Predominant Rab-GTPase amplicons contributing to oral squamous cell carcinoma progression to metastasis
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Sabrina Daniela da Silva1,2,3, Fabio Albuquerque Marchi4,5, Bin Xu2, Krikor Bijian2, Faisal Alobaid1, Alex Mlynarek1, Silvia Regina Rogatto4, Michael Hier1, Luiz Paulo Kowalski3, Moulay A. Alaoui-Jamali2
1Department of Otolaryngology Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, Canada
2Segal Cancer Centre and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Departments of Medicine, Oncology, and Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Canada
3Department of Head and Neck Surgery and Otorhinolaryngology, AC Camargo Cancer Center and National Institute of Science and Technology on Oncogenomics (INCITO), Brazil
4NeoGene Laboratory, Department of Urology, Faculty of Medicine, UNESP, and International Research Center (CIPE), AC Camargo Cancer Center, Brazil
5Inter-institutional Grad Program on Bioinformatics, University of São Paulo, Brazil
Moulay A. Alaoui-Jamali, e-mail: [email protected]
Sabrina Daniela da Silva, e-mail: [email protected]
Keywords: aCGH, genomic, metastasis, oral squamous cell carcinoma, rab GTPases
Received: March 20, 2015 Accepted: June 03, 2015 Published: June 15, 2015
Metastatic oral squamous cell carcinoma (OSCC) is frequently associated with recurrent gene abnormalities at specific chromosomal loci. Here, we utilized array comparative genomic hybridization and genome-wide screening of metastatic and non-metastatic tongue tumors to investigate genes potentially contributing to OSCC progression to metastasis. We identified predominant amplifications of chromosomal regions that encompass the RAB5, RAB7 and RAB11 genes (3p24-p22, 3q21.3 and 8p11–12, respectively) in metastatic OSCC. The expression of these Rab GTPases was confirmed by immunohistochemistry in OSCC tissues from a cohort of patients with a follow-up of 10 years. A significant overexpression of Rab5, Rab7 and Rab11 was observed in advanced OSCC cases and co-overexpression of these Rabs was predictive of poor survival (log-rank test, P = 0.006). We generated a Rab interaction network and identified central Rab interactions of relevance to metastasis signaling, including focal adhesion proteins. In preclinical models, mRNA and protein expression levels of these Rab members were elevated in a panel of invasive OSCC cell lines, and their down-regulation prevented cell invasion at least in part via inhibition of focal adhesion disassembly. In summary, our results provide insights into the cooperative role of Rab gene amplifications in OSCC progression and support their potential utility as prognostic markers and therapeutic approach for advanced OSCC.
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