Clinical Research Papers:
Heterotrimeric G-protein alpha-12 (Gα12) subunit promotes oral cancer metastasis
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Chai Phei Gan1, Vyomesh Patel1,2, Constantinos M. Mikelis2, Rosnah Binti Zain3,4, Alfredo A. Molinolo2, Mannil Thomas Abraham5, Soo-Hwang Teo1, Zainal Ariff Abdul Rahman3, J. Silvio Gutkind2, Sok Ching Cheong1,3
1Oral Cancer Research Team, Cancer Research Initiatives Foundation (CARIF), Selangor, Malaysia
2Oral and Pharyngeal Cancer Branch, National Institutes of Dental and Craniofacial Research, National Institutes of Health, Bethesda, USA
3Department of Oro-Maxillofacial Surgical and Medical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
4Oral Cancer Research and Coordinating Centre (OCRCC), University of Malaya, Kuala Lumpur, Malaysia
5Department of Oral and Maxillofacial Surgery, Tengku Ampuan Rahimah Hospital, Klang, Malaysia
Sok Ching Cheong, e-mail: firstname.lastname@example.org
Keywords: Oral squamous cell carcinoma, G-protein alpha-12, Lymph node, Metastasis
Received: June 23, 2014 Accepted: September 04, 2014 Published: November 12, 2014
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.
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