The expression of cell polarity proteins and its role in gastric carcinogenesis

Abstract

Cell polarity is a crucial for normal tissue integrity and tissue homeostasis. Loss of cell polarity results in tissue disorganization and promotes the initiation and progression of cancer. We investigated the role of epithelial cell polarity proteins during gastric carcinoma progression, and evaluated their correlation with epithelial-mesenchymal transition (EMT) markers. The expression of 5 proteins of cell polarity complexes (LGL2, DLG1, SCRIB, PKCiota and CRB3) and 7 EMT-related proteins (β-catenin, E-cadherin, MMP2, S100A4, SNAIL1, Vimentin and ZEB1) was examined in a series of samples from 409 gastric carcinoma patients who underwent gastrectomy by immunohistochemistry. Additionally, LGL2 expression was determined by immunohistochemistry and RNA in situ hybridization using 154 gastric tissues (75 early gastric carcinoma, 79 gastric adenoma) from ESD specimens and 90 non-neoplastic gastric tissues. Loss of membranous expression of LGL2, DLG1 and CRB3 as well as cytoplasmic overexpression of SCRIB was frequently observed in diffuse type than in intestinal type carcinomas (P < 0.001 for each). Loss of membranous expression of LGL2 and DLG1 as well as cytoplasmic overexpression of SCRIB and PKCiota was significantly associated with advanced stage (P < 0.05 for each) and poor prognosis (P < 0.05 for each). We showed that complex correlation between expression of cell polarity proteins and EMT proteins. Each of cell polarity proteins was not independent prognostic factors in multivariable analysis adjusting for age, pTNM stage, tumor size, lymphatic invasion and radicality. The combination of LGL2, DLG1, SCRIB, PKCiota, MMP2 and S100A4 with significant value in univariate analysis added predictive information beyond the model consisting of individual markers. In addition, LGL2 membranous expression was found to be gradually lost from normal and active gastritis to adenoma and carcinoma. In conclusion, we revealed that loss of membranous expression of LGL2 and DLG1 as well as cytoplasmic overexpression of SCRIB and PKCiota may be associated with gastric carcinoma progression. The complex networks may regulate epithelial cell polarity by, at least, EMT-related proteins in gastric carcinoma. The combination of cell polarity proteins and EMT proteins could provide a more precise estimation of prognosis in gastric carcinoma. We suggest that cell polarity proteins play a role in gastric carcinoma progression related to EMT.