Concordant repression and aberrant methylation of transforming growth factor-beta signaling pathway genes occurs early in gastric cardia adenocarcinoma

Abstract

The loss of transforming growth factor-β (TGF-β) response due to the dysregulation of TGF-β receptor type I (TGFBR1), type II (TGFBR2) and Smad4 is well known for its contribution to oncogenesis, although the role of the genes of TGF-β/Smad signalling pathway in gastric cardia adenocarcinoma (GCA) is poorly understood. In the present study, the methylation status and expression of TGF-β receptor type I (TGFBR1), type II (TGFBR2), and Smad4 was investigated in GCA and dysplasia. MSP approach was used to detect the methylation status of TGFBR1, TGFBR2, and Smad4. Immunohistochemistry and quantitative RT-PCR methods were used respectively to examine the protein and mRNA expression of them in tissues. The methylation frequency of TGFBR1 and TGFBR2 in the tissues of high grade dysplasia and GCA was significantly higher than that in corresponding normal tissues (p < 0.01) and was significantly associated with mRNA and protein expression of the two genes (p < 0.05). The methylation frequency of Smad4 in the 30 ~ 171 sites was higher than that in the -248 ~ 26 sites and was associated with the loss of Smad4 expression. The decreased expression of TGFBR1, TGFBR2 and Smad4 was correlated with increased expression of TGF-β1 in GCA. In all, these data suggest that methylation of TGFBR1, TGFBR2 and Smad4 may exist in the gastric cardia dysplasia stages and plays an important role in these genes silencing and subsequently affect the TGF-β/Smad signaling pathway.