Genomic analysis of the endosomal sorting required for transport complex III pathway genes as therapeutic and prognostic biomarkers for endometrial carcinoma.

Abstract

BackgroundThe genes involved in the endosomal sorting required for transport complex (ESCRT)-III pathway is a protective mechanism that delays cell death by repairing damaged plasma membranes. We aimed to evaluate if targeting ESCRT-III genes may be used as biomarkers for predicting the clinical outcomes of endometrial carcinoma (EC).MethodsTranscriptome RNA sequence (RNA-seq) data and genomic information of EC samples were obtained from The Cancer Genome Atlas (TCGA). The expression level, pathological relationship, pathway alterations, mutation, functional enrichment, associations with tumor infiltrating lymphocytes (TILs), and survival information of ESCRT-III genes including charged multivesicular body protein 2A (CHMP2A), CHMP2B, CHMP3, CHMP4B, CHMP4C, CHMP5, CHMP5, and CHMP7 in EC and normal tissues were explored through multiple datasets analysis.ResultsOur study demonstrated that CHMP2B, CHMP3, CHMP4B, CHMP5, CHMP5, and CHMP7 were significantly lower, whereas CHMP2A and CHMP4C were significantly higher in EC tissue than in normal tissue. All ESCRT pathway genes were significantly differentially expressed between tumor grades 2 and 3 and were positively correlated with each other. Except for CHMP5, the other seven ESCRT pathway genes were the most frequently mutated genes in the EC samples among all cancer types. Moreover, CHMP2A and CHMP7 had better prognostic potential in EC. CHMP2A, CHMP4B, and CHMP7 were significantly correlated with all four molecular subtypes in TCGA. Increased expression of CHMP2A and CHMP7 and decreased expression of CHMP4B were observed in EC samples than in serous carcinoma type samples. Furthermore, they were associated with tumor stages 1 and 2 and good survival outcomes for EC. Functional analysis revealed that the ESCRT-III genes were involved in the biological process (BP) of the membrane budding and multivesicular body (MVB) pathway; CHMP2A and CHMP7 participated in the ESCRT and ESCRT III complex disassembly, while CHMP5 was involved in ESCRT and ESCRT III complex assembly.ConclusionsMutations in CHMP2A and CHMP7 correspond to a better prognostic potential in EC. Upregulation of CHMP2A and CHMP7 and downregulation of CHMP4B are good prognostic indicators of the histological type, early tumor grade, and promising survival markers, thus becoming potential biomarkers and therapeutic targets for EC.