Objective: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a member of the carcinoembryonic antigen family. Although its expression has been found in chronic oral inflammatory epithelium, this study aimed to know whether CEACAM1 in oral keratinocytes participates in host immune response against Candida albicans. Methodology: We investigated CEACAM1 expression in oral keratinocytes induced by C. albicans as well as by Candida cell wall component β-glucan particles (β-GPs). Furthermore, the effects of CEACAM1 on β-GPs-induced heme oxygenase-1 (HO-1) expression and its related signals were examined. Results: Fluorescence staining showed CEACAM1 expression in oral keratinocytes (RT7) cells, whereas quantitative reverse transcription (RT)-PCR indicated that both live and heat-killed C. albicans increased CEACAM1 mRNA expression in RT7 cells. Examinations using quantitative RT-PCR and western blotting indicated that CEACAM1 expression was also increased by β-GPs derived from C. albicans. Specific siRNA for CEACAM1 decreased HO-1 expression induced by β-GPs from C. albicans as well as the budding yeast microorganism Saccharomyces cerevisiae. Moreover, knockdown of CEACAM1 decreased β-GPs-induced ROS activity in the early phase and translocation of Nrf2 into the nucleus. Conclusion: CEACAM1 in oral keratinocytes may have a critical role in regulation of HO-1 for host immune defense during Candida infection.

Background Melatonin is a hormone that is primarily produced in the pineal gland and is involved in wide range of biological functions. However, the impact of melatonin on chemotherapy‐induced cell death remains to be elucidated in oral squamous cell carcinoma (OSCC) cells. The objective of this study was to clarify the role of melatonin in cisplatin‐induced cytotoxicity in CD44high OSCC cells. Methods CD44high OSCC cells were cultured on fibronectin‐coated hydrogel. A lactate dehydrogenase cytotoxicity assay was performed to evaluate cisplatin‐induced cell death. The effect of melatonin on cisplatin‐induced cell death and Derlin‐1 (DERL1) endoplasmic reticulum membrane protein expression was investigated. Results CD44high OSCC cells exhibited mesenchymal‐like features when cultured on fibronectin‐coated hydrogel. Mesenchymal‐like CD44high OSCC cells demonstrated strong resistance to cisplatin‐induced cell death compared with epithelial‐like CD44high OSCC cells. DERL1 mRNA and DERL1 protein expression levels were significantly higher in mesenchymal‐like CD44high cells compared with epithelial‐like CD44high cells. Cisplatin‐induced cell death was significantly enhanced after DERL1 siRNA knockdown, suggesting that DERL1 is involved in resistance to cisplatin‐induced cell death. Melatonin significantly inhibited DERL1 expression and enhanced cisplatin‐induced cell death in mesenchymal‐like CD44high cells. miR‐181c‐5p expression was significantly upregulated in the presence of melatonin. Furthermore, melatonin‐inhibited DERL1 expression was significantly recovered by miR‐181c‐5p inhibitor. In addition, melatoninenhanced cisplatin‐induced cell death was attenuated by miR‐181c‐5p inhibitor. These results suggest that melatonin‐induced miR‐181c‐5p enhances cisplatin‐induced cell death through inhibition of DERL1 in mesenchymal‐like CD44high cells. Conclusions Melatonin plays a vital role in promoting cisplatin‐induced cytotoxicity in mesenchymal‐like CD44high OSCC cells.

ObjectiveSunitinib, a targeted cancer drug, inhibits tyrosine kinases receptors and is widely used as first‐line treatment for metastatic renal cell carcinoma. Patients undergoing chemotherapy with sunitinib frequently have oral mucosal complications, such as oral stomatitis, though cytotoxic effects of the drug on oral keratinocytes remain unknown.MethodsThe effects of sunitinib on immortalized oral keratinocytes, RT7 cells, in regard to cell injury and apoptosis, as well as apoptosis‐mediated signaling pathways were investigated.ResultsSunitinib treatment caused a significant increase in lactate dehydrogenase (LDH) in RT7 cells and primary oral keratinocytes. Additionally, the drug induced apoptosis‐related events, such as DNA fragmentation, decreased anti‐apoptotic Bcl‐2 protein expression, and induction of cleaved PARP and caspase 3/9 in RT7 cells. Furthermore, phosphorylation of p38 MAPK, but not of ERK or JNK, was increased. On the contrary, constitutive phosphorylated STAT3 was decreased by sunitinib treatment, which was recovered by exposure to SB203580, a p38 MAPK inhibitor. Finally, SB203580 was found to reduce sunitinib‐induced cell injury and apoptosis.ConclusionThe present results indicate that sunitinib promotes cell injury and apoptosis in oral keratinocytes via p38 activation and STAT3 downregulation. Sunitinib‐mediated oral complications may be associated with cytotoxic effects of the drug on oral keratinocytes.

innate immune systems in the oral cavity have important roles in the host defense against viral invasion of oral mucosa. Poly(adP-ribose) polymerase 13 (ParP13), which has a strong antiviral ability, has been reported to possess two isoforms; a full-length protein, zinc-finger antiviral protein long (ZaPl), and a shorter protein (ZaPS). However, the expression and function of these two isoforms in oral mucosa remain unknown. in the present study, the expression levels of ZaPl and ZaPS induced by transfected double-stranded (ds) rna, Poly(i:c), and dsdna, Poly(da:dT), in immortalized oral keratinocytes and fibroblasts (RT7 and GT1 cell lines, respectively) were investigated. Subsequently, the effects of the knockdown of ZaPl and ZaPS on transfected nucleotide-induced antiviral factors were examined. The results demonstrated constitutive expression of ZaPl and ZaPS in RT7 and GT1 cells, and their expression in both cell types was notably increased by transfection of Poly(i:c) and Poly(da:dT) when compared with no transfection. Specific knockdown of ZAPL and ZAPS in RT7 cells decreased IFN-β and c-X-c motif chemokine ligand 10 (cXcl10) expression induced by transfected Poly(i:c) and Poly(da:dT). on the other hand, knockdown of ZAPL and ZAPS in GT1 cells decreased the expression of cXcl10 induced by the transfected nucleotides, whereas that had no effect on IFN-β expression induced by Poly(da:dT). Their knockdown was also associated with transfected nucleotides-induced IFN regulatory factor 3 phosphorylation in both cell types. Taken together, these results indicate that ZaPl and ZaPS, isoforms of ParP13, in oral mucosal cells participate in host defense against viral infection of oral mucosa.

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