Lactate dehydrogenase isoform expressions differing impacts on gastrointestinal carcinogenesis

Abstract

In cancer cells, metabolic alterations support tumor growth, survival, and progression. This study aims to examine the effects of lactate metabolism on the carcinogenesis of gastrointestinal subtypes. Hence, signatures relevant to lactate metabolism were gathered from the molecular signatures database and investigated in the genome-wide expression profiles of gastrointestinal cancer cohorts' using gene sets-based pathway activation scoring analysis. The results of this study represent that the lactate metabolism signatures are significantly expressed across gastrointestinal subtype tumors such as intestinal histopathological subtype of gastric tumor, intraductal papillary mucinous neoplasm (IPMN) subtype of pancreatic cancer, and hepatocellular carcinoma (HCC) stage of liver tumors, respectively. As a result, these metabolisms were dysregulated across subtypes of gastrointestinal carcinogenesis. The identified dysregulation was further reconfirmed by examining corresponding metabolic gene expression patterns across various subtypes encompassing single-cell RNA sequence profiles. These outcomes also reassured that lactate dehydrogenase isoform genes such as LDHA, LDHC, and its transporter gene SLC16A1 are highly enriched in intestinal, IPMN, and HCC subtypes' tumors, respectively. In contrast, LDHB and LDHD genes are vastly elevated in non-tumorous tissues than in gastrointestinal cancer. Furthermore, overall survival plots also reconfirmed that these gene expressions were associated with poor survival in the corresponding subtype's patient cohorts. All of these findings demonstrate the existence of lactate metabolic rewiring and involvement in gastrointestinal carcinogenesis. These results may help develop therapeutic target therapies for malignancies of the gastrointestinal subtype.