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

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

doi:10.1073/pnas.1011777108

Cited by 82 publications

(97 citation statements)

References 38 publications

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“…The levels of the VHL transcript are increased in cervical carcinoma, which is the opposite of the demonstrated lower expression of VHL in renal cell carcinoma (49), multiple myeloma (50), pancreatic endocrine tumors (51), chronic lymphocytic leukemia (52) and squamous cell carcinoma of the vulva (53). The observed abnormal expression of VHL in cervical cancer could be associated with increased levels of HIF-1A, because we found a statistically significant, positive Spearman's rank correlation between HIF-1A and VHL expression.…”

Section: Normal Tissue Cancerous Tissue -----------------------------mentioning

confidence: 86%

Increased expression of HIF-1A and its implication in the hypoxia pathway in primary advanced uterine cervical carcinoma

Łuczak

Roszak²,

Pawlik³

et al. 2011

Oncol Rep

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Abstract. The development of cervical cancer exhibits some unique differences compared to other solid tumors. Normal cervical stratified epithelia have characteristics of hypoxic tissue. Lack of oxygen (hypoxia) induces the HIF-1 (hypoxiainducible factor-1) transcription factor, which is a heterodimer composed of a constitutively expressed β subunit and a hypoxia-inducible α-subunit. HIF-1A targets the transcription of over 70 genes involved in many aspects of cancer biology. In well-oxygenated environments, the HIF-1A subunit is hydroxylated, recognized and marked for proteosomal destruction by an E3 ubiquitin ligase, the von Hippel-Lindau protein (pVHL) complex. Under hypoxic stress, proline hydroxylase (PHD) activity is diminished, and stabilized HIF-1A is involved in the activation of the tissue response to hypoxia. Here, we examined the HIF-1A and VHL transcript levels and HIF-1A protein levels in cancerous tissue (n=30) and non-cancerous, normal uterine cervical tissue (n=30). We also compared the methylation status of HIF-1A and of the VHL promoter regions in cancerous and normal tissue samples. Significantly higher levels of HIF-1A and VHL transcripts (p<0.0001 and p= 0.0042, respectively) and of HIF-1A protein (p= 0.0037) were detected in cancerous tissue compared to normal samples. We did not observe DNA methylation in the HIF-1A and VHL promoter region in either control or cancerous tissue samples. VHL has a functional hypoxia response element (HRE) in the promoter region, and the induction of this HRE acts within a negative feedback loop to limit the hypoxic HIF-1A response. Our findings may suggest that HIF-1A could promote its own degradation by the induction of VHL gene expression (Spearman correlation coefficient, 0.515; p=0.003). Our study shows for the first time that this increase in VHL expression could be HIF-1A-dependent and serves within a negative feedback pathway during hypoxia to regulate the cell-specific oxygen threshold for HIF-1A activation.

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Section: Normal Tissue Cancerous Tissue -----------------------------mentioning

confidence: 86%

Increased expression of HIF-1A and its implication in the hypoxia pathway in primary advanced uterine cervical carcinoma

Łuczak

Roszak²,

Pawlik³

et al. 2011

Oncol Rep

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“…EGF increases the lifespan of CDCP1 promoting its availability on the cell surface where our data indicate it is available to mediate pro-cancer phenotypes such as cell migration. Based on published analysis of patient cohorts and animal models, antibody targeting of CDCP1 has been proposed for cancer treatment (9,10,18,20). This is supported by molecular analysis demonstrating that CDCP1 is pro-cancerous in vivo by promoting cell survival via pathways involving Src, PKCδ, FAK, PI3K and Akt (14,18,19), and that anti-CDCP1 antibodies efficiently block survival, inducing apoptosis (18)(19)(20)22).…”

Section: Discussionmentioning

confidence: 99%

EGF inhibits constitutive internalization and palmitoylation-dependent degradation of membrane-spanning procancer CDCP1 promoting its availability on the cell surface

Adams

Harrington

et al. 2014

Oncogene

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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: 89%

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

Cited by 82 publications

References 38 publications

Increased expression of HIF-1A and its implication in the hypoxia pathway in primary advanced uterine cervical carcinoma

Increased expression of HIF-1A and its implication in the hypoxia pathway in primary advanced uterine cervical carcinoma

EGF inhibits constitutive internalization and palmitoylation-dependent degradation of membrane-spanning procancer CDCP1 promoting its availability on the cell surface

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

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