Expression and Mutation Analysis of TIG1 (Tazarotene-Induced Gene 1) in Human Gastric Cancer

Abstract

Tazarotene-induced gene 1 (TIG1) has been known to function as a cell adhesion molecule, which leads to better cell to cell contact and reduced proliferation. We investigated expression and mutation status of TIG1 in primary gastric tumors and cell lines to explore the candidacy of the gene as a tumor suppressor. A total of 172 gastric tissue specimes, including 80 primary adenocarcinomas, 12 benign tumors, and 80 adjacent normal mucosa, and 15 gastric cancer cell lines were used. TIG1 expression was analyzed by semiquantitative RT-PCR and immunoblot analysis. To screen for the presence of somatic mutations, RT-PCR-SSCP analysis was carried out. The effect of 5-aza-2'-deoxycytidine treatment was examined to elicit whether TIG1 reduction is associated with abnormal DNA hypermethylation. Compared to noncancerous tissues, a substantial reduction of TIG1 expression was observed in 73.3% (11115) cancer cell lines, and seven of these exhibited nearly undetectable levels of expression. Decreased expression of TIG1 was also found in 62 (77.5%) primary carcinoma tissues compared to adjacent noncancerous tissues, indicating a tumor-specific reduction of TIG1. Expression levels of TIG1 were significantly low in primary carcinomas and cancer cell lines compared to those of normal tissues. Moreover, loss or reduction of TIG1 was significantly high in advanced tumors compared to early tumors and more frequent in poorly differentiated tumors than well or moderately differentiated tumors. TIG1 expression was reactivated or its level was elevated following 5-aza-2'-deoxycytidine treatment, indicating that TIG1 expression is transcriptionally silenced in these cancer cells by abnormal DNA hypermethylation. These data indicate that TIG1 undergoes frequent epigenetic inactivation due to aberrant DNA hypermethylation in gastric cancers, and its altered expression is associated with the malignant progression of tumors.