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 in vitro 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.

中文翻译：

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CEBPα的油酸刺激HMMR表达与非酒精性脂肪性肝炎和肝细胞癌有关

非酒精性脂肪性肝炎（NASH）是一种非酒精性脂肪性肝病，已成为肝细胞癌（HCC）的主要危险因素。然而，潜在的病理生理机制仍然难以捉摸。在这里，我们通过生物信息学分析和功能实验相结合，将透明质酸介导的运动受体 (HMMR) 确定为与 NASH/HCC 相关的关键基因。对正常对照和 NASH/HCC 之间的差异表达基因 (DEG) 的分析确定了 5 个中枢基因（HMMR、UBE2T、TYMS、PTTG1 和 GINS2）。基于常见的 DEG，单变量和多变量 Cox 回归分析以及接受者操作特征 (ROC) 的曲线下面积 (AUC) 值表明 HMMR 是五个中心基因中与 NASH/HCC 相关的最重要的基因。油酸（OA），一种诱导细胞脂肪生成的脂肪酸，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来增加 HMMR 的表达。HMMR促进HCC细胞增殖在体外通过激活 G1/S 和 G2/M 检查点转换，伴随着细胞周期正调节因子的显着增加，包括细胞周期蛋白 D1、细胞周期蛋白 E 和细胞周期蛋白 B1。敲除 HMMR 可抑制裸鼠中 HCC 肿瘤的生长。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标。