The upregulation of heat shock protein 70 expression in areca quid chewing-associated oral squamous cell carcinomas.

Heat shock protein 70 (HSP70) is an important stress-induced protein. Areca quid chewing is a major risk factor of oral squamous cell carcinoma (OSCC). The aim of this study was to compare HSP70 expression in normal human oral epithelium and OSCC and further to explore the potential mechanisms that may lead to induce HSP70 expression. 41 OSCC and 10 normal epithelium specimens were examined by immunohistochemistry and analyzed by the clinico-pathological profiles. The oral epithelial cell line GNM cells were challenged with arecoline, a major areca nut alkaloid, by using Western blot analysis. Furthermore, glutathione precursor N-acetyl-l-cysteine (NAC), AP-1 inhibitor curcumin, extracellular signal-regulated protein kinase inhibitor PD98059, and protein kinase C inhibitor staurosporine were added to find the possible regulatory mechanisms. The results from immunohistochemistry demonstrated that HSP70 expression was significantly higher in OSCC specimens (p<0.05). No significant difference in HSP70 expression was observed with respect to age, sex, T category, and stage (p>0.05). The low HSP70 expression was associated with lymph node metastasis (p=0.005). The high HSP70 expression was found in poor differentiated tumor groups (p=0.036). Arecoline was found to elevate HSP70 expression in a dose- and time-dependent manner (p<0.05). The addition of NAC, curcumin, PD98059, and staurosporine markedly inhibited the arecoline-induced HSP70 expression (p<0.05). Taken together, HSP70 expression is significantly upregulated in areca quid chewing-associated OSCC. HSP70 could be used clinically as a marker for tumors possessing the potential for differentiation as well as lymph node metastasis. In addition, arecoline-induced HSP70 expression was downregulated by NAC, curcumin, PD98059, and staurosporine.