Oral cancer is one of the drastic human cancers due to its aggressiveness and high mortality rate. Of all oral cancers, squamous cell carcinoma is the most common accounting for more than 90%. Epithelial-mesenchymal transition (EMT) is suggested to play an important role during cancer invasion and metastasis. Recently, emerging knowledge on EMT in carcinogenesis is explosive, tempting us to analyze previous studies on EMT in oral squamous cell carcinoma (OSCC). In this paper, we have first addressed the general molecular mechanisms of EMT, evidenced by alterations of cell morphology during EMT, the presence of cadherin switching, turning on and turning off of many specific genes, the activation of various signaling pathways, and so on. The remaining part of this paper will focus on recent findings of the investigations of EMT on OSCC. These include the evidence of EMT taking place in OSCC and the signaling pathways employed by OSCC cells during their invasion and metastasis. Collectively, with the large body of new knowledge on EMT in OSCC elaborated here, we are hopeful that targeting treatment for OSCC will be developed.

Probiotic supplementation can reduce mutans streptococci (MS) numbers. One of its proposed mechanisms is immunomodulation. Salivary human neutrophil peptide 1–3 (HNP1-3) levels have previously been demonstrated to be higher in caries-free than in caries-susceptible children, suggesting their preventive role against caries. We aimed to compare salivary HNP1-3 levels between an intervention group with probiotics and a control group. A randomized double-blinded clinical trial was conducted. Sixty schoolchildren were equally allocated to either an intervention or control group. The use of a probiotic strain, Lactobacillus paracasei SD1, has shown to reduce MS numbers in volunteers. In unstimulated whole saliva, HNP1-3 levels were assayed by ELISA, and MS and lactobacilli counts were assayed by colony counting at baseline (T0) and at 3 (T3), 6 (T6), and 12 months (T12). The International Caries Detection and Assessment system was used to assess caries status. In the intervention group, salivary HNP1-3 levels were significantly greater than those in the control group at T3 and T6 (p < 0.001), whereas MS counts were significantly decreased (p < 0.01). In the intervention group, positive and negative correlations were found between HNP1-3 levels and lactobacilli counts and between MS and lactobacilli counts, respectively. However, there was no significant correlation between enhanced HNP1-3 levels and decreased MS numbers. The caries increment for the pit and fissure surface, but not for the smooth surfaces, was significantly decreased in the intervention group compared with the control group (p = 0.01). Probiotics can temporarily enhance salivary HNP1-3 levels; however, their action to reduce new pit and fissure caries probably involves microbial interactions. TCTR20130904001 (registration date: September 04, 2013).

Up-regulated expression of programmed death-ligand 1 (PD-L1) by interferon-gamma (IFN-γ) has been associated with promotion of cancer cell survival and tumor cell escape from anti-tumor immunity. Therefore, a blockade of PD-L1 expression can potentially be used as a molecular target for cancer therapy. The aim of this study was to investigate whether suppression of IFN-γ induced PD-L1 expression in two oral cancer cell lines, HN6 and HN15, by hesperidin effectively decreased cell proliferation and migration. Further, our objective was to elucidate the involvement of the signal transducer and activator of transcription 1 (STAT1) and STAT3 in the inhibition of induced PD-L1 expression by hesperidin. Our findings indicate that IFN-γ induced expression of PD-L1 protein in HN6 and HN15 via phosphorylation of STAT1 and STAT3 and that hesperidin significantly reduced that induction through suppression of phosphorylated STAT1 and STAT3 in both cell lines. Moreover, hesperidin also significantly decreased the viability, proliferation, migration, and invasion of both cell lines. In conclusion, hesperidin exerted anticancer effects against oral cancer cells through the suppression of PD-L1 expression via inactivation of the STAT1 and STAT3 signaling molecules. The findings of this study support the use of hesperidin as a potential adjunctive treatment for oral cancer.

Uncoupled bone resorption leads to net alveolar bone loss in periodontitis. The deficiency of LL-37, the only human antimicrobial peptide in the cathelicidin family, in patients with aggressive periodontitis suggests that LL-37 may play a pivotal role in the inhibition of alveolar bone destruction in periodontitis. We aimed to investigate a novel function of LL-37 in osteoimmunity by blocking osteoclastogenesis in vitro. Human osteoclast progenitor cells were isolated from a buffy coat of blood samples. The cells were cultured in the presence of various concentrations of LL-37 during an in vitro induction of osteoclastogenesis. Non-toxic doses of LL-37 could block multinuclear formation of the progenitor cells and significantly diminish the number of tartrate-resistant acid-phosphatase-positive cells and the formation of resorption pits (p < 0.05), whereas these concentrations induced cellular proliferation, as demonstrated by increased expression of proliferating cell nuclear antigen. Expression of several osteoclast genes was down-regulated by LL-37 treatment. It was demonstrated that nuclear translocation of nuclear-factor-activated T-cells 2 (NFAT2) was blocked by LL-37 treatment, consistent with a significant reduction in the calcineurin activity (p < 0.005). Collectively, our findings demonstrate that LL-37 inhibits the in vitro osteoclastogenesis by inhibiting the calcineurin activity, thus preventing nuclear translocation of NFAT2. Abbreviations: CALCR, calcitonin receptor; ClC-7, chloride-proton exchanger; CTSK, cathepsin K; DAPI, 4′,6-diamidino-2-phenylindole; EGTA, ethylene glycol tetraacetic acid; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; M-CSF/CSF1, macrophage-colony- stimulating factor; MMP-9, matrix metalloproteinase-9; MTT, [3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]; NFAT2, nuclear factor of activated T-cells 2; PBS, phosphate-buffered saline; PCNA, proliferating cell nuclear antigen; PCR, polymerase chain reaction; RANK, receptor activator of nuclear factor kappa-B; RANKL, receptor activator of nuclear factor kappa-B ligand; RT-PCR, reverse-transcription polymerase chain-reaction; TBS, Tris-buffered saline; TCIRG1, T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3; TRAcP, tartrate-resistant acid phosphatase.

Periodontal disease is caused by microorganisms and host-derived inflammation involving increased cyclooxygenase-2 (COX-2) expression and prostaglandin E₂ (PGE₂) production. We previously demonstrated that human β-defensin-3 induces COX-2 and PGE₂ in human gingival fibroblasts (HGFs). We, therefore, aimed to examine the inducible effects of LL-37, the only cathelicidin expressed in humans, on COX-2 expression and PGE₂ synthesis in HGFs and to elucidate the relevant signaling pathways. The COX-2 expression was upregulated by LL-37 in dose- and time-dependent manners. Accordingly, the synthesis of PGE₂ in cell-free culture supernatants was raised by LL-37 (p < 0.01) and blocked by NS-398, a specific COX-2 inhibitor (p < 0.01). P2X inhibitors and a neutralizing antibody against P2X₇ purinergic receptor significantly abrogated COX-2 induction and PGE₂ production by LL-37 (p < 0.01). LL-37 upregulated COX-2 expression and PGE₂ synthesis via activation of extracellular signal-regulated kinase (ERK) and p46 c-Jun N-terminal kinase (JNK), while interleukin-1β did so via nuclear factor-ĸB and all three mitogen-activated protein kinases. In summary, LL-37 can control arachidonic acid metabolism by induction of COX-2 expression and PGE₂ synthesis via the P2X₇ receptor, ERK, and p46 JNK. The pro-inflammatory effects of LL-37 may be essential for initiating oral mucosal inflammation in periodontal disease.