Abstract
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.
Highlights
Renal cell carcinoma (RCC) is a heterogeneous tumor caused by alterations in different genes
The pVHL levels were significantly lower in clear cell renal cell carcinoma (ccRCC) (n=143) than its corresponding kidney cortex (n=35) (P=0.012), as well as non-ccRCC (n=54) (P
For non-ccRCC (n= 54) there was no difference in pVHL levels (P=0.663) when compared with corresponding kidney cortex (n=20)
Summary
Renal cell carcinoma (RCC) is a heterogeneous tumor caused by alterations in different genes. Main RCC types are clear cell RCC (ccRCC), papillary (pRCC), and chromophobe RCC (chRCC) [3]. Papillary type represents 15-20% of RCC with five years survival rate about 70-90%, and chromophobe type counts for 6-11% of RCC with a five years survival rate of 80-95%. Both pRCC and chRCC revealed the hypovascular feature unlike ccRCC [4]. The differences in prognosis and tumor behavior of the different RCC types are due to the involvement of various genes and signaling pathways [5]. Recurrent genetic alterations found in chRCC are the loss of heterozygosity (LOH) at chromosomes 1, 2, 6, 10, 13, 17 and 21, and are associated with Brit Hogg Dube syndrome [6]
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