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Understanding the Interplay between COX-2 and hTERT in Colorectal Cancer Using a Multi-Omics Analysis

Laboratory of Gastroenterology Research, University of Crete, School of Medicine, 71013 Heraklion, Greece
1st Department of Surgery, Tzaneio General Hospital, 18536 Piraeus, Greece
Laboratory of Experimental Endocrinology, University of Crete, School of Medicine, 71013 Heraklion, Greece
Department of Pathology, Tzaneio General Hospital, 18536 Piraeus, Greece
2nd Department of Surgery, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece
Department of Gastroenterology and Hepatology, University Hospital of Heraklion, 71013 Heraklion, Greece
Department of Life Sciences European University Cyprus, Nicosia 1516, Cyprus
Author to whom correspondence should be addressed.
Cancers 2019, 11(10), 1536;
Received: 23 August 2019 / Revised: 7 September 2019 / Accepted: 8 October 2019 / Published: 11 October 2019
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
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. View Full-Text
Keywords: colorectal cancer; COX-2; PGE2; hTERT colorectal cancer; COX-2; PGE2; hTERT
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Ayiomamitis, G.D.; Notas, G.; Vasilakaki, T.; Tsavari, A.; Vederaki, S.; Theodosopoulos, T.; Kouroumalis, E.; Zaravinos, A. Understanding the Interplay between COX-2 and hTERT in Colorectal Cancer Using a Multi-Omics Analysis. Cancers 2019, 11, 1536.

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