Zhang Deyu, Liu Jiahong, Xie Tian, Jiang Qiwei, Ding Lihua, Zhu Jianhua, Ye Qinong
Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, China.
Department of Oncology, The Fourth Medical Center, PLA General Hospital, Beijing 100048, China.
Int J Biol Sci. 2020 Aug 27;16(15):2812-2827. doi: 10.7150/ijbs.49785. eCollection 2020.
Non-alcoholic steatohepatitis (NASH) is a type of nonalcoholic fatty liver disease and has become a major risk factor for hepatocellular carcinoma (HCC). However, the underlying pathophysiological mechanisms are still elusive. Here, we identify hyaluronan-mediated motility receptor (HMMR) as a critical gene associated with NASH/HCC by combination of bioinformatic analysis and functional experiments. Analysis of differentially expressed genes (DEGs) between normal controls and NASH/HCC identified 5 hub genes (HMMR, UBE2T, TYMS, PTTG1 and GINS2). Based on the common DEGs, analyses of univariate and multivariate Cox regression and the area under the curve (AUC) value of the receiver operating characteristic (ROC) indicate that HMMR is the most significant gene associated with NASH/HCC among five hub genes. Oleate acid (OA), one of fatty acids that induce cellular adipogenesis, stimulates HMMR expression via CCAAT/enhancer-binding protein α (CEBPα). CEBPα increases the expression of HMMR through binding to its promoter. HMMR promotes HCC cell proliferation via activation of G1/S and G2/M checkpoint transitions, concomitant with a marked increase of the positive cell cycle regulators, including cyclin D1, cyclin E, and cyclin B1. Knockdown of HMMR suppresses HCC tumor growth in nude mice. Our study identifies an important role of HMMR in NASH/HCC, and suggests that HMMR may be a useful target for therapy and prognostic prediction of NASH/HCC patients.
非酒精性脂肪性肝炎（NASH）是一种非酒精性脂肪肝病，已成为肝细胞癌（HCC）的主要危险因素。然而，其潜在的病理生理机制仍不清楚。在此，我们通过生物信息学分析和功能实验相结合的方法，确定透明质酸介导的运动受体（HMMR）是与NASH/HCC相关的关键基因。对正常对照与NASH/HCC之间的差异表达基因（DEG）分析确定了5个枢纽基因（HMMR、UBE2T、TYMS、PTTG1和GINS2）。基于共同的DEG，单变量和多变量Cox回归分析以及受试者工作特征（ROC）曲线下面积（AUC）值表明，HMMR是五个枢纽基因中与NASH/HCC相关最显著的基因。油酸（OA）是诱导细胞脂肪生成的脂肪酸之一，通过CCAAT/增强子结合蛋白α（CEBPα）刺激HMMR表达。CEBPα通过与其启动子结合增加HMMR的表达。HMMR通过激活G1/S和G2/M检查点转换促进HCC细胞增殖，同时包括细胞周期蛋白D1、细胞周期蛋白E和细胞周期蛋白B1在内的阳性细胞周期调节因子显著增加。敲低HMMR可抑制裸鼠体内HCC肿瘤生长。我们的研究确定了HMMR在NASH/HCC中的重要作用，并表明HMMR可能是NASH/HCC患者治疗和预后预测的有用靶点。
