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.
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Authors | 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 |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 110
Issue 9
Pg. 3483-8
(Feb 26 2013)
ISSN: 1091-6490 [Electronic] United States |
PMID | 23378636
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antigens, CD
- Antigens, Neoplasm
- Basic Helix-Loop-Helix Transcription Factors
- CDCP1 protein, human
- Cell Adhesion Molecules
- Neoplasm Proteins
- endothelial PAS domain-containing protein 1
- src-Family Kinases
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Topics |
- Animals
- Antigens, CD
(genetics, metabolism)
- Antigens, Neoplasm
- Basic Helix-Loop-Helix Transcription Factors
(metabolism)
- Carcinoma, Renal Cell
(genetics, metabolism, pathology)
- Cell Adhesion Molecules
(genetics, metabolism)
- Cell Hypoxia
(genetics)
- Cell Line, Tumor
- Cell Proliferation
- Genes, Neoplasm
(genetics)
- Humans
- Kidney Neoplasms
(genetics, metabolism, pathology)
- Mice
- Mice, Nude
- Neoplasm Proteins
(genetics, metabolism)
- Signal Transduction
- Survival Analysis
- Xenograft Model Antitumor Assays
- src-Family Kinases
(metabolism)
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