ESR1 regulates the obesity and metabolism-differential gene MMAA to inhibit the occurrence and development of hepatocellular carcinoma

Background: Obesity is often regarded as one of the factors that promote tumorigenesis, but the role of obesity in promoting hepatocellular carcinoma (HCC) is still controversial. Methods: We compared the trend change of 14 obesity-related genes in formation and development of HCC in normal, adjacent and HCC tissues. Mendelian randomization (MR) analysis was used to verify the relationship between obesity and HCC occurrence. MMAA was discovered as an obesity and metabolism-differential gene, and its function in HCC was testified in vivo and in vitro . Finally, we explored how obese female with originally high expression of female estrogen receptor (ESR1), directly upregulated MMAA to interfere with the progression of HCC. Results: Fourteen obesity-related genes were downregulated in adjacent and tumoral tissues compared with normal liver tissues, which indicated that obesity may be inversely related to the occurrence of HCC and was consistent with the result in MR analysis. We also discovered MMAA is a metabolic gene closely related to the occurrence and development of HCC via mining TCGA database, and it functioned as an anti-tumor-promoting role in HCC by damaging the mitochondrial function and preserving the redox balance. We further verified obese female with originally high expression of ESR1 can regulate MMAA to protect HCC from progression. Conclusions: This study elucidates obesity might be a protective factor for female HCC patients, as they originally highly expressed ESR1 which could upregulate MMAA to suppress tumor growth and participate in metabolic reprogram.