VHL status regulates transforming growth factor-β signaling pathways in renal cell carcinoma
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Pramod Mallikarjuna1,*, Raviprakash T. Sitaram1,2,*, Maréne Landström1,** and Börje Ljungberg2,**
1Department of Medical Biosciences, Pathology, Umeå University, Umeå SE-90187, Sweden
2Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå SE-90187, Sweden
*These authors have contributed equally to this work as first author
**These authors have contributed equally to this work as last author
Raviprakash T. Sitaram, email: [email protected]
Keywords: ccRCC; non-ccRCC; ALK5; pVHL; TGF-β signaling
Received: November 16, 2017 Accepted: February 27, 2018 Published: March 27, 2018
To evaluate the role of pVHL in the regulation of TGF-β signaling pathways in clear cell renal cell carcinoma (ccRCC) as well as in non-ccRCC; the expression of pVHL, and the TGF-β pathway components and their association with clinicopathological parameters and patient’s survival were explored. Tissue samples from 143 ccRCC and 58 non-ccRCC patients were examined by immunoblot. ccRCC cell lines were utilized for mechanistic in-vitro studies. Expression levels of pVHL were significantly lower in ccRCC compared with non-ccRCC. Non-ccRCC and ccRCC pVHL-High expressed similar levels of pVHL. Expression of the TGF-β type I receptor (ALK5) and intra-cellular domain were significantly higher in ccRCC compared with non-ccRCC. In non-ccRCC, expressions of ALK5-FL, ALK5-ICD, pSMAD2/3, and PAI-1 had no association with clinicopathological parameters and survival. In ccRCC pVHL-Low, ALK5-FL, ALK5-ICD, pSMAD2/3, and PAI-1 were significantly related with tumor stage, size, and survival. In ccRCC pVHL-High, the expression of PAI-1 was associated with stage and survival. In-vitro studies revealed that pVHL interacted with ALK5 to downregulate its expression through K48-linked poly-ubiquitination and proteasomal degradation, thus negatively controlling TGF-β induced cancer cell invasiveness. The pVHL status controls the ALK5 and can thereby regulate the TGF-β pathway, aggressiveness of tumors, and survival of the ccRCC and non-ccRCC patients.
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