Desregulação da p53 nos carcinomas gástricos associados ao EBV

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Desregulação da p53 nos carcinomas gástricos associados ao EBV

Sexta, 11.08.2017

O cancro gástrico é a quinta neoplasia mais frequente em todo o mundo, sendo a terceira causa de morte por cancro. Na década de 90, o vírus de Epstein-Barr (EBV) foi pela primeira vez detetado em amostras de carcinoma do estômago e desde então tem sido associado a cerca de 10% de todas estas neoplasias. Nos últimos anos, um grupo de investigadores do IPO-Porto tem-se dedicado ao estudo dos carcinomas gástricos associados à infeção por EBV. Neste trabalho, recentemente publicado na revista ‘’Cancer Letters’’, os investigadores descrevem pela primeira vez uma alteração na via da p53, um gene supressor tumoral frequentemente mutado nos carcinomas gástricos. O estudo demonstra que os carcinomas gástricos associados ao EBV raramente apresentam mutações no gene da p53. Para além disso, também revela que os tumores gástricos EBV-positivos são caracterizados por baixos níveis de RNA mensageiro e uma sobre-expressão da proteína p53. Com base nestes resultados, os autores sugerem que o EBV induz a estabilização da p53 por meio das suas oncoproteínas.


Joana Ribeiroa,b,1, Mariana Maltab,c,1, Ana Galaghard, Fernanda Silvad, Luís Pedro Afonsod, Rui Medeirosb,c,e,f, Hugo Sousab,e

1Joint first authors

a Faculty of Medicine, University of Porto, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal

b Molecular Oncology & Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portugal

c Abel Salazar Institute for the Biomedical Sciences, University of Porto, Rua de Jorge Viterbo Ferreira, 4050-313 Porto, Portugal

d Department of Pathology, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal

e Virology Service, Portuguese Oncology Institute of Porto FG EPE, Rua Dr. Antonio Bernardino de Almeida, 4200-072 Porto, Portugal

f Research Department, Portuguese League Against Cancer (LPCC-NRNorte), Estrada Interior da Circunvalação 6657, 4200 Porto, Portugal


TP53 is a tumour suppressor gene frequently mutated in human cancers; nevertheless, in EBV-associated malignancies mutations are uncommon despite frequent deregulation of the p53 pathway. In this study, we aimed to investigate p53 expression, TP53 mRNA levels and TP53 mutations in EBV-associated gastric carcinoma (EBVaGC). A case-control study was performed using 46 patients: 15 EBVaGC and 31 EBV-negative GC (EBVnGC) cases. p53 expression was detected by immunohistochemistry (IHC), the evaluation of p53 mRNA levels was performed by RT-qPCR and TP53 mutations were investigated only in EBVaGC cases using the DNA sanger sequencing method. p53 expression was found in 97.8% (45/46) of all gastric cancer cases (including EBVaGC and EBVnGC groups). Despite the high frequency of p53 expression in both groups, the percentages of cells are significantly higher among EBVaGC cases (p = 0.027). Regarding the mRNA levels, we found a significantly increased expression of p53 mRNA in EBVnGC (2-ΔΔCt = 13.4 ± 2.4; p = 0.0029) when compared with EBVaGC. Furthermore, the sequencing analysis of TP53 gene revealed that only one of the 15 EBVaGC cases presented a missense mutation. Our results demonstrated that EBV-associated gastric carcinomas are characterized by a significant decrease of TP53 mRNA levels with a strong p53 expression and rare TP53 mutations when compared with EBV-negative cancers. Considering these results, EBV seems to induce a stabilization of p53 in the EBVaGC independently of the presence of mutations, which remains to be explained.

Cancer Letters

http://www.cancerletters.info/article/S0304-3835(17)30436-6/fulltext