Interactions between TGF-? type I receptor and hypoxia-inducible factor-? mediates a synergistic crosstalk leading to poor prognosis for patients with clear cell renal cell carcinoma.

ABSTRACT: To investigate the significance of expression of HIF-1?, HIF-2?, and SNAIL1 proteins; and TGF-? signaling pathway proteins in ccRCC, their relation with clinicopathological parameters and patient's survival were examined. We also investigated potential crosstalk between HIF-? and TGF-? signaling pathway, including the TGF-? type 1 receptor (ALK5-FL) and the intracellular domain of ALK5 (ALK5-ICD). Tissue samples from 154 ccRCC patients and comparable adjacent kidney cortex samples from 38 patients were analyzed for HIF-1?/2?, TGF-? signaling components, and SNAIL1 proteins by immunoblot. Protein expression of HIF-1? and HIF-2? were significantly higher, while SNAIL1 had similar expression levels in ccRCC compared with the kidney cortex. HIF-2? associated with poor cancer-specific survival, while HIF-1? and SNAIL1 did not associate with survival. Moreover, HIF-2? positively correlated with ALK5-ICD, pSMAD2/3, and PAI-1; HIF-1? positively correlated with pSMAD2/3; SNAIL1 positively correlated with ALK5-FL, ALK5-ICD, pSMAD2/3, PAI-1, and HIF-2?. Intriguingly, in vitro experiments performed under normoxic conditions revealed that ALK5 interacts with HIF-1? and HIF-2?, and promotes their expression and the expression of their target genes GLUT1 and CA9, in a VHL dependent manner. We found that ALK5 induces expression of HIF-1? and HIF-2?, through its kinase activity. Under hypoxic conditions, HIF-? proteins correlated with the activated TGF-? signaling pathway. In conclusion, we reveal that ALK5 plays a pivotal role in synergistic crosstalk between TGF-? signaling and hypoxia pathway, and that the interaction between ALK5 and HIF-? contributes to tumor progression.

SUBMITTER: Mallikarjuna P 

PROVIDER: S-EPMC6986558 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature