Clinical relevance of the transcriptional signature regulated by CDC42 in colorectal cancer
Entity
UAM. Departamento de Medicina; Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ)Publisher
Impact JournalsDate
2017-03-01Citation
10.18632/oncotarget.15815
Oncotarget 8.16 (2017): 26755-26770
ISSN
1949-2553DOI
10.18632/oncotarget.15815Funded by
This work has been supported by grants to JCL from Ministerio de Ciencia e Innovación (SAF2008- 03750, RD06-0020-0016 and RD12/0036/0019) and to DGO Cancer Institute New South Wales (2017/CDF625). FVM is a National Breast Cancer Foundation/Cure Cancer Australia Foundation Postdoctoral Training Fellow.Project
Gobierno de España. SAF2008- 03750; Gobierno de España. RD06-0020-0016; Gobierno de España. RD12/0036/0019Editor's Version
https://doi.org/10.18632/oncotarget.15815Subjects
Colorectal cancer; CACNA2D2; CDC42; Tumor suppressor genes; Prognostic factor; MedicinaRights
© 2017 Valdés-Mora et al.Abstract
CDC42 is an oncogenic Rho GTPase overexpressed in colorectal cancer (CRC). Although CDC42 has been shown to regulate gene transcription, the specific molecular mechanisms regulating the oncogenic ability of CDC42 remain unknown. Here, we have characterized the transcriptional networks governed by CDC42 in the CRC SW620 cell line using gene expression analysis. Our results establish that several cancer-related signaling pathways, including cell migration and cell proliferation, are regulated by CDC42. This transcriptional signature was validated in two large cohorts of CRC patients and its clinical relevance was also studied. We demonstrate that three CDC42-regulated genes offered a better prognostic value when combined with CDC42 compared to CDC42 alone. In particular, the concordant overexpression of CDC42 and silencing of the putative tumor suppressor gene CACNA2D2 dramatically improved the prognostic value. The CACNA2D2/CDC42 prognostic classifier was further validated in a third CRC cohort as well as in vitro and in vivo CRC models. Altogether, we show that CDC42 has an active oncogenic role in CRC via the transcriptional regulation of multiple cancer-related pathways and that CDC42-mediated silencing of CACNA2D2 is clinically relevant. Our results further support the use of CDC42 specific inhibitors for the treatment of the most aggressive types of CRC
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Google Scholar:Valdés-Mora, Fátima
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Locke, Warwick J.
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Bandrés, Eva
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Gallego-Ortega, David
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Cejas, Paloma
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García-Cabezas, Miguel Ángel
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Colino-Sanguino, Yolanda
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Feliú Batlle, Jaime
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Gómez del Pulgar, Teresa
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Lacal, Juan Carlos
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