Carcinogenesis Advance Access originally published online on January 18, 2007
Carcinogenesis 2007 28(6):1145-1152; doi:10.1093/carcin/bgm008
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Persistent activation of Rac1 in squamous carcinomas of the head and neck: evidence for an EGFR/Vav2 signaling axis involved in cell invasion
1 Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
2 Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, University of Salamanca-CSIC, Campus Unamuno, E-37007 Salamanca, Spain
3 Present address: Cancer Biology Program, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, Australia
4 Present address: Endocrinology, Hospital Clinic de Barcelona, Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain
* To whom correspondence should be addressed. Tel: +1 301 496 6259; Fax: +1 301 402 0823; Email: sg39v{at}nih.gov
The poor prognosis associated with head and neck squamous cell carcinoma (HNSCC) is primarily due to both local invasion and the regional and/or distant metastatic spread. Recent findings have provided evidence that the acquisition of a motile and invasive phenotype by cancer cells involves the dysregulated function of key intracellular molecular mechanisms together with aberrant signaling events initiated by the surrounding microenvironment. These intrinsic and extrinsic biochemical pathways in turn often converge to stimulate the activity of members of the Rho family of Ras-related guanosine triphosphate (GTP)-binding proteins, including RhoA, Rac and Cdc42, which control the organization of the actin cytoskeleton thereby regulating cell adhesion, polarity and motility. In this study, we examined the status of activation of these GTPases in a representative collection of HNSCC cell lines. Surprisingly, we found that most HNSCC cells exhibit remarkably high levels of GTP-bound Rac1. Further analysis revealed that the activation of Rac1 in these HNSCC cells could be due to two independent signaling events, an epidermal growth factor receptor (EGFR)-based autocrine loop that leads to the activation of the Rac1 exchange factor Vav2 and an EGFR/Vav2-independent pathway that arises as a consequence of the oncogenic mutation of the H-ras proto-oncogene. Indeed, we provide evidence that the EGFR/Vav2/Rac1 axis is a crucial pathway for the acquisition of motile and invasive properties of most HNSCC cells. These findings shed light onto the molecular mechanisms involved in HNSCC cell invasion, and may reveal new therapeutic opportunities to halt the metastatic spread of these aggressive malignancies.
Abbreviations: BSA, bovine serum albumin; DMEM, Dulbecco's modified Eagle's medium; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; GTP, guanosine triphosphate; HNSCC, head and neck squamous cell carcinoma
Received April 7, 2006; revised December 22, 2006; accepted December 27, 2006.
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