Mitochondrial dysregulation is a key regulator of gastric cancer subtype carcinogenesis

Abstract

The tumor microenvironment, tissue origin, stage, and subtype can influence mitochondrial function. This study investigated the impact of mitochondrial dysregulation on the carcinogenesis of stomach cancer subtypes. Therefore, gene sets collected related to mitochondria and mitochondrial-dependent processes, from the molecular signatures database. Their expression patterns were analyzed in mRNA expression profiles derived from various cohorts of gastric cancer, as well as RNA sequence TCGA stomach adenocarcinoma profiles. In addition, the Pan-Cancer Atlas expression profile is also used for further validation. Z score-based pathway activation scoring showed that gene sets related to mitochondrial dynamics (fission, fusion, and localizations) were significantly activated and involved in the migration and metastasis of diffuse subtype gastric tumors. By contrast, mitochondrial biogenesis and turnover-associated signatures (such as mitochondrial morphogenesis, membrane organization, depolarization, and mitophagy), were significantly enriched in intestinal subtype gastric tumors. These processes might aid in maintaining mitochondrial mass homeostasis, which in turn helps intestinal-type tumor tissues survive under conditions of nutritional deficiency and/or hypoxia. Results from a single-cell RNA sequence analysis confirmed this dysregulation in gastric cancers. Furthermore, receiver operating characteristic curves showed that diffuse subtype-specific mitochondrial dynamics genes (DNM1L, MFF, FIS1, and OPA1) and intestinal subtype-specific mitochondrial biogenesis and turnover genes (ATP5C1, OXA1L, TIMM10, and PINK1) exhibited a significantly greater degree of sensitivity and specificity in the corresponding subtype of gastric tumors. Finally, overall survival plot studies showed a correlation between the expression of these genes with survival in patients with gastric tumors. The current study concludes that mitochondrial dysregulation might have dual carcinogenic roles in the pathogenesis of diffuse and intestinal subtype gastric tumors. This study should be helpful for the development of targeted treatments for gastric cancer.

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