Involvement of inactive GSK3beta overexpression in tumorigenesis and progression of gastric carcinomas.

Glycogen synthase kinase 3beta is reported to repress Wnt/beta-catenin pathway and regulate the balance between cellular proliferation and apoptosis. Its inactivation by ser(9) phosphorylation might play a critical role in the tumorigenesis and development of malignancies. Here, the expression of phosphorylated glycogen synthase kinase 3beta at ser(9) was examined in gastric carcinoma and adjacent non-neoplastic mucosa by immunohistochemistry and Western blot, and compared with the clinicopathological parameters of carcinomas, including the expression of vascular endothelial growth factor, extracellular matrix metalloproteinase inducer and beta-catenin, and microvessel density labeled by CD34, as well as survival data. Gastric carcinoma cell lines (MKN28, MKN45, AGS, GT-3 TKB, KATO-III and HGC-27) were studied for the phosphorylated kinase by Western blot and for its encoding mRNA by RT-PCR, followed by sequencing. All carcinoma cell lines showed strong expression of the phosphorylated kinase and its encoding mRNA.There were two isoforms of glycogen synthase kinase 3beta in all carcinoma cell lines and a synonymous mutation in HGC-27 carcinoma cell line at codon 65(GGA-->GGT: Gly). The phosphorylated kinase was localized in the cytoplasm of gastric carcinoma cell lines or carcinomas. It was more expressed in gastric carcinomas than that in non-neoplastic mucosa (P < .05) in line with the data of Western blot. There was a higher expression of the phosphorylated kinase in men carcinoma patients than that in women (P < .05). Its expression was positively correlated with depth of invasion, lymphatic and venous invasion, lymph node metastasis, Union Internationale le Contre Cancer staging, expression of vascular endothelial growth factor and extracellular matrix metalloproteinase inducer in gastric carcinoma (P < .05). Survival analysis indicated the phosphorylated kinase expression to be positively linked to poor prognosis (P< 05), but not independent (P>.05). Three independent prognostic factors, depth of invasion, lymphatic and venous invasion, concordantly influenced its relationship with prognosis (P < .05). Our study indicated that up-regulated expression of phosphorylated glycogen synthase kinase 3beta at ser(9) was closely linked to gastric carcinogenesis and subsequent progression, and could be employed as a good indicator of aggressive behaviors and prognosis of gastric carcinoma. Crown Copyright 2010. Published by Elsevier Inc. All rights reserved.