Relación de la expresión de los genes de síntesis y señalización de melatonina en el cáncer colorrectal conel estatus de P53.

Abstract

Introduction: Colorectal cancer (CRC) is the third most common cancer worldwide. TP53 is a key tumor suppressor gene that regulates the cell cycle in response to different stress signals and is mutated in around half of diagnosed CRC cases. Melatonin is an indolamine synthesized from tryptophan in various organs, including the GIT, in which enzymes involved in its synthesis (AA-NAT and ASMT), membrane melatonin receptors (MT1 and MT2), and the nuclear receptor RORα have been found. Some studies have shown a relationship between a decrease in melatonin synthesis and its signaling in CRC. It was recently reported that p53 activation (phosphorylation) is mediated by melatonin via its transmembrane receptors. Objectives: To determine the relationship of AA-NAT, ASMT, MT1, MT2 and RORα expression with p53 status in CRC. Materials and methods: p53 mutations were analyzed in both normal and tumor tissue samples from 177 patients diagnosed with CRC in San Cecilio University Hospital (Granada), using cyclic sequencing and multicapillary electrophoresis. The mRNA expression of AA-NAT, ASMT, RORα, MT1 and MT2 in the samples was determined by QRT-PCR. These parameters were also analyzed in four CRC cell lines: RKO, HCT-116 (p53wt), HT-29, and DLD-1 (mutated p53). Results: Expression of AA-NAT, MT1 and MT2 was lower in tumor versus normal mucosa samples, but no difference in ASMT or RORα expression was found. In cases with mutated p53, expression of AA-NAT, MT2 and RORα was higher in tumor versus normal samples. MT1 expression was not related to p53 status, being lower in CRCs with mutated or non-mutated p53. Similar results were obtained in the cell lines. Conclusion: Expression of AA-NAT, MT2 and RORα is related to p53 status (mutated/non-mutated) in samples from CRC patients and in CRC cell lines.