10.1007/s00535-014-0932-4

MicroRNA-122 (miR-122), a highly abundant and liver-specific miRNA, acts as a tumor suppressor against hepatocellular carcinoma (HCC). Decreased expression of miR-122 in HCC is frequently observed and is associated with poor differentiation, larger tumor size, metastasis and invasion, and poor prognosis. Mutant mice with knockout (KO) of the miR-122 locus developed steatohepatitis due to increased triglyceride (TG) synthesis and decreased TG secretion from hepatocytes, and eventually developed HCC. Exogenic miR-122 introduction into miR-122 KO mice inhibited the development of HCC. Target genes of miR-122, including cyclin G1, a disintegrin and metalloprotease (ADAM)10, serum response factor, insulin-like growth factor-1 receptor, ADAM17, transcription factor CUTL1, the embryonic isoform of pyruvate kinase (Pkm2), Wnt1, pituitary tumor-transforming gene 1 binding factor, Cut-like homeobox 1, and c-myc, are involved in hepatocarcinogenesis, epithelial mesenchymal transition, and angiogenesis. MiR-122 expression is regulated by liver-enriched transcription factors such as hepatocyte nuclear factor (HNF)1α, HNF3β, HNF4α, HNF6, and CCAAT/enhancer-binding protein (C/EBP)α. A positive feedback loop exists between C/EBPα and miR-122 and between HNF6 and miR-122, whereas a negative feedback loop exists between c-myc and miR-122. Since cotreatment of 5-Aza-Cd and histone deacetylase inhibitor restored miR-122 expression in HCC cells, epigenetic modulation of miR-122 expression is involved in the suppression of miR-122 in HCC. Several experiments suggest that increasing miR-122 levels in HCC with or without antitumor agents may be a promising strategy for HCC treatment.