Chronic inflammation contributes to the development of hepatocellular carcinoma by decreasing miR-122 levels

// Changfei Li 1 , Mengmeng Deng 1 , Jun Hu 1 , Xin Li 1 , Lizhao Chen 1 , Ying Ju 1 , Junli Hao 2 , Songdong Meng 1 1 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China 2 School of Biomedical Sciences, Chengdu Medical college, Chengdu, China Correspondence to: Songdong Meng, e-mail: mengsd@im.ac.cn Junli Hao, e-mail: haojunli00@163.com Keywords: C/EBPα, miR-122, IL-6, c-myc, TNF-α Received: October 19, 2015 Accepted: February 05, 2016 Published: February 26, 2016 ABSTRACT Persistent inflammation in chronic hepatitis plays a major role in the development of hepatocellular carcinoma (HCC). In this study, the major inflammatory cytokines expressed in chronic hepatitis, IL-6 and TNF-α, induced a marked decrease in microRNA-122 (miR-122) levels, and miR-122 expression was downregulated in the livers of chronic hepatitis B (CHB) patients. The decrease of miR-122 caused upregulation of the proinflammatory chemokine CCL2. IL-6 and TNF-α suppressed miR-122 both by directly downregulating the transcription factor C/EBPα and indirectly upregulating c-myc, which blocks C/EBPα-mediated miR-122 transcription. In addition, IL-6 and TNF-α levels were elevated and miR-122 levels were decreased in mouse and rat models of diethylnitrosamine (DEN)-induced HCC. Restoration of miR-122 levels through delivery of agomir-122 suppressed DEN-induced hepatocarcinogenesis in mice. Our results show that inflammation-induced miR-122 downregulation in hepatitis contributes to carcinogenesis and suggest that increasing miR-122 may be an effective strategy for preventing HCC development in CHB patients.