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Ror2, a developmentally regulated kinase, promotes tumor growth potential in renal cell carcinoma.

ABSTRACT: Inappropriate kinase expression and subsequent promiscuous activity defines the transformation of many solid tumors including renal cell carcinoma (RCC). Thus, the expression of novel tumor-associated kinases has the potential to dramatically shape tumor cell behavior. Further, identifying tumor-associated kinases can lend insight into patterns of tumor growth and characteristics. Here, we report the identification of the RTK-like orphan receptor 2 (Ror2), a new tumor-associated kinase in RCC cell lines and primary tumors. Ror2 is an orphan receptor tyrosine kinase with physiological expression normally seen in the embryonic kidney. However, in RCC, Ror2 expression correlated with expression of genes involved at the extracellular matrix, including Twist and matrix metalloprotease-2 (MMP2). Expression of MMP2 in RCC cells was suppressed by Ror2 knockdown, placing Ror2 as a mediator of MMP2 regulation in RCC and a potential regulator of extracellular matrix remodeling. The suppression of Ror2 not only inhibited cell migration, but also inhibited anchorage-independent growth in soft agar and growth in an orthotopic xenograft model. These findings suggest a novel pathway of tumor-promoting activity by Ror2 within a subset of renal carcinomas, with significant implications for unraveling the tumorigenesis of RCC.

SUBMITTER: Wright TM

PROVIDER: S-EPMC2771692 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Ror2, a developmentally regulated kinase, promotes tumor growth potential in renal cell carcinoma.

Wright T M TM Brannon A R AR Gordan J D JD Mikels A J AJ Mitchell C C Chen S S Espinosa I I van de Rijn M M Pruthi R R Wallen E E Edwards L L Nusse R R Rathmell W K WK

Oncogene 20090518 27

Inappropriate kinase expression and subsequent promiscuous activity defines the transformation of many solid tumors including renal cell carcinoma (RCC). Thus, the expression of novel tumor-associated kinases has the potential to dramatically shape tumor cell behavior. Further, identifying tumor-associated kinases can lend insight into patterns of tumor growth and characteristics. Here, we report the identification of the RTK-like orphan receptor 2 (Ror2), a new tumor-associated kinase in RCC ce ...[more]

PMID: 19448672

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Project description:BackgroundClinically, the median survival in patients with metastatic renal cell carcinoma (RCC) was only 6-12 months and a 5-year survival rate of less than 20%. Therefore, an in-depth study of the molecular mechanisms involved in RCC is of great significance for improving the survival of patients with advanced RCC. Acylglycerol kinase (AGK) is a newly discovered lipid kinase that has been reported to be a potent oncogene that may be involved in the regulation of malignant progression in a variety of tumours. However, the expression and biological characteristics of the AGK gene in RCC remain unclear.MethodsAGK expression was quantified by quantitative real-time PCR, Western blotting and immunohistochemistry in RCC cell lines and paired patient tissues. Kaplan-Meier method and Cox proportional hazards models were used to evaluate the prognostic value of AGK in human RCC tissue samples. Chi-squared test was performed to analyse the correlation between AGK expression and the clinicopathological features. Stable overexpression and knockdown of AGK in RCC cells was constructed with lentivirus. The oncogenic effects of AGK in human RCC progression were investigated using assays of colony formation, anchorage-independent growth, EdU assay, cell cycle analysis, wound-healing, trans-well analysis and xenograft tumour model. GSEA and KEGG analysis were conducted to detect the potential pathway of AGK involved in RCC. These results were further confirmed using the luciferase reporter assays, immunofluorescence and in vivo experiments.ResultsAGK expression is significantly elevated in RCC and closely related to the malignant development and poor prognosis in RCC patients. By in vitro and in vivo experiments, AGK was shown to enhance the proliferation of RCC cells by promoting the transition from the G1 phase to the S phase in the cell cycle and to enhance the migration and invasion by promoting epithelial-mesenchymal transition. By activating the PI3K/AKT/GSK3β signalling pathway in RCC, AGK can increase nuclear accumulation of β-catenin, which further upregulated TCF/LEF transcription factor activity.ConclusionsAGK promotes the progression of RCC via activating the PI3K/AKT/GSK3β signalling pathway and might be a potential target for the further research of RCC.

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Ror2, a developmentally regulated kinase, promotes tumor growth potential in renal cell carcinoma.

Publications

Ror2, a developmentally regulated kinase, promotes tumor growth potential in renal cell carcinoma.

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