Overexpression of XIAP expression in renal cell carcinoma predicts a worse prognosis

Abstract

X-linked inhibitor of apoptosis protein (XIAP) is the most potent caspase-inhibitory IAP family member and a negative regulator of various apoptotic stimuli. Thus, XIAP overexpression in cancer cells may select for tumor cell survival following various cytotoxic therapeutic modalities. The anatomical staging system in renal cell carcinoma (RCC) currently provides good prognostic information, albeit insufficient. We hypothesize that overexpression of XIAP in RCC may serve as a molecular prognostic marker in RCC and improve the staging of RCC. This study examined the protein level of XIAP in lysates from surgical specimens of 109 patients with RCC and 109 normal kidney specimens from the same patients. The level of XIAP expression was quantified by Western blot analysis using non-fixed fresh frozen tissues of RCCs and normal kidneys. Results indicated that the mean level of XIAP expression was higher in RCC compared to autologous normal kidney, and the XIAP expression level in 38/109 (35%) of RCC was more than 2-fold greater than that in normal kidney tissue. In Stage I/II RCC, the mean XIAP expression level was almost identical to that detected in normal kidney, whereas XIAP expression in Stage III/IV was 2.5-fold higher than that in Stage I/II RCC. Levels of XIAP expression also correlated with the grade of RCC. Patients with RCC with low XIAP expression had a longer postoperative disease-specific survival as compared to those with high expression in the 5-year follow-up. The suggested role of XIAP in the regulation of resistance in apoptosis was examined in vitro following treatment of RCC cell lines with XIAP antisense oligonucleotide and the cells were sensitized to both Fas-mediated and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. The present study demonstrates at the protein level that XIAP is overexpressed in RCC, and that high XIAP expression in RCC predicted a worse prognosis. In addition, XIAP antisense oligonucleotide sensitized RCC to Fas/TRAIL-induced apoptosis. These results suggest that XIAP expression in RCC may be used as a prognostic parameter, and that downregulation or inhibition of XIAP expression in RCC may reverse immune resistance.