Prostanoid Signaling in Cancers: Expression and Regulation Patterns of Enzymes and Receptors

Abstract

Cancer-associated disturbance of prostanoid signaling provides an aberrant accumulation of prostanoids. This signaling consists of 19 target genes, encoding metabolic enzymes and G-protein-coupled receptors, and prostanoids (prostacyclin, thromboxane, and prostaglandins E2, F2α, D2, H2). The study addresses the systems biology analysis of target genes in 24 solid tumors using a data mining pipeline. We analyzed differential expression patterns of genes and proteins, promoter methylation status as well as tissue-specific master regulators and microRNAs. Tumor types were clustered into several groups according to gene expression patterns. Target genes were characterized as low mutated in tumors, with the exception of melanoma. We found at least six ubiquitin ligases and eight protein kinases that post-translationally modified the most connected proteins PTGES3 and PTGIS. Models of regulation of PTGIS and PTGIR gene expression in lung and uterine cancers were suggested. For the first time, we found associations between the patient’s overall survival rates with nine multigene transcriptomics signatures in eight tumors. Expression patterns of each of the six target genes have predictive value with respect to cytostatic therapy response. One of the consequences of the study is an assumption of prostanoid-dependent (or independent) tumor phenotypes. Thus, pharmacologic targeting the prostanoid signaling could be a probable additional anticancer strategy.