Clinical significance of α- and β-Klotho in urothelial carcinoma of the bladder

Non-muscle invasive bladder cancer (NMIBC) accounts for similar to 70% of all bladder cancers. One of the serious clinical issues related to the management of NMIBC is that it has significant potential to progress to muscle invasive bladder cancer (MIBC) after initial treatments. alpha-Klotho (KL alpha), originally identified as an anti-aging gene, has recently been reported to have antitumor effects in various malignancies. In contrast, beta-Klotho (KL beta) has been reported to have protumoral functions. However, the associations between KL alpha/KL beta and the biological behavior of urothelial carcinoma remain unclear. In the present study, we evaluated the association between clinicopathological background factors of NMIBC and the expression levels of KL alpha or KL beta. A high expression level of KL beta, but not KL alpha, was an independent predictive factor of short progression-free survival for NMIBC. An elevated level of KL beta correlated with a higher incidence of lymphovascular invasion (LVI). We added in vitro assays using human bladder cancer cell lines to investigate the role of KL beta. Treatment with exogenous KL beta protein increased the proliferation, migration, transendothelial migration abilities and anchorage-independent growth of the cell lines. In addition, the KL beta concentration in voided urine samples obtained before initial transurethral surgery was quantitated with enzyme-linked immunosorbent assay (ELISA). The urine KL beta concentration was found to be higher in patients with bladder cancer than that in healthy volunteers. Our results suggest that KL beta plays important roles in tumor invasion and progression, and its concentration may be a valuable urine-based marker for the detection of bladder cancer.