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

Awakura, Yasuhiro; 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

doi:10.1007/s00432-008-0412-4

Cited by 62 publications

(68 citation statements)

References 27 publications

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“…CDCP1 expression is positively correlated with poor prognosis in patients with lung, renal, or pancreatic cancer (8)(9)(10). These findings strongly suggest that CDCP1 promotes cancer metastasis and invasion.…”

Section: Discussionmentioning

confidence: 75%

“…The expression of CDCP1 was reported in several human malignancies, such as colon and breast cancers (3,7). CDCP1 expression is strongly associated with cancer progression and poor prognosis in renal cell carcinoma, lung adenocarcinoma, and pancreatic cancer (8)(9)(10). We previously reported that CDCP1 is a critical regulator of anoikis resistance in lung cancer cells (11), peritoneal dissemination of gastric scirrhous carcinoma (12), and invasion of pancreatic cancer cells (8).…”

Section: Introductionmentioning

confidence: 99%

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CDCP1 Regulates the Function of MT1-MMP and Invadopodia-Mediated Invasion of Cancer Cells

Miyazawa

Uekita

Ito

et al. 2013

Molecular Cancer Research

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Complement C1r/C1s, Uegf, Bmp1 (CUB) domain-containing protein 1 (CDCP1) is a transmembrane protein that regulates anchorage-independent growth and cancer cell migration and invasion. Expression of CDCP1 is detected in a number of cancer cell lines and tissues and is closely correlated with poor prognosis. Invadopodia are actin-based protrusions on the surface of invasive cancer cells that promote the degradation of the extracellular matrix (ECM) via localized proteolysis, which is mainly mediated by membrane type 1 matrix metalloproteinase (MT1-MMP). MT1-MMP is accumulated at invadopodia by targeted delivery via membrane trafficking. The present study shows that CDCP1 is required for ECM degradation by invadopodia in human breast cancer and melanoma cells. CDCP1 localized to caveolin-1-containing vesicular structures and lipid rafts and was detected in close proximity to invadopodia. Further biochemical analysis revealed that substantial amounts of CDCP1 existed in the Triton X-100 insoluble lipid raft fraction. CDCP1 was coimmunoprecipitated with MT1-MMP and colocalized with MT1-MMP at the vesicular structures. The siRNA-mediated knockdown of the CDCP1 expression markedly inhibited MT1-MMP-dependent ECM degradation and Matrigel invasion and reduced the accumulation of MT1-MMP at invadopodia, as shown by immunofluorescence analysis. These results indicate that CDCP1 is an essential regulator of the trafficking and function of MT1-MMP-and invadopodia-mediated invasion of cancer cells. Mol Cancer Res; 11(6); 628-37.

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Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

CDCP1 Regulates the Function of MT1-MMP and Invadopodia-Mediated Invasion of Cancer Cells

Miyazawa

Uekita

Ito

et al. 2013

Molecular Cancer Research

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“…In several tumor types that commonly metastasize via vascular routes, including lung, kidney, pancreas and colon cancer, elevated or cell-surface expression of CDCP1 is associated with poor patient outcome. [12][13][14][15][16][17] Consistent with a role in hematogenous metastasis, in animal models of vascular dissemination, survival of cancer cells undergoing extravasation is markedly enhanced by a mechanism involving serine protease cleavage to generate 70 kDa CDCP1. This initiates pro-survival signaling via focal adhesion kinase 1 and phosphoinositide 3-kinase (PI3K) dependent protein kinase B (Akt) activation resulting in suppression of poly (ADP-ribose) polymerase 1 (PARP1) mediated apoptosis.…”

Section: Introductionmentioning

confidence: 92%

Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance

Harrington

et al. 2015

Oncogene

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Hematogenous metastases are rarely present at diagnosis of ovarian clear cell carcinoma (OCC). Instead dissemination of these tumors is characteristically via direct extension of the primary tumor into nearby organs and the spread of exfoliated tumor cells throughout the peritoneum, initially via the peritoneal fluid, and later via ascites that accumulates as a result of disruption of the lymphatic system. The molecular mechanisms orchestrating these processes are uncertain. In particular, the signaling pathways used by malignant cells to survive the stresses of anchorage-free growth in peritoneal fluid and ascites, and to colonize remote sites, are poorly defined. We demonstrate that the transmembrane glycoprotein CUB-domain-containing protein 1 (CDCP1) has important and inhibitable roles in these processes. In vitro assays indicate that CDCP1 mediates formation and survival of OCC spheroids, as well as cell migration and chemoresistance. Disruption of CDCP1 via silencing and antibody-mediated inhibition markedly reduce the ability of TOV21G OCC cells to form intraperitoneal tumors and induce accumulation of ascites in mice. Mechanistically our data suggest that CDCP1 effects are mediated via a novel mechanism of protein kinase B (Akt) activation. Immunohistochemical analysis also suggested that CDCP1 is functionally important in OCC, with its expression elevated in 90% of 198 OCC tumors and increased CDCP1 expression correlating with poor patient disease-free and overall survival. This analysis also showed that CDCP1 is largely restricted to the surface of malignant cells where it is accessible to therapeutic antibodies. Importantly, antibody-mediated blockade of CDCP1 in vivo significantly increased the anti-tumor efficacy of carboplatin, the chemotherapy most commonly used to treat OCC. In summary, our data indicate that CDCP1 is important in the progression of OCC and that targeting pathways mediated by this protein may be useful for the management of OCC, potentially in combination with chemotherapies and agents targeting the Akt pathway.

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“…Four studies assessed the possibility of using the level of CDCP1 expression as a prognostic factor for survival of lung adenocarcinoma, conventional RCC, pancreatic cancer patients, and endometrioid adenocarcinoma (29,(32)(33)(34). All of them indicated that elevated CDCP1 expression correlates with low overall survival.…”

Section: Cdcp1 Expression On the Cell Surface Of Tumor Cells Correlatmentioning

confidence: 99%

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

Razorenova

Finger

Colavitti

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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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.

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

Abstract: We identified CDCP1 as a potential prognostic marker for conventional RCC. Further studies might be required to confirm the prognostic value of CDCP1 and to understand its function in RCC progression.

Cited by 62 publications

References 27 publications

CDCP1 Regulates the Function of MT1-MMP and Invadopodia-Mediated Invasion of Cancer Cells

CDCP1 Regulates the Function of MT1-MMP and Invadopodia-Mediated Invasion of Cancer Cells

Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance

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

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