Abstract
The molecular mechanisms whereby transforming growth factor-β (TGF-β) promotes clear cell renal cell carcinoma (ccRCC) progression is elusive. The cell membrane bound TGF-β type I receptor (ALK5), was recently found to undergo proteolytic cleavage in aggressive prostate cancer cells, resulting in liberation and subsequent nuclear translocation of its intracellular domain (ICD), suggesting that ALK5-ICD might be a useful cancer biomarker. Herein, the possible correlation between ALK5 full length (ALK5-FL) and ALK5-ICD protein, phosphorylated Smad2/3 (pSmad2/3), and expression of TGF-β target gene PAI-1, was investigated in a clinical ccRCC material, in relation to tumor grade, stage, size and cancer specific survival. Expression of ALK5-FL, ALK5-ICD, pSmad2/3 and PAI-1 protein levels were significantly higher in higher stage and associated with adverse survival. ALK5-ICD, pSmad2/3 and PAI-1 correlated with higher grade, and ALK5-FL, pSmad2/3 and PAI-1 protein levels were significantly correlated with larger tumor size. Moreover, the functional role of the TGF-β - ALK5-ICD pathway were investigated in two ccRCC cell lines by treatment with ADAM/MMP2 inhibitor TAPI-2, which prevented TGF-β-induced ALK5-ICD generation, nuclear translocation, as well as cell invasion. The present study demonstrated that canonical TGF-β Smad2/3 pathway and generation of ALK5-ICD correlates with poor survival and invasion of ccRCC in vitro.
Highlights
Renal cell carcinoma (RCC) accounts for about 90% of all tumors of the kidney [1] and includes different tumor types, classified according to their histology and specific gene alterations [2, 3]
We investigated the role of transforming growth factor-β (TGF-β) signaling in the progression and aggressiveness of clear cell RCC (ccRCC) with emphasis on ALK5 full length (ALK5-FL), ALK5-intracellular domain (ICD), pSmad2/3, and Plasminogen activator inhibitor type-1 (PAI-1)
When considering only tumor samples that had corresponding kidney cortex tissues (n = 36), ALK5-ICD was significantly lower in ccRCC (P = 0.005), and PAI-1 mRNA was significantly higher in ccRCC (P < 0.0001, n = 39)
Summary
Renal cell carcinoma (RCC) accounts for about 90% of all tumors of the kidney [1] and includes different tumor types, classified according to their histology and specific gene alterations [2, 3]. Active ALK5-FL phosphorylates the receptor-associated Smad proteins (R-Smad), an assembly that forms a complex with co-Smad (Smad4) and translocates to the nucleus to induce target genes [1012]. In www.impactjournals.com/oncotarget the non-canonical TGF-β pathway, TGF-β activates the ubiquitin ligase tumor necrosis factor receptor (TNFR)associated factor 6 (TRAF6) that ubiquitinates TβRI in a TRAF6 mediated Lys63-linked polyubiquitination manner. ALK5-ICD translocates to the nucleus and associates with transcriptional coactivator p300, promoting tumor invasion by induction of target genes (SNAIL1, ZEB, and MMP2) [18, 20]. Nuclear localization of ALK5-ICD promotes its own expression by binding to the TβRI promoter [18] and regulates cell cycle, differentiation, and invasiveness in prostate cancer through cyclin D1 (CCND1) [19]. The exact mechanism of tumor aggressiveness by this pathway is still unclear, and the role of TβRI-ICD has not yet been studied clinically in RCCs
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