Key result
HMMR is a critical hub gene overexpressed in NASH and HCC, where its high expression correlates with shorter overall survival, and is stimulated by oleate acid via CEBPα to promote HCC cell proliferation.
Why the study?
NASH is a major risk factor for hepatocellular carcinoma, but the underlying pathophysiological mechanisms remain elusive.
p-value: p=<0.05
HMMR plays a critical role in the progression from NASH to HCC and may serve as a therapeutic target and prognostic biomarker.
HMMR targeting should not yet inform HCC care; hypothesis-generating for its role in NASH progression.
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 (CEBP). CEBP 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.
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Zhang et al. (2020) studied Nonalcoholic steatohepatitis and hepatocellular carcinoma (n=489). HMMR expression vs. Low HMMR expression / Normal controls was evaluated on Overall survival in HCC patients based on HMMR expression (p=<0.05). HMMR is a critical hub gene overexpressed in NASH and HCC, where its high expression correlates with shorter overall survival, and is stimulated by oleate acid via CEBPα to promote HCC cell proliferation.
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