VHL status regulates transforming growth factor-ß signaling pathways in renal cell carcinoma.
Oncotarget
; 9(23): 16297-16310, 2018 Mar 27.
Article
en En
| MEDLINE
| ID: mdl-29662646
To evaluate the role of pVHL in the regulation of TGF-ß signaling pathways in clear cell renal cell carcinoma (ccRCC) as well as in non-ccRCC; the expression of pVHL, and the TGF-ß 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-ß 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-ß induced cancer cell invasiveness. The pVHL status controls the ALK5 and can thereby regulate the TGF-ß pathway, aggressiveness of tumors, and survival of the ccRCC and non-ccRCC patients.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Oncotarget
Año:
2018
Tipo del documento:
Article
País de afiliación:
Suecia
Pais de publicación:
Estados Unidos