Expression of p53, pRb, Ki-67 and bcl-2 in betel quid induced oral mucosal lesions
Introduction: The variability of clinical outcomes in oral cancer patients and the heterogeneity of the disease are the main challenges for the improvement of current treatment modalities. Efforts in our laboratory have focused on the molecular profiling of oral cancer to understand the mechanisms underlying the disease. In a previous microarray study, we found Guanine nucleotide binding protein alpha-12 (GNA12) to be up-regulated in oral cancer. Materials and methods: In this study, we validated the expression of GNA12 at the mRNA level in 47 oral squamous cell carcinoma (OSCC) and 18 non-malignant oral mucosa tissues, by quantitative polymerase chain reaction (qPCR). Further, GNA12 protein expression was accessed by immunohistochemistry (IHC) on 44 tumors and 23 non-malignant oral mucosa tissues. Using OSCC cell lines, we examined the effects of GNA12 signaling by in vitro functional assays. Results: We demonstrated that GNA12 mRNA levels were significantly up-regulated in OSCC in comparison to the non-malignant oral mucosa tissues. Consistently, high levels of GNA12 protein expression were detected in 75% of OSCC tissues, while the non-malignant tissues showed negative or weak expression. We demonstrated that expression of activated GNA12 (GQ231L) promoted oral cancer cell migration in a monolayer wound healing assay and cell invasion through the matrigel barrier, but cell proliferation was not changed. Correspondingly, exogenous expression of the regulator of G-protein signaling (RGS) blocked G12 family signaling through RhoA, which resulted in the inhibition of cancer cell migration and invasion. Discussion: In summary, we demonstrated for the first time in OSCC that GNA12 is over-expressed in a large percentage of these patients and notably, the over-expression drives migration and invasion of oral cancer cells. Taken together, this information indicates that targeting GNA12 could benefit oral cancer patients by preventing the spread of the disease.