Gα(12) Drives Invasion of Oral Squamous Cell Carcinoma through Up-Regulation of Proinflammatory Cytokines

Oral squamous cell carcinoma (OSCC) ranks among the top ten most prevalent cancers worldwide. Like most head and neck squamous cell carcinomas (HNSCCs), OSCC is highly inflammatory and aggressive. However, the signaling pathways triggering the activation of its inflammatory processes remain elusive. G protein-coupled receptor signaling regulates the inflammatory response and invasiveness of cancers, but it remains unclear whether Gα(12) is a critical player in the inflammatory cytokine pathway during the tumorigenesis of OSCC. This study was undertaken to determine the role of Gα(12) signaling in the regulation of proinflammatory cytokines in their mediation of OSCC invasion. We found that both the transcription and protein levels of Gα(12) are up-regulated in OSCC tumors. The elevated Gα(12) expressions in OSCC patients also correlated with extra-capsular spread, an indicator of tumor invasiveness in HNSCCs. This clinical finding was supported by the studies of overexpression and RNAi knockdown of Gα(12) in OSCC cells, which demonstrated that Gα(12) promoted tumor cell migration and invasion. To understand how Gα(12) modulates OSCC invasiveness, we analyzed key biological processes in microarray data upon depletion of Gα(12) and found that cytokine- and other immune-related pathways were severely impaired. Importantly, the mRNA levels of IL-6 and IL-8 proinflammatory cytokines in clinical samples were found to be significantly correlated with the increased Gα(12) levels, suggesting a potential role of Gα(12) in modulating the IL-6 and IL-8 expressions. Supporting this hypothesis, overexpression or RNAi knockdown of Gα(12) in OSCC cell lines both showed that Gα(12) positively regulated the mRNA and protein levels of IL-6 and IL-8. Finally, we demonstrated that the Gα(12) promotion of tumor cell invasiveness was suppressed by the neutralization of IL-6 and IL-8 in OSCC cells. Together, these findings suggest that Gα(12) drives OSCC invasion through the up-regulation of IL-6 and IL-8 cytokines.