TY - JOUR
TI - Understanding the interplay between COX-2 and hTERT in colorectal cancer using a multi-omics analysis
AU - Ayiomamitis, G.D.
AU - Notas, G.
AU - Vasilakaki, T.
AU - Tsavari, A.
AU - Vederaki, S.
AU - Theodosopoulos, T.
AU - Kouroumalis, E.
AU - Zaravinos, A.
JO - Blood cancer journal
PY - 2019
VL - 11
TODO - 10
SP - null
PB - MDPI AG
SN - null
TODO - 10.3390/cancers11101536
TODO - B Raf kinase;  cyclooxygenase 1;  cyclooxygenase 2;  cyclooxygenase 3;  messenger RNA;  prostaglandin E2;  protein serine threonine kinase;  telomerase reverse transcriptase, adult;  aged;  Article;  cancer staging;  carcinogenesis;  clinical article;  colorectal cancer;  controlled study;  copy number variation;  disease free survival;  DNA methylation;  enzyme activity;  enzyme linked immunosorbent assay;  epithelium cell;  female;  gene expression;  human;  human cell;  human tissue;  immunohistochemistry;  indel mutation;  male;  multi omics analysis;  omics;  oncogene K ras;  overall survival;  promoter region;  protein analysis;  protein expression;  protein protein interaction;  proto oncogene;  RNA sequence;  single nucleotide polymorphism;  structure analysis;  telomeric repeat amplification protocol;  tumor cell;  tumor cell stroma;  tumor microenvironment
TODO - 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. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
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