Identification and characterization of Ror2 as a tumor cancer cell specific kinase in renal cell carcinoma Public Deposited

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  • March 21, 2019
Creator
  • Wright, Tricia M.
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • With the recent advent of molecularly targeted therapy, the potential for novel treatment options for carcinomas has been brought to the forefront. However, few tumor cell-specific targets exist for many cancers. Our goal was to identify and characterize cell specific kinases for the difficult to treat epithelial cancer renal cell carcinoma (RCC). Using a phospho-specific receptor tyrosine kinase screen, we identified Ror2, a developmentally regulated orphan receptor kinase, to be overexpressed in RCC tumors and cell lines. Ror2 is normally expressed in the heart, brain, kidney and lungs of developing mice and has also been implicated in the Wnt/β-catenin signaling pathway. Using archival RCC tumor specimens, we show that Ror2 was coordinately overexpressed with genes involved at the extracellular matrix (ECM), including MMP2. Consequently, when Ror2 was suppressed in cell lines, MMP2 expression was also suppressed, suggesting Ror2 may play a role in directing MMP2 expression. Ror2 suppression also supported cellular migration, without affecting doubling time or viability. Additionally, inhibition of Ror2 limited RCC growth in soft agar, a surrogate for invasive growth potential and anchorage independence, and produced fewer tumors in vivo in xenografts. Since the discovery of Ror2 in RCC, Ror2 has since been implicated in several other cancers, where it is associated with invasive tumor characteristics. However, the regulatory or mechanistic events contributing to increased Ror2 expression had yet to be defined. We sought to place Ror2 in the most studied pathway in RCC, the inactivation of the tumor suppressor von Hippel-Lindau, VHL, leading to hypoxia induced factor (HIF)-1α and 2α dysregulation. We found that Ror2 expression was associated with pVHL loss and that VHL somatic mutations tightly coordinated with HIF-2α stabilization. Knockdown and rescue analysis of HIF expression suggests that Ror2 is dependent on the pathologic stabilization of both HIF1 and HIF2. However, induction of HIF by physiological hypoxia did not affect Ror2, suggesting a unique regulation of Ror2 dependent on non-physiologic HIF activation. This study identifies a novel putative kinase involved in key aspects of RCC tumorigenesis and also offers insight into how Ror2 is deregulated in RCC with potential application to other cancers.
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  • In Copyright
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum in Genetics and Molecular Biology."
Advisor
  • Rathmell, W. Kimryn
Degree granting institution
  • University of North Carolina at Chapel Hill
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  • Chapel Hill, NC
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  • Open access
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