Int J Biol Sci 2020; 16(15):2812-2827. doi:10.7150/ijbs.49785

Research Paper

Oleate acid-stimulated HMMR expression by CEBPα is associated with nonalcoholic steatohepatitis and hepatocellular carcinoma

Deyu Zhang1#, Jiahong Liu1,2#, Tian Xie1, Qiwei Jiang1, Lihua Ding1, Jianhua Zhu1,2✉, Qinong Ye1✉

1. Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, China.
2. Department of Oncology, The Fourth Medical Center, PLA General Hospital, Beijing 100048, China.
#These authors contributed equally to this work.

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Citation:
Zhang D, Liu J, Xie T, Jiang Q, Ding L, Zhu J, Ye Q. Oleate acid-stimulated HMMR expression by CEBPα is associated with nonalcoholic steatohepatitis and hepatocellular carcinoma. Int J Biol Sci 2020; 16(15):2812-2827. doi:10.7150/ijbs.49785. Available from http://www.ijbs.com/v16p2812.htm

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Abstract

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.

Keywords: non-alcoholic steatohepatitis, hepatocellular carcinoma, bioinformatics, oleate acid, cell cycle, CEBPα