Abstract
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 Gα12 is a critical player in the inflammatory cytokine pathway during the tumorigenesis of OSCC. This study was undertaken to determine the role of Gα12 signaling in the regulation of proinflammatory cytokines in their mediation of OSCC invasion. We found that both the transcription and protein levels of Gα12 are up-regulated in OSCC tumors. The elevated Gα12 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 Gα12 in OSCC cells, which demonstrated that Gα12 promoted tumor cell migration and invasion. To understand how Gα12 modulates OSCC invasiveness, we analyzed key biological processes in microarray data upon depletion of Gα12 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 Gα12 levels, suggesting a potential role of Gα12 in modulating the IL-6 and IL-8 expressions. Supporting this hypothesis, overexpression or RNAi knockdown of Gα12 in OSCC cell lines both showed that Gα12 positively regulated the mRNA and protein levels of IL-6 and IL-8. Finally, we demonstrated that the Gα12 promotion of tumor cell invasiveness was suppressed by the neutralization of IL-6 and IL-8 in OSCC cells. Together, these findings suggest that Gα12 drives OSCC invasion through the up-regulation of IL-6 and IL-8 cytokines.
Highlights
Head and neck squamous cell carcinomas (HNSCCs) rank as the sixth most prevalent cancer worldwide, affecting up to 600,000 people each year [1,2]
Because the elevation of Ga12 expression is highly associated with tumor invasiveness in several human cancers [27,28,29], we examined the correlation between the Ga12 transcription level and clinicopathological characteristics, including tumor differentiation, pathologic T-status, N-status, pathological stage, tumor depth, extra-capsular spread (ECS), and lymphatic invasion in 55 oral squamous cell carcinoma (OSCC) patients
We found evidence to support that the increase of Ga12 is an important stimulator for the production of proinflammatory cytokines IL-6 and IL-8 and tumor invasiveness in OSCC
Summary
Head and neck squamous cell carcinomas (HNSCCs) rank as the sixth most prevalent cancer worldwide, affecting up to 600,000 people each year [1,2]. Among the various HNSCC subtypes, about 10% are accounted by oral squamous cell carcinoma (OSCC) [1]. Similar to other subtypes of HNSCC, the development of OSCC is closely intertwined with behavioral and environmental risk factors, including the consumption of alcohol, tobacco, and betel nut as well as the infection by human papillomavirus [3,4,5]. These risk factors induce proinflammatory cytokine responses, which contribute to the high aggressiveness of malignancy associated with OSCC [6,7]. The cellular regulatory molecules for the modulation of IL-6 and IL8 responses in OSCC remain to be defined
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