The WNT/beta-catenin signaling pathway in the molecular pathogenesis of esophageal adenocarcinoma.

摘要

Primary esophageal adenocarcinomas (EADC) are thought to arise from Barrett esophagus (BE) and the progression to invasive adenocarcinoma is reflected histologically by the metaplasia-dysplasia-carcinoma sequence. Gastroesophageal reflux (GERD) is an established risk factor for both BE and EADC, and consequently there is a plausible link between GERD, BE, and EADC. Aberrant activation of the WNT/beta-catenin signaling pathway has been implicated in the molecular pathogenesis of EADC. The caudal-related homologues, CDX1 and CDX2, are two target genes of the WNT pathway and they are suggested to be the primary molecular determinants of Barrett metaplasia. To test the hypothesis that aberrant activation of the WNT/beta-catenin signaling pathway contributes to the molecular pathogenesis of EADC, mRNA and protein expression levels of beta-catenin, CDX1, and CDX2 were evaluated in specimens obtained from patients with GERD, BE, and EADC. Furthermore, the frequency of polymorphisms of the FZD4 gene, a WNT pathway receptor, was evaluated in populations at risk of developing EADC.; Aberrant activation of the WNT/beta-catenin pathway was demonstrated in a significant proportion of EADC tumour samples and was associated with the progression of BE to EADC. Furthermore, aberrant activation of the WNT pathway was significantly associated with increased expression of CDX1 and CDX2 in EADC samples, implicating the caudal-related homologues as mediators of the WNT pathway in this disease process. Although not statistically significant, a potential protective role for a FZD4 gene polymorphism, c1616g→t, was identified in a cohort study of patients with GERD, BE, and EADC, implicating the importance of this WNT pathway gene in the molecular pathogenesis of EADC.