Oral squamous cell carcinoma has a striking tendency to migrate and metastasize. Cyclooxygenase (COX)-2, the inducible isoform of prostaglandin (PG) synthase, has been implicated in tumor metastasis. However, the effects of COX-2 on human oral cancer cells are largely unknown. We found that overexpression of COX-2 or exogenous PGE 2 increased migration and intercellular adhesion molecule 1 (ICAM)-1 expression in human oral cancer cells. Using pharmacological inhibitors, activators, and genetic inhibition of EP receptors, we discovered that the EP1 receptor, but not other PGE receptors, is involved in PGE 2 -mediated cell migration and ICAM-1 expression. PGE 2 -mediated migration and ICAM-1 up-regulation were attenuated by inhibitors of protein kinase C (PKC)␦, and c-Src. Activation of the PKC␦, c-Src, and AP-1 signaling pathway occurred after PGE 2 treatment. PGE 2 -induced expression of ICAM-1 and migration activity were inhibited by a specific inhibitor, siRNA, and mutants of PKC␦, c-Src, and AP-1. In addition, migration-prone sublines demonstrated that cells with increased migration ability had higher expression of COX-2 and ICAM-1. Taken together, these results indicate that the PGE 2 and EP1 interaction enhanced migration of oral cancer cells through an increase in ICAM-1 production.

Oral cancer is the fourth common male cancer and causally associated with environmental carcinogens in Taiwan. The reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) has a significant effect on tumorigenesis by limiting angiogenesis and invasion of tumors through the extracellular matrix. RECK downregulation has been confirmed in many human cancers and associated with lymph node metastasis clinically. In the present hospital-based case-controlled study, the demographic, RECK genotype and clinicopathologic data from 341 male oral cancer patients and 415 cancer-free controls were investigated. We found that RECK rs10814325, rs16932912, rs11788747 or rs10972727 polymorphisms were not associated with oral cancer susceptibility. Among 488 smokers, RECK polymorphisms carriers with betel quid chewing have a 7.62-fold [95% confidence interval (CI), 2.96-19.64] to 25.33-fold (95% CI, 9.57-67.02) risk to have oral cancer compared with RECK wild-type carrier without betel quid chewing. Among 352 betel quid chewers, RECK polymorphisms carriers with smoking have a 6.68-fold (95% CI, 1.21-36.93) to 18.57-fold (95% CI, 3.80-90.80) risk to have oral cancer compared with those who carried wild-type without smoking. In 263 betel quid chewing oral cancer patients, RECK rs10814325 polymorphism have a 2.26-fold (95% CI, 1.19-4.29) risk to have neck lymph node metastasis compared with RECK wild-type carrier. These results support that gene-environment interactions between the RECK polymorphisms, smoking and betel quid may alter oral cancer susceptibility and metastasis.

The prevalence of the Epstein-Barr virus (EBV) Taiwan variant was investigated in the throat washing (A1W) samples from patients with head and neck tumors, persons with nonmalignant diseases, and healthy adults in Taiwan. By using the EBV (BNLF-1 gene)-specific primers and PCR, the EBV latent membrane protein gene BNLF-1 was detected in 91 (61%,b) of the 150 TW samples from patients with tumors, including 25 (78%) of 32 patients with nasopharyngeal carcinoma and 66 (56%o) of 118 other patients with head and neck tumors. The TW samples from the 26 patients with nonmalignant tumors and 53 healthy adults were also examined. Approximately 47% of these samples were positive for the EBV gene. The PCR products of the BNLF-1 gene were then subjected to XhoI digestion. Sixby-eight of 91 PCR products (75%) showed the loss of the XhoI site, which indicated the presence ofa Taiwan strain ofEBV in patients with tumors. The DNA sequence of the BNLF-1 gene of the Taiwan variant revealed that the loss of the XhoI site was due to a nucleotide change from a G to a T at position 169,426 in comparison with the sequence of prototype EBV B95-8 cells. Furthermore, the Taiwan strain appeared significantly more frequently in the TWs and tissue samples from patients with nasopharyngeal carcinoma (88%; P < 0.001) and laryngeal carcinoma (80%o; P < 0.02) than in those samples from healthy adults (about 40o). These data indicate that a Taiwan variant of EBV may be closely associated with head and neck tumors and suggest that this variant may be important in the pathogenesis of head and neck tumors.