title: Heterotrimeric G-protein alpha-12 (Gα12) subunit promotes oral cancer metastasis.
abstract: Oral squamous cell carcinoma (OSCC) has a propensity to spread to the cervical lymph nodes (LN). The presence of cervical LN metastases severely impacts patient survival, whereby the two-year survival for oral cancer patients with involved LN is ~30% compared to over 80% in patients with non-involved LN. Elucidation of key molecular mechanisms underlying OSCC metastasis may afford an opportunity to target specific genes, to prevent the spread of OSCC and to improve patient survival. In this study, we demonstrated that expression of the heterotrimeric G-protein alpha-12 (Gα12) is highly up-regulated in primary tumors and LN of OSCC patients, as assessed by quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC). We also found that exogenous expression of the constitutively activated-form of Gα12 promoted cell migration and invasion in OSCC cell lines. Correspondingly, inhibition of Gα12 expression by shRNA consistently inhibited OSCC cell migration and invasion in vitro. Further, the inhibition of G12 signaling by regulator of G-protein signaling (RGS) inhibited Gα12-mediated RhoA activation, which in turn resulted in reduced LN metastases in a tongue-orthotopic xenograft mouse model of oral cancer. This study provides a rationale for future development and evaluation of drug candidates targeting Gα12-related pathways for metastasis prevention.
authors.affiliation: Oral Cancer Research Team, Cancer Research Initiatives Foundation (CARIF), Selangor, Malaysia.
authors.forename: Chai Phei
authors.initials: CP
authors.lastname: Gan
authors.affiliation: Oral Cancer Research Team, Cancer Research Initiatives Foundation (CARIF), Selangor, Malaysia. Oral and Pharyngeal Cancer Branch, National Institutes of Dental and Craniofacial Research, National Institutes of Health, Bethesda, USA.
authors.forename: Vyomesh
authors.initials: V
authors.lastname: Patel
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institutes of Dental and Craniofacial Research, National Institutes of Health, Bethesda, USA.
authors.forename: Constantinos M
authors.initials: CM
authors.lastname: Mikelis
authors.affiliation: Department of Oro-Maxillofacial Surgical and Medical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia. Oral Cancer Research and Coordinating Centre (OCRCC), University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Rosnah Binti
authors.initials: RB
authors.lastname: Zain
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institutes of Dental and Craniofacial Research, National Institutes of Health, Bethesda, USA.
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Molinolo
authors.affiliation: Department of Oral and Maxillofacial Surgery, Tengku Ampuan Rahimah Hospital, Klang, Malaysia.
authors.forename: Mannil Thomas
authors.initials: MT
authors.lastname: Abraham
authors.affiliation: Oral Cancer Research Team, Cancer Research Initiatives Foundation (CARIF), Selangor, Malaysia.
authors.forename: Soo-Hwang
authors.initials: SH
authors.lastname: Teo
authors.affiliation: Department of Oro-Maxillofacial Surgical and Medical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Zainal Ariff
authors.initials: ZA
authors.lastname: Abdul Rahman
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institutes of Dental and Craniofacial Research, National Institutes of Health, Bethesda, USA.
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.affiliation: Oral Cancer Research Team, Cancer Research Initiatives Foundation (CARIF), Selangor, Malaysia. Department of Oro-Maxillofacial Surgical and Medical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Sok Ching
authors.initials: SC
authors.lastname: Cheong
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002465:Cell Movement / Q000502:physiology; D005260:Female; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck; D015533:Transcriptional Activation; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D044365:GTP-Binding Protein alpha Subunits, G12-G13