title: Klotho suppresses tumor progression via inhibiting PI3K/Akt/GSK3β/Snail signaling in renal cell carcinoma.
abstract: Klotho is an anti-aging protein predominantly expressed in renal tubular epithelial cells. Although Klotho was recently identified as a tumor suppressor gene in a variety of cancers, the potential role and molecular events for Klotho in renal cell carcinoma (RCC) remain obscure. In the present study, immunohistochemical staining in tissue microarrays containing 125 RCC samples showed that intratumoral Klotho levels were negatively correlated with tumor size, TNM stage and nuclear grade. The overall survival rate of RCC patients with high Klotho expression was significantly higher than that of patients with low Klotho expression. Functional analysis after gain and loss of Klotho expression revealed that Klotho blunted epithelial-mesenchymal transition and cellular migration and invasion in RCC. Also, no alteration of α-2,6-sialidase activity was found after Klotho overexpression in RCC. The molecular signals for this phenomenon involved the Klotho-mediated inhibition of PI3K/Akt/GSK3β/Snail pathway. Importantly, compared to localized RCC tissues, advanced RCC tissues exhibited low Klotho expression accompanied with high pAkt and Snail expression. These results indicate Klotho acts as a tumor suppressor by inhibiting PI3K/Akt/GSK3β/Snail signaling, thus suppressing epithelial-mesenchymal transition and tumor migration and invasion during RCC progression. As a result, Klotho might be used as a potential therapy for advanced RCC.
authors: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors: Yu
authors: Y
authors: Zhu
authors: Le
authors: L
authors: Xu
authors: Jianping
authors: J
authors: Zhang
authors: Wenping
authors: W
authors: Xu
authors: Yujun
authors: Y
authors: Liu
authors: Hankun
authors: H
authors: Yin
authors: Tao
authors: T
authors: Lv
authors: Huimin
authors: H
authors: An
authors: Li
authors: L
authors: Liu
authors: Hongyong
authors: H
authors: He
authors: Heng
authors: H
authors: Zhang
authors: Jing
authors: J
authors: Liu
authors: Jiejie
authors: J
authors: Xu
authors: Zongming
authors: Z
authors: Lin
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D016147:Genes, Tumor Suppressor; D005966:Glucuronidase / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000090265:Klotho Proteins; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
chemical_list: D014408:Biomarkers, Tumor; D005966:Glucuronidase; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D000090265:Klotho Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C000605506:GSK3B protein, human