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: Chai Phei Gan, Vyomesh Patel, Constantinos M Mikelis, Rosnah Binti Zain, Alfredo A Molinolo, Mannil Thomas Abraham, Soo-Hwang Teo, Zainal Ariff Abdul Rahman, J Silvio Gutkind, Sok Ching Cheong
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 20 Pg. 9626-40 (Oct 30 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 25275299 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GTP-Binding Protein alpha Subunits, G12-G13

Topics

• Animals
• Carcinoma, Squamous Cell (genetics, metabolism, pathology)
• Cell Movement (physiology)
• Female
• GTP-Binding Protein alpha Subunits, G12-G13 (antagonists & inhibitors, genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Head and Neck Neoplasms (genetics, metabolism, pathology)
• Humans
• Lymphatic Metastasis
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Middle Aged
• Mouth Neoplasms (genetics, metabolism, pathology)
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Signal Transduction
• Squamous Cell Carcinoma of Head and Neck
• Transcriptional Activation
• Up-Regulation
• Xenograft Model Antitumor Assays