Heterotrimeric G-protein alpha-12 (G′12) subunit promotes oral cancer metastasis

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 similar to 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 (G'12) 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 G'12 promoted cell migration and invasion in OSCC cell lines. Correspondingly, inhibition of G'12 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 G'12-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 G'12-related pathways for metastasis prevention.