VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKCδ-driven migration

Olga V. Razorenova, Elizabeth C. Finger, Renata Colavitti, Sophia B. Chernikova, Alexander D. Boiko, Charles K.F. Chan, Adam Krieg, Barbara Bedogni, Edward LaGory, Irving L. Weissman, Marianne Broome-Powell, Amato J. Giaccia

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Abstract

A common genetic mutation found in clear cell renal cell carcinoma (CC-RCC) is the loss of the von Hippel-Lindau (VHL) gene, which results in stabilization of hypoxia-inducible factors (HIFs), and contributes to cancer progression and metastasis. CUB-domain-containing protein 1 (CDCP1) was shown to promote metastasis in scirrhous and lung adenocarcinomas as well as in prostate cancer. In this study, we established a molecular mechanism linking VHL loss to induction of the CDCP1 gene through the HIF-1/2 pathway in renal cancer. Also, we report that Fyn, which forms a complex with CDCP1 and mediates its signaling to PKCδ, is a HIF-1 target gene. Mechanistically, we found that CDCP1 specifically regulates phosphorylation of PKCδ, but not of focal adhesion kinase or Crk-associated substrate. Signal transduction from CDCP1 to PKCδ leads to its activation, increasing migration of CC-RCC. Furthermore, patient survival can be stratified by CDCP1 expression at the cell surface of the tumor. Taken together, our data indicates that CDCP1 protein might serve as a therapeutic target for CC-RCC.

Original languageEnglish (US)
Pages (from-to)1931-1936
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number5
DOIs
StatePublished - Feb 1 2011

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Razorenova, O. V., Finger, E. C., Colavitti, R., Chernikova, S. B., Boiko, A. D., Chan, C. K. F., Krieg, A., Bedogni, B., LaGory, E., Weissman, I. L., Broome-Powell, M., & Giaccia, A. J. (2011). VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKCδ-driven migration. Proceedings of the National Academy of Sciences of the United States of America, 108(5), 1931-1936. https://doi.org/10.1073/pnas.1011777108