Journal
CANCER LETTERS
Volume 370, Issue 2, Pages 313-323Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2015.11.006
Keywords
Renal cell carcinoma; Hedgehog pathway; VHL; PI3K/AKT; Therapeutic target
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Funding
- National Natural Science Foundation of China [NSFC 81202014, NSFC 81372736]
- National High Technology Research and Development Program of China (863 Program) [SS2014AA020607]
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Renal cell carcinoma (RCC) is the most lethal urologic malignancy; however, the molecular events supporting RCC carcinogenesis and progression remain poorly understood. In this study, based on the analysis of gene expression profile data from human clear cell RCC (ccRCC) and the corresponding normal tissues, we discovered that Hedgehog (HH) pathway component genes GLI1 and GLI2 were significantly elevated in ccRCC. Survival analysis of a large cohort of ccRCC samples demonstrated that the expression of GLI1 and GLI2 was negatively correlated with patient overall survival. Clinical sample-based VHL mutation and cell model-based VHL manipulation studies all indicated that the activation of GLI1 and GLI2 was not affected by VHL status. Further signaling pathway dissections demonstrated that GM and GLI2 were activated by the phosphoinositide 3-kinase (PI3K)/AKT pathway, but not mediated by the canonical HH/SMO/GLI signaling. Up-regulation of GLI1 and GLI2 promoted RCC proliferation and clonogenic ability, whereas, a combination of GLIs inhibitor Gant61 and AKT inhibitor Perifosine synergistically suppressed RCC growth and induced apoptosis in vitro and in vivo. Therefore, this study identifies that GM and GLI2 are critical for RCC carcinogenesis, and also provides an alternative therapeutic strategy for RCC. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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