K lotho suppresses tumor progression via inhibiting PI 3 K / A kt/ GSK 3β/Snail signaling in renal cell carcinoma

Klotho is an anti‐aging protein predominantly expressed in renal tubular epithelial cells. Although K lotho was recently identified as a tumor suppressor gene in a variety of cancers, the potential role and molecular events for K lotho in renal cell carcinoma ( RCC ) remain obscure. In the present study, immunohistochemical staining in tissue microarrays containing 125 RCC samples showed that intratumoral K lotho levels were negatively correlated with tumor size, TNM stage and nuclear grade. The overall survival rate of RCC patients with high K lotho expression was significantly higher than that of patients with low K lotho expression. Functional analysis after gain and loss of K lotho expression revealed that K lotho blunted epithelial‐mesenchymal transition and cellular migration and invasion in RCC . Also, no alteration of α‐2,6‐sialidase activity was found after K lotho overexpression in RCC . The molecular signals for this phenomenon involved the K lotho‐mediated inhibition of PI 3 K / A kt/ GSK 3β/ S nail pathway. Importantly, compared to localized RCC tissues, advanced RCC tissues exhibited low K lotho expression accompanied with high p A kt and Snail expression. These results indicate K lotho acts as a tumor suppressor by inhibiting PI 3 K / A kt/ GSK 3β/ S nail signaling, thus suppressing epithelial‐mesenchymal transition and tumor migration and invasion during RCC progression. As a result, K lotho might be used as a potential therapy for advanced RCC .