title: Predominant Rab-GTPase amplicons contributing to oral squamous cell carcinoma progression to metastasis.
abstract: 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.
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, Canada.|Segal 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.|Department of Head and Neck Surgery and Otorhinolaryngology, AC Camargo Cancer Center and National Institute of Science and Technology on Oncogenomics (INCITO), Brazil.
authors.forename: Sabrina Daniela
authors.initials: SD
authors.lastname: da Silva
authors.affiliation: NeoGene Laboratory, Department of Urology, Faculty of Medicine, UNESP, and International Research Center (CIPE), AC Camargo Cancer Center, Brazil.|Inter-Institutional Grad Program on Bioinformatics, University of São Paulo, Brazil.
authors.forename: Fabio Albuquerque
authors.initials: FA
authors.lastname: Marchi
authors.affiliation: Segal 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.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: Segal 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.
authors.forename: Krikor
authors.initials: K
authors.lastname: Bijian
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, Canada.
authors.forename: Faisal
authors.initials: F
authors.lastname: Alobaid
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, Canada.
authors.forename: Alex
authors.initials: A
authors.lastname: Mlynarek
authors.affiliation: NeoGene Laboratory, Department of Urology, Faculty of Medicine, UNESP, and International Research Center (CIPE), AC Camargo Cancer Center, Brazil.
authors.forename: Silvia Regina
authors.initials: SR
authors.lastname: Rogatto
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Sir Mortimer B. Davis-Jewish General Hospital, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Hier
authors.affiliation: Department of Head and Neck Surgery and Otorhinolaryngology, AC Camargo Cancer Center and National Institute of Science and Technology on Oncogenomics (INCITO), Brazil.
authors.forename: Luiz Paulo
authors.initials: LP
authors.lastname: Kowalski
authors.affiliation: Segal 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.
authors.forename: Moulay A
authors.initials: MA
authors.lastname: Alaoui-Jamali
mesh_terms: D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D018450:Disease Progression; D005260:Female; D022001:Focal Adhesions / Q000235:genetics / Q000473:pathology; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D009362:Neoplasm Metastasis; D000077195:Squamous Cell Carcinoma of Head and Neck; D020691:rab GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins
chemical_list: D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins; D000090802:rab7 GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C427755:RAB5C protein, human
keywords: aCGH; genomic; metastasis; oral squamous cell carcinoma; rab GTPases