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Protease-activated receptor 1 (PAR1) is known as a thrombin receptor. Recent studies have reported PAR1 expression in various malignancies; however, its role in oral squamous cell carcinoma (OSCC) requires clarification. A previous study showed that down-regulation of ΔNp63, a homolog of p53, augments PAR1 expression in OSCC. In the present study, the association of PAR1 expression with clinicopathological findings in OSCC was examined retrospectively. Expression of PAR1, thrombin, and ΔNp63 was examined immunohistochemically in OSCC specimens. Patients were divided into three groups based on the expression pattern of PAR1 at the invasive front: group A, PAR1-negative in both cancer and stromal cells; group B, positive in stromal cells but negative in cancer cells; group C, positive in both cancer and stromal cells. Histologically high-grade tumours were significantly more common in group C. Patients in group C had the highest incidence rate of nodal metastasis (P

Programmed cell death ligand 1 (PD-L1) and its receptor PD-1 are immune checkpoint molecules that attenuate the immune response. Blockade of PD-L1 enhances the immune response in a variety of tumours and thus serves as an effective anti-cancer treatment. However, the biological and prognostic roles of PD-L1/PD-1 signalling in oral squamous cell carcinoma (OSCC) remain to be elucidated. The purpose of this study was to examine the correlation of PD-L1/PD-1 signalling with the prognosis of OSCC patients to assess its potential therapeutic relevance. The expression of PD-L1 and of PD-1 was determined immunohistochemically in 97 patients with OSCC and the association of this expression with clinicopathological characteristics was examined. Increased expression of PD-L1 was found in 64.9% of OSCC cases and increased expression of PD-1 was found in 61.9%. Univariate and multivariate analysis revealed that increased expression of PD-L1 and PD-1 positively correlated with cervical lymph node metastasis. The expression of CD25, an activated T-cell marker, was negatively correlated with the labelling index of PD-L1 and PD-1. Moreover, the patient group with PD-L1-positive and PD-1-positive expression showed a more unfavourable prognosis than the group with PD-L1-negative and PD-1-negative expression. These data suggest that increased PD-L1 and PD-1 expression is predictive of nodal metastasis and a poor prognosis and is possibly involved in cancer progression via attenuating the immune response.

Recent studies have revealed that cancer cells are exacerbated by chronic inflammation. The present study examined the immunohistochemical expression for interleukin-6 (IL-6), a pleiotropic inflammatory cytokine, in oral squamous cell carcinoma (OSCC) to elucidate the association of IL-6 expression with tumor progression, chemoresistance and prognosis. Seventy-eight patients with primary OSCC were analyzed by immunohistochemical staining for IL-6. These labeling indexes (LIs) were calculated and evaluated in association with the clinicopathologic characteristics and prognosis in the OSCC patients. The patients were divided into three groups as follows: negative group = LI

Despite diagnostic and therapeutic advances, the 5-year survival rate of oral squamous cell carcinoma (OSCC) remains between 70–80% due to recurrences and secondary metastases to cervical lymph nodes. It is difficult to find these recurrences and metastases postoperatively, thus, careful follow-up is recommended. Cytokeratins (CKs) are intermediate filaments of the cytoskeleton and candidate prognostic biomarkers for OSCC, as they are overexpressed in OSCC compared with normal mucosa. The aim of the present study was to determine the relative levels of occurrence of 3 CK mRNA (CK17, CK19, CK20) transcripts in peripheral blood mononuclear cells (PBMC) using reverse transcription-quantitative polymerase chain reaction. The study comprised pre- and post-operative PBMC samples from 19 OSCC patients. In the good-prognosis group, 10 of 13 patients demonstrated reduced CK17 mRNA expression post-operatively, compared with pre-operative samples, conversely, only 3 of 6 patients in the poor-prognosis group had reduced post-operative CK17 mRNA expression. This difference was statistically significant (P

Epithelial-to-mesenchymal transition (EMT), an essential developmental program, is involved in tumor progression. ΔNp63, a homolog of p53, is associated with the EMT program, but the detailed mechanism remains to be elucidated. In this study, we investigated the role of ΔNp63 in EMT during progression of oral squamous cell carcinoma (OSCC). Five OSCC cell lines and specimens from 78 patients with OSCC were used. The expressions of ΔNp63, p63α, p63β and epithelial markers (cytokeratins 5 and 14) was detected in the OSCC cells, but not in SQUU-B cells (high metastatic potential). E-cadherin was expressed in all OSCC cells. Mesenchymal markers were strongly expressed in the SQUU-B cells. Knockdown of endogenous ΔNp63 in HSC-2 cells induced morphological changes to the spindle shape, decreased the expression of epithelial markers, increased the expression of mesenchymal markers, increased migration and reduced proliferation. By contrast, SQUU-B cells overexpressing ΔNp63β showed changed their morphology from stromal cell-like to epithelial cells. However, E-cadherin expression was not affected by ΔNp63 knockdown or overexpression. Immunohistochemical staining revealed that cancer cells expressing vimentin were found at the invasive front in the OSCC specimens. The intensity of ΔNp63 expression was also decreased in these cells. Interestingly, the vimentin positivity or decreased intensity of ΔNp63 was positively associated with metastases and poor prognosis in the OSCC patients. These results indicated that ΔNp63 downregulation in cancer cells induces a mesenchymal phenotype that is related to tumor progression of OSCC.

Objectives We previously showed that ΔNp63β, a splicing variant of ΔNp63, mediated EMT and affected cell motility. DNA microarray was thus performed to elucidate the mechanism that ΔNp63β affects cell motility. As the results, Wnt5a was significantly down-regulated by ΔNp63β overexpression in tongue SCC cell line (SQUU-B) with EMT phenotype. Materials and methods Seven OSCC cell lines were used. Expression of ΔNp63, Wnt5a, its receptor Ror2, and matrix metalloproteinases (MMPs) were analyzed by RT-PCR, real-time PCR, and western blotting, and gelatin zymography. Furthermore, we examined the effects of siRNA for Wnt5a or Ror2 and recombinant human Wnt5a (rhWnt5a) on motility of tongue SCC cells. Biopsy specimens from tongue SCC patients were used for immunohistochemical staining of Wnt5a and Ror2. Results Wnt5a and Ror2 were expressed only in SQUU-B cells without ΔNp63 expression, and negatively associated with ΔNp63 expression in other cells. ΔNp63β overexpression in SQUU-B cells decreased Wnt5a and Ror2 expression. By Wnt5a or Ror2 knockdown, cell motility was remarkably inhibited, but EMT markers expression was unaffected. MMP-2 expression and the activities inversely correlated with ΔNp63 expression, and were inhibited by Wnt5a or Ror2 knockdown. Cell motility and MMP-2 activities were recovered by adding rhWnt5a in the cells with Wnt5a knockdown, but not in those with Ror2 knockdown. Moreover, immunohistochemical analyses in tongue SCC specimens found that high expression of Wnt5a or Ror2 was associated with poorer prognosis. Conclusion Wnt5a–Ror2 signaling enhanced tongue SCC cell aggressiveness and promoted production of MMP-2 following ΔNp63β-mediated EMT.

The administration of pre-operative chemotherapy with S-1 and concurrent radiotherapy at a total dose of 30 Gy was clinicopathologically evaluated as a treatment for locally advanced oral squamous cell carcinoma (OSCC) in the present study. The participants comprised 81 patients with OSCC, consisting of 29 patients with stage II disease, 12 patients with stage III disease and 40 patients with stage IV disease. All patients received a total radiation dose of 30 Gy in daily fractions of 2 Gy, 5 times a week, for 3 weeks, and the patients were concurrently administered S-1 at a dose of 80-120 mg, twice daily, over 4 consecutive weeks. Radical surgery was performed in all cases at 2-6 weeks subsequent to the end of pre-operative chemoradiotherapy. The most common adverse event was oropharyngeal mucositis, but this was transient in all patients. No severe hematological or non-hematological toxicities were observed. The clinical and histopathological response rates were 70.4 and 75.3%, respectively. Post-operatively, local failure developed in 6 patients (7.4%) and neck failure developed in 2 patients (2.5%). Distant metastases were found in 7 patients (8.6%). The overall survival rate, disease-specific survival rate and locoregional control rate at 5 years were 87.7, 89.9 and 90.6%, respectively. Locoregional recurrence occurred more frequently in patients that demonstrated a poor histopathological response compared with patients that demonstrated a good response (P

Purpose The aim of this study was to confirm the expression profile of cytokeratin (CK)17 in comparison with that of CK13 in oral squamous cell carcinoma (OSCC) and leukoplakia and to clarify an association of CK17 with the OSCC differentiation. Materials The expression of CK17 and CK13 was immunohistochemically examined in 105 patients with OSCC and 108 patients with leukoplakia. A correlation of CK expression with clinicopathological variables was carried out. The over-expression levels of CK17 mRNA were analyzed by real-time RT-PCR in 5 OSCC cell lines (HSC-2, HSC-3, SAS, SQUU-A, SQUU-B). Results CK17 and CK13 were detected in 101 (96.2 %) and three (2.9 %) of the 105 OSCCs, respectively. CK17 was significantly expressed in well-differentiated OSCC compared to moderately/poorly differentiated OSCC (p

The aim of this study was to clarify candidate peptides for peptide-based specific immunotherapy of patients with oral squamous cell carcinoma (SCC). Thirteen peptides were examined for in vitro induction of peptide-specific CD8(+) T lymphocyte (CD8(+)TL) activity in peripheral blood mononuclear cells from 35 patients with oral SCC. A correlation between the induction ability of CD8(+)TL and in vivo immune response of host was carried out immunohistochemically in 23 patients. Peptide-specific activities of CD8(+)TL for at least one peptide were detectable in 21/35 patients (60.0%). The potent peptides were SART-1(690) in 9/35 (25.7%), SART-2(93), and ART4(75) in 7/35 (20.0%), respectively. In the 9 patients with SART-1(690)-specific activity, the whole of activities was significantly inducible for more number of other peptides compared to that in 26 patients without the activity (P=0.035). Cellular responses in 7 patients with SART-1(690)-specific activity were significantly stronger than those in 16 patients without the activity (P=0.027). Furthermore, the number of CD3(+) T cells around the SCC was also significantly different between the 2 groups of patients (P=0.041). In conclusion, SART-1(690), SART-2(93), and ART4(75) could be applicable as peptide-based specific immunotherapies for the majority of patients with oral SCC.

This study examined immunohistochemical expression of ΔNp63, a keratinocyte stem cell marker, in oral leukoplakia (OL) and oral squamous cell carcinoma (OSCC) and then to elucidate usefulness of ΔNp63 as a marker for diagnosis and prognosis. One-hundred and twelve cases of OL and 81 cases of OSCC were analyzed by immunohistochemical staining for ΔNp63, Ki-67, and cytokeratin 14. These labeling indices (LIs) were calculated, and the association of these LIs with clinicopathologic characteristics in the OL and OSCC was evaluated. In the OL, these LIs increased significantly according to the severity of epithelial dysplasia (p0.0001). ΔNp63-LI in the OL with malignant transformation was significantly higher than that in the OL without (49.3 vs. 34.2%; p0.01). In the OSCC, the LIs increased significantly in association with the histologic grade (p0.0001). A significant difference between the high and low ΔNp63-LI groups was found in the incidence of cervical lymph node and distant metastasis (p0.05). The prognosis of the high ΔNp63-LI (mean value73.8%) group is poorer than that of the low ΔNp63-LI (mean value ≤73.8%) group (p0.05). These results suggested that increased ΔNp63 expression is involved in malignant transformation in epithelial dysplasia and poor prognosis in OSCC.