Low circulating serum levels of second mitochondria-derived activator of caspase (Smac/DIABLO) in patients with bladder cancer

Smac/DIABLO promotes apoptosis by antagonizing inhibitor of apoptosis proteins. The expression of Smac/DIABLO in tissues has been reported in various cancers; however, little is known about circulating levels of Smac/DIABLO. The present study was designed to first determine if Smac/DIABLO can be detected in the serum and then assess whether the circulating levels of Smac/DIABLO are of prognostic significance in patients with bladder cancer. The levels of Smac/DIABLO in the sera of 173 patients with bladder cancer and 36 normal donors were determined by using an enzyme-linked immunosorbent assay. The mean serum level of Smac/DIABLO in patients with bladder cancer was approximately 2-fold lower than that in normal donors. The mean level of serum Smac/DIABLO in patients with muscle-invasive bladder cancer was lower than that in patients with non-muscle invasive cancer. In addition, the mean serum Smac/DIABLO level in patients with T4 muscle-invasive bladder cancer was lower than that in patients with T2 and T3 cancers. The mean serum level of Smac/DIABLO in patients with Grade 3 bladder cancer was lower than that in patients with Grade 1 and Grade 2 cancers. Analysis by Kaplan-Meier revealed that patients with Ta and T1 non-muscle invasive bladder cancer with high level of serum Smac/DIABLO (more than mean value) had a longer postoperative tumor-free interval than those with low level (less than mean value) in the 3-year follow-up. Furthermore, patients with T2–T4 muscle-invasive bladder cancer with high serum Smac/DIABLO level (more than mean value) had a higher postoperative disease-free rate when compared with patients with low level (less than mean value) in the 5-year follow-up. The present study is the first to analyze circulating levels of Smac/DIABLO in the serum. The findings demonstrate that the mean serum level of Smac/DIABLO was downregulated in patients with bladder cancer compared to control healthy individuals, especially high grade muscle-invasive bladder cancer. Noteworthy, lower serum level of Smac/DIABLO predicted early recurrence in patients with bladder cancer. Overall, the findings suggest that measuring the levels of Smac/DIABLO in the serum may be considered a prognostic parameter in patients with bladder cancer. Furthermore, Smac/DIABLO may be a molecular therapeutic target in bladder cancer.