Oncotarget

Research Papers:

Clinical relevance of the transcriptional signature regulated by CDC42 in colorectal cancer

Fatima Valdés-Mora, Warwick J. Locke, Eva Bandrés, David Gallego-Ortega, Paloma Cejas, Miguel Angel García-Cabezas, Yolanda Colino-Sanguino, Jaime Feliú, Teresa Gómez del Pulgar and Juan Carlos Lacal _

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Oncotarget. 2017; 8:26755-26770. https://doi.org/10.18632/oncotarget.15815

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Abstract

Fatima Valdés-Mora1,2, Warwick J. Locke3, Eva Bandrés4, David Gallego-Ortega2,5, Paloma Cejas6, Miguel Angel García-Cabezas7, Yolanda Colino-Sanguino1,2, Jaime Feliú6,8, Teresa Gómez del Pulgar6,*, Juan Carlos Lacal6,*

1Histone Variants Group, Epigenetics Research Program, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

2St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales Sydney, New South Wales, Australia

3Epigenetics Research Program, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

4Immunology Unit, Department of Haematology, Complejo Hospitalario de Navarra, Navarra Health Service, Pamplona, Spain

5Tumour Development Group, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

6Laboratorio de Oncología Translacional, Servicio de Oncología Médica, IdiPAZ, Madrid, Spain

7Servicio de Anatomía Patológica, Hospital Universitario La Paz, Madrid, Spain

8Servicio de Oncología Médica, IdiPAZ, CIBERONC, Madrid, Spain

*Co-senior authors

Correspondence to:

Juan Carlos Lacal, email: jclacal10@gmail.com

Fatima Valdes-Mora, email: f.valdesmora@garvan.org.au

Keywords: colorectal cancer, CACNA2D2, CDC42, tumor suppressor genes, prognostic factor

Received: June 16, 2016     Accepted: February 20, 2017     Published: March 01, 2017

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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