Identification of CDCP1 as a hypoxia-inducible factor 2α (HIF-2α) target gene that is associated with survival in clear cell renal cell carcinoma patients

Brooke M. Emerling, Cyril H. Benes, George Poulogiannis, Eric L. Bell, Kevin Courtney, Hui Liu, Rayman Choo-Wing, Gary Bellinger, Kazumi S. Tsukazawa, Victoria Brown, Sabina Signoretti, Stephen P. Soltoff, Lewis C. Cantley

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

CUB domain-containing protein 1 (CDCP1) is a transmembrane protein that is highly expressed in stem cells and frequently overexpressed and tyrosine-phosphorylated in cancer. CDCP1 promotes cancer cell metastasis. However, the mechanisms that regulate CDCP1 are not well-defined. Here we show that hypoxia induces CDCP1 expression and tyrosine phosphorylation in hypoxia- inducible factor (HIF)-2α-, but not HIF-1α-, dependent fashion. shRNA knockdown of CDCP1 impairs cancer cell migration under hypoxic conditions, whereas overexpression of HIF-2α promotes the growth of tumor xenografts in association with enhanced CDCP1 expression and tyrosine phosphorylation. Immunohistochemistry analysis of tissue microarray samples from tumors of patients with clear cell renal cell carcinoma shows that increased CDCP1 expression correlates with decreased overall survival. Together, these data support a critical role for CDCP1 as a unique HIF-2α target gene involved in the regulation of cancer metastasis, and suggest that CDCP1 is a biomarker and potential therapeutic target for metastatic cancers.

Original languageEnglish (US)
Pages (from-to)3483-3488
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number9
DOIs
StatePublished - Feb 26 2013

Keywords

  • Kidney cancer
  • Oxygen deprivation

ASJC Scopus subject areas

  • General

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    Emerling, B. M., Benes, C. H., Poulogiannis, G., Bell, E. L., Courtney, K., Liu, H., Choo-Wing, R., Bellinger, G., Tsukazawa, K. S., Brown, V., Signoretti, S., Soltoff, S. P., & Cantley, L. C. (2013). Identification of CDCP1 as a hypoxia-inducible factor 2α (HIF-2α) target gene that is associated with survival in clear cell renal cell carcinoma patients. Proceedings of the National Academy of Sciences of the United States of America, 110(9), 3483-3488. https://doi.org/10.1073/pnas.1222435110