The protein tyrosine phosphatase receptor type J is regulated by the pVHL-HIF axis in clear cell renal cell carcinoma

Mass spectrometry analysis of renal cancer cell lines recently suggested that the protein-tyrosine phosphatase receptor type J (PTPRJ), an important regulator of tyrosine kinase receptors, is tightly linked to the von Hippel-Lindau protein (pVHL). Therefore, we aimed to characterize the biological relevance of PTPRJ for clear cell renal cell carcinoma (ccRCC). In pVHL-negative ccRCC cell lines, both RNA and protein expression levels of PTPRJ were lower than those in the corresponding pVHL reconstituted cells. Quantitative RT-PCR and western blot analysis of ccRCC with known VHL mutation status and normal matched tissues as well as RNA in situ hybridization on a tissue microarray (TMA) confirmed a decrease of PTPRJ expression in more than 80% of ccRCCs, but in only 12% of papillary RCCs. ccRCC patients with no or reduced PTPRJ mRNA expression had a less favourable outcome than those with a normal expression status (p = 0.05). Sequence analysis of 32 PTPRJ mRNA-negative ccRCC samples showed five known polymorphisms but no mutations, implying other mechanisms leading to PTPRJ's down-regulation. Selective silencing of HIF-α by siRNA and reporter gene assays demonstrated that pVHL inactivation reduces PTPRJ expression through a HIF-dependent mechanism, which is mainly driven by HIF-2α stabilization. Our results suggest PTPRJ as a member of a pVHL-controlled pathway whose suppression by HIF is critical for ccRCC development.