VHL status regulates transforming growth factor-β signaling pathways in renal cell carcinoma

• Published in: Oncotarget 2018-03, Vol.9 (23), p.16297-16310
• Main Authors: Mallikarjuna, Pramod, Sitaram, Raviprakash T, Landström, Maréne, Ljungberg, Börje
• Format: Article
• Language: English
• Subjects: ALK5; Cancer Epidemiology; cancerepidemiologi; ccRCC; molecular cell biology; molekylär cellbiologi; non-ccRCC; pVHL; Research Paper; TGF-β signaling
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.24631

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 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. 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.