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

被引：57

作者：

Emerling, Brooke M. ^{[1
,2
]}

Benes, Cyril H. ^{[3
,4
]}

Poulogiannis, George ^{[1
,2
]}

Bell, Eric L. ^{[5
]}

Courtney, Kevin ^{[6
,7
]}

Liu, Hui ^{[1
,2
]}

Choo-Wing, Rayman ^{[1
,2
]}

Bellinger, Gary ^{[1
,2
]}

Tsukazawa, Kazumi S. ^{[1
,2
]}

Brown, Victoria ^{[6
,8
]}

Signoretti, Sabina ^{[6
,8
]}

Soltoff, Stephen P. ^{[2
]}

Cantley, Lewis C. ^{[1
,2
]}

机构：

[1] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA

[2] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02115 USA

[3] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA

[4] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[5] MIT, Dept Biol, Paul F Glenn Lab, Cambridge, MA 02139 USA

[6] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[7] Univ Texas SW Med Ctr Dallas, Div Hematol Oncol, Dallas, TX 75390 USA

[8] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2013年 / 110卷 / 09期

基金：

美国国家卫生研究院;

关键词：

kidney cancer; oxygen deprivation; DOMAIN-CONTAINING PROTEIN-1; CUB-DOMAIN; HIF-ALPHA; PKC-DELTA; VHL LOSS; SRC; INHIBITION; SUBSTRATE; SUPPRESSION; EXPRESSION;

D O I：

10.1073/pnas.1222435110

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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)-2 alpha-, but not HIF-l alpha-, dependent fashion. shRNA knockdown of CDCP1 impairs cancer cell migration under hypoxic conditions, whereas overexpression of HIF-2 alpha 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-2 alpha target gene involved in the regulation of cancer metastasis, and suggest that CDCP1 is a biomarker and potential therapeutic target for metastatic cancers.

引用

页码：3483 / 3488

页数：6

共 34 条

[1] Microarray-based identification of CUB-domain containing protein 1 as a potential prognostic marker in conventional renal cell carcinoma [J].

Awakura, Yasuo ;

Nakamura, Eijiro ;

Takahashi, Takeshi ;

Kotani, Hirokazu ;

Mikami, Yoshiki ;

Kadowaki, Tadashi ;

Myoumoto, Akira ;

Akiyama, Hideo ;

Ito, Noriyuki ;

Kamoto, Toshiyuki ;

Manabe, Toshiaki ;

Nobumasa, Hitoshi ;

Tsujimoto, Gozoh ;

Ogawa, Osamu .

JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY, 2008, 134 (12) :1363-1369

[2] The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production [J].

Bell, Eric L. ;

Klimova, Tatyana A. ;

Eisenbart, James ;

Moraes, Carlos T. ;

Murphy, Michael P. ;

Budinger, G. R. Scott ;

Chandel, Navdeep S. .

JOURNAL OF CELL BIOLOGY, 2007, 177 (06) :1029-1036

[3] The SRC-associated protein CUB Domain-Containing Protein-1 regulates adhesion and motility [J].

Benes, C. H. ;

Poulogiannis, G. ;

Cantley, L. C. ;

Soltoff, S. P. .

ONCOGENE, 2012, 31 (05) :653-663

[4] The C2 domain of PKCδ is a phosphotyrosine binding domain [J].

Benes, CH ;

Wu, N ;

Elia, AEH ;

Dharia, T ;

Cantley, LC ;

Soltoff, SP .

CELL, 2005, 121 (02) :271-280

[5] Adhesion signaling by a novel mitotic substrate of src kinases [J].

Bhatt, AS ;

Erdjument-Bromage, H ;

Tempst, P ;

Craik, CS ;

Moasser, MM .

ONCOGENE, 2005, 24 (34) :5333-5343

[6] A conserved family of prolyl-4-hydroxylases that modify HIF [J].

Bruick, RK ;

McKnight, SL .

SCIENCE, 2001, 294 (5545) :1337-1340

[7] Functional Role of Cell Surface CUB Domain-Containing Protein 1 in Tumor Cell Dissemination [J].

Deryugina, Elena I. ;

Conn, Erin M. ;

Wortmann, Andreas ;

Partridge, Juneth J. ;

Kupriyanova, Tatyana A. ;

Ardi, Veronica C. ;

Hooper, John D. ;

Quigley, James P. .

MOLECULAR CANCER RESEARCH, 2009, 7 (08) :1197-1211

[8] C-elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation [J].

Epstein, ACR ;

Gleadle, JM ;

McNeill, LA ;

Hewitson, KS ;

O'Rourke, J ;

Mole, DR ;

Mukherji, M ;

Metzen, E ;

Wilson, MI ;

Dhanda, A ;

Tian, YM ;

Masson, N ;

Hamilton, DL ;

Jaakkola, P ;

Barstead, R ;

Hodgkin, J ;

Maxwell, PH ;

Pugh, CW ;

Schofield, CJ ;

Ratcliffe, PJ .

CELL, 2001, 107 (01) :43-54

[9] Inhibition of Tumor Metastasis: Functional Immune Modulation of the CUB Domain Containing Protein 1 [J].

Fukuchi, Keisuke ;

Steiniger, Sebastian C. J. ;

Deryugina, Elena ;

Liu, Ying ;

Lowery, Colin A. ;

Gloeckner, Christian ;

Zhou, Bin ;

Kaufmann, Gunnar F. ;

Quigley, James P. ;

Janda, Kim D. .

MOLECULAR PHARMACEUTICS, 2010, 7 (01) :245-253

[10] Hypoxia-inducible factors: central regulators of the tumor phenotype [J].

Gordan, John D. ;

Simon, M. Celeste .

CURRENT OPINION IN GENETICS & DEVELOPMENT, 2007, 17 (01) :71-77

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