Doku transglutaminaz (TG2) izoformlarının böbrek hücreli karsinom oluşumu ile ilişkisi

Transglutaminase 2 (TG2) is a multifunctional protein that is ubiquitously expressed in all tissues. TG2-related events in the context of tumorigenesis placed TG2 in the center of cancer cell research, where it was recognized as an important mediator in cancer development and progression. Later studies showing the involvement of TG2 in cancer progression, drug resistance, epithelial-mesenchymal transition (EMT), metastasis, and the acquisition of cancer stem cell properties showed that these effects were tightly associated with the GTPase activity of TG2. Our group previously demonstrated the relationship of TG2 with RCC, whereby the increase in TG2 levels was associated with low survival time and a high risk of metastasis. Following studies have shown that increased TG2 expression tightly correlates with high nuclear grade and poor prognosis in patients with RCC. Thus, the TG2 protein is implicated in the progression of RCC and stands out as an important molecular target in cancer therapy. The TG2 protein has four isoforms hitherto identified. These C-terminally truncated isoforms produced by alternative splicing events have reduced GTP binding affinity and transamidase activity and display a high GTPase activity compared with the full-length TG2. A gene expression study examining intact kidney and tumor tissues revealed the presence of different TG2 transcripts in RCC. In light of this initial finding, the present thesis first focused on showing the upregulation of TG2 isoforms in a larger RCC patient population. Next, to understand the molecular basis of TG2 isoform-mediated cellular transformation, the effects of the expression of each TG2 isoform on the cellular transformation were investigated in renal proximal tubule epithelial cell (RPTEC) models. In this regard, we demonstrated that inducing the expressions of TG2 or its isoforms increased the proliferation rate, promoted cell cycle progression, contributed to the activation of EMT, and caused an increased invasion potential in RPTECs. Our findings demonstrate the importance of TG2 isoforms in cellular transformation in RCC and elucidate the importance of targeting TG2 and its isoforms in clinical practice.