ESR1 Regulates the Obesity- and Metabolism-Differential Gene MMAA to Inhibit the Occurrence and Development of Hepatocellular Carcinoma

Abstract

Obesity is often regarded as a factor that promotes tumorigenesis, but the role of obesity in promoting hepatocellular carcinoma (HCC) is still controversial. We compared the trend change of 14 obesity-related genes in the 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. Metabolism of cobalamin-associated A (MMAA) was discovered as an obesity- and metabolism-differential gene, and its function in HCC was tested in vitro and in vivo. Finally, we explored how obese female patients with an originally high expression of female estrogen receptor (ESR1) directly upregulated MMAA to interfere with the progression of HCC. 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 results of MR analysis. We also discovered that MMAA is a metabolic gene closely related to the occurrence and development of HCC by mining the TCGA database, and it functioned an anti-tumor-promoting role in HCC by damaging the mitochondrial function and preserving the redox balance. We further verified that obese females with a high expression of ESR1 can regulate MMAA to protect HCC from progression. This study elucidates that 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 reprogramming.

Identification of novel prognostic targets in acute kidney injury using bioinformatics and next generation sequencing data analysis

“…IGF2 [632], RPPH1 [633], PRKCB (protein kinase C beta) [634], CCL5 [635], VASH2 [636], GREM1 [637], CYP11B2 [638], HIC1 [639], PCK1 [640], HSD11B2 [641], MME (membrane metalloendopeptidase) [642], FABP1 [142], MIOX (myo-inositol oxygenase) [643], ARG2 [644], PPARGC1A [645], VNN1 [646], NOX4 [647], EPHX2 [577], DDIT4 [648], SLC2A1 [649], PFKFB2 [650], CDH2 [651], SLC22A2 [294], AQP2 [652], ANGPT1 [653], KL (klotho) [654], ACE2 [655], STC1 [656], REN (renin) [608], ERRFI1 [657], ERBB4 [658], NTNG1 [659], VCAM1 [660], PTGER3 [661] and BBOX1 [662] expression levels are associated with diabetic nephropathy. IGF2 [663], IRF7 [664], PRKCB (protein kinase C beta) [665], CCL5 [666], ACTN3 [667], AMH (anti-Mullerian hormone) [668], E2F1 [669], UBE2M [670], TP73 [671], AGER (advanced glycosylation end-product specific receptor) [672], SMPD3 [118], NR2E1 [673], ANGPTL3 [674], CYP3A5 [675], PCK1 [676], LRP2 [677], FABP1 [678], SLC22A12 [279], CYP8B1 [679], MIOX (myo-inositol oxygenase) [680], ARG2 [681], FGF1 [450], CRY1 [682], PPARGC1A [451], CRYM (crystallin mu) [683], SLC19A3 [283], FH (fumaratehydratase) [684], SLC2A9 [286], GC (GC vitamin D binding protein) [685], RGN (regucalcin) [686], MMAA (metabolism of cobalamin associated A) [687], NOX4 [688], ABHD6 [689], EPHX2 [690], DDIT4 [691], EGF (epidermal growth factor) [173], DEFB1 [692], ACE2 ...…”

RNA methylation patterns mediated by m 6 A regulators are involved in the regulation of immune microenvironment in hepatocellular carcinoma

“…The important role of ESR1 in HCC has also been partially studied. Zhang et al, found that ESR1 could inhibit the occurrence and development of HCC by regulating the gene MMAA, an obesity and metabolism differential gene [31]. In addition, Hu et al, revealed that ESR1 also could promote HCC progression via transcriptionally regulating HS1BP3 [32].…”

The causality between CD8 + NKT cells and CD16 - CD56 on NK cells with hepatocellular carcinoma: a Mendelian randomization study

“…Mendelian randomization (MR) effectively avoids the effects of confounding factors and reverse causality in observational studies by using genetic mutations as an instrumental variable for exposure to infer a causality of research results [17]. Presently, the causal relationship between HCC and potential risk factors has been extensively explored, including alcohol consumption[18]dysbacteriosis of the gut ora [19], telomere length [20], and metabolic syndrome [21]. In this paper, the causality between NK cell relevant immune traits and HCC was assessed by two-sample MR study using aggregated data from the newest and largest GWAS meta-analyses.…”