Up-regulation of TGM2 with ITGB1 and SDC4 is important in the development and metastasis of renal cell carcinoma

Objective: Tissue transglutaminase (TGM2) up-regulation is involved in the progression and dissemination of carcinomas through β1 integrin (ITGB1) association. Given that TGM2 interaction with syndecan-4 (SDC4) on the cell surface is important in the activation of ITGB1 and integrin-mediated survival signaling, we investigated the roles of TGM2, ITGB1, and SDC4 in the development and metastasis of renal cell carcinoma (RCC). Material and methods: Expression levels of TGM2, ITGB1, and SDC4 mRNA were analyzed in primary tumor samples (n = 95) and their healthy counterparts in addition to control and RCC epithelial cell lines. TGM2 catalytic activity in 60 randomly selected patient samples was measured by enzyme-linked sorbent plate assay. Results: TGM2 expression ratio showed a significant 2.9-fold decrease in 67 (70.5%) of the primary RCC tumors (P <0.0001) independent of clinical covariates, including tumor node metastasis (TNM) staging and histopathologic grading. For the remaining 28 (29.5%) tumors, a 1.95-fold increase was recorded in the TGM2 expression levels, which also showed a significant increase in ITGB1 and SDC4 expression levels in 82.6% of the overexpression cases (P <0.001). Up-regulation of TGM2 along with ITGB1 and SCD4 was associated with metastasis and a marked decrease in tumor necrosis. Consistently, RCC cell lines exhibited higher levels of TGM2 expression compared with the control epithelial cell line with a significant up-regulation of ITGB1 and SCD4 recorded for the metastatic lines. Conclusions: Our findings suggest that TGM2 up-regulation along with ITGB1 and SDC4 plays an important role in the development of RCC tumors and advanced RCC with metastasis.