Gene Expression Profiling of Pancreatic Ductal Adenocarcinoma Cells in Hypercapnia Identifies SIAH3 as a Novel Prognostic Biomarker

Hypercapnia is a key feature of the respiratory microenvironment in many pathologic conditions. It occurs both as a regional and as a systemic process, and it is associated with multiple metabolic changes such as mitochondrial dysfunction, decreased ATP production, and metabolic shift from glycolytic energy production to fatty acid metabolism. In the Cancer tumor microenvironment, hypercapnia has been linked at times to enhanced cell migration, invasion, and chemoresistance. Our previous work has shown that hypercapnia-associated gene signatures can be used as prognostic biomarkers. However, unlike the hypoxia-inducible factor pathway, there are no validated targets to quantify hypercapnia. In this study, we investigated the phenotypic and transcriptomic changes occurring in pancreatic ductal adenocarcinoma (PDAC) due to chronic exposure to hypercapnic atmospheres. We then identified and validated SIAH3 as a hypercapnia-affected target and explored its clinical relevance as a prognostic factor in PDAC.