Abstract
Background: Cyclooxygenase 2 (COX-2) is involved in the initial steps of colorectal cancer (CRC) formation, playing a key role in the catalysis of arachidonic acid to prostaglandin E2 (PGE2). The human telomerase reverse transcriptase (hTERT or TERT) also plays an important role in colorectal cancer growth, conferring sustained cell proliferation and survival. Although hTERT induces COX-2 expression in gastric and cervical cancer, their interaction has not been investigated in the context of CRC. Methods: COX-2, PGE2 levels, and telomerase activity were evaluated by immunohistochemistry, ELISA, and TRAP assay in 49 colorectal cancer samples. PTGS1, PTGS2, PTGES3, TERT mRNA, and protein levels were investigated using RNA-seq and antibody-based protein profiling data from the TCGA and HPA projects. A multi-omics comparison was performed between PTGS2 and TERT, using RNAseq, DNA methylation, copy number variations (CNVs), single nucleotide polymorphisms (SNPs), and insertions/deletions (Indels) data. Results: COX-2 expression was positive in 40/49 CRCs, bearing cytoplasmic and heterogeneous staining, from moderate to high intensity. COX-2 staining was mainly detected in the stroma of the tumor cells and the adjacent normal tissues. PGE2 expression was lower in CRC compared to the adjacent normal tissue, and inversely correlated to telomerase activity in right colon cancers. COX-1 and COX-2 were anticorrelated with TERT. Isoform structural analysis revealed the most prevalent transcripts driving the differential expression of PTGS1, PTGS2, PTGES3, and TERT in CRC. COX-2 expression was significantly higher among B-Raf proto-oncogene, serine/threonine kinase, mutant (BRAFmut) tumors. Kirsten ras oncogene (KRAS) mutations did not affect COX-2 or TERT expression. The promoter regions of COX-2 and TERT were reversely methylated. Conclusions: Our data support that COX-2 is involved in the early stages of colorectal cancer development, initially affecting the tumor’s stromal microenvironment, and, subsequently, the epithelial cells. They also highlight an inverse correlation between COX-2 expression and telomerase activity in CRC, as well as differentially methylated patterns within the promoter regions of COX-2 and TERT.
Highlights
IntroductionColorectal cancer (CRC) is the third most common cancer worldwide among both sexes [1]
Colorectal cancer (CRC) is the third most common cancer worldwide among both sexes [1]. its incidence and mortality rates have been declining for several decades, a deeper understanding of the cellular mechanisms involved in it is imperative
We further investigated the expression of COX-1, Cyclooxygenase 2 (COX-2), PTGES3, and telomerase reverse transcriptase (TERT) genes, using bioinformatics analysis on the the Cancer Genome Atlas (TCGA)-COAD and READ datasets, and found that COX-1 and COX-2 are mainly correlated to TERT expression, and that high COX-2 expression is associated with a better overall survival of the colorectal cancer (CRC) patients
Summary
Colorectal cancer (CRC) is the third most common cancer worldwide among both sexes [1]. Most of the NSAIDs that are used today inhibit the action of prostaglandin endoperoxide H synthases 1 and 2 (PGHS-1 and PGHS-2; known as PTGS-1 and -2 or cyclooxygenases-1 and -2, COX-1/-2, respectively). These are intracellular enzymes that catalyze the conversion of arachidonic acid into prostaglandins (PGs) and other eicosanoids. We biopsied tissues from patients diagnosed with colorectal cancer, and studied the differences in COX-2 expression between epithelial and stromal cells of tumor and adjacent normal tissues. We provide evidence that the promoter regions of the PTGS2 and TERT genes are reversely methylated, but this does not seem to affect the reverse expression levels of these genes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
