Extensive alteration in the expression profiles of TGFB pathway signaling components and TP53 is observed along the gastric dysplasia-carcinoma sequence.

AIMS The expression patterns of TGFB signaling proteins, such as TGFB1/2, TGFBR1(ALK5), TGFBR2, SMAD1/2/3, SMAD2/3, SMAD4, SMAD7, and of downstream targets of TGFB signaling, CDKN1A (p21CIP1), CDKN1B (p27KIP1), MYC, CDC25A, TP53, and RELA (p65NF-kB) were investigated in gastric carcinomas and other gastric lesions. METHODS AND RESULTS A total of 112 gastric carcinomas, 37 dysplasias, 54 intestinal metaplasias, 29 chronic atrophic gastritis and 54 normal gastric epithelium were analyzed by tissue microarray-based immunohistochemical analysis. Extensive changes in expression profiles of these proteins were observed. Three types of expression patterns were observed along the normal epithelium-atrophic gastritis-dysplasia-carcinoma sequence. (1) Expression of TGFB1/2, TGFBR1, MYC, and TP53 continually increased along this sequence. (2) Expression of SMAD4, CDKN1A, SMAD1/2/3, SMAD2/3, and CDKN1B was enhanced in dysplasia but decreased in carcinoma. (3) Expression of TGFBR2, SMAD7, RELA, and CDC25A was enhanced in dysplasia and the enhanced level was maintained in carcinoma. In addition, we also evaluated the clinical significance of the expression of TGFB signaling proteins in gastric carcinoma. TGFB and MYC were positively correlated with advanced stages, whereas SMAD1/2/3 and SMAD4 were strongly associated with earlier stages. CONCLUSIONS The extensive change in expression of TGFB signaling components is implicated during tumorigenesis of gastric neoplasias.