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Arecoline N-oxide (ANO), an oxidative metabolite of the areca nut, is a predictable initiator in carcinogenesis. The mechanisms of arecoline metabolites in human cancer specimens is still limited. This present study aims to estimate the oral squamous cell carcinoma (OSCC) inductive activity between arecoline metabolites in human cancer specimens/OSCC cells. We have collected 22 pairs (tumor and non-tumor part) of patient's specimens and checked for clinical characteristics. The identification of arecoline and its metabolites levels by using LC-MS/MS. The NOD/SCID mice model was used to check the OSCC inductive activity. The tumor part of OSCC samples exhibited higher levels of arecoline and ANO. Besides, ANO treated mice accelerates the NOTCH1, IL-17a and IL-1β expressions compared to the control mice. ANO exhibited higher cytotoxicity, intracellular ROS levels and decline in antioxidant enzyme levels in OC-3 cells. The protein expression of NOTCH1 and proliferation marker levels are significantly lower in NOM treated cells. Overall, ANO induced initial stage carcinogenesis in the oral cavity via inflammation, ROS and depletion of antioxidant enzymes. Arecoline N-oxide mercapturic acid (NOM) attenuates the initiation of oral carcinogenesis., (Copyright © 2021. Published by Elsevier Inc.)

Background/aim: Glycogen synthase kinase 3 beta (GSK3-β) acts either as a tumor suppressor or an oncogene in various human cancers. The present study aimed to investigate the expression and activity of p-GSK3-β (Ser9) in oral cancer patients., Materials and Methods: We investigated the levels of p-GSK3β in 152 oral cancer tissues by immunohistochemistry, and explored their prognostic impact., Results: To investigate the role of p-GSK3β (Ser9) in OSCC progression, we first analyzed the expression levels of protein p-GSK3β in normal and oral cancer tissues using immunohistochemical staining. p-GSK3β immunostaining was detected in 32 of 152 (21.1%) oral cancer specimens. High p-GSK3β expression was significantly associated with T (III/IV) stage. Kaplan-Meier survival analysis revealed that high levels of p-GSK3β were correlated with poor survival (p=0.001) in T stage (III/IV) OSCC patients. Multivariate analyses indicated that TN stage, AJCC tumor stage, tumor differentiation status and clinical therapy, but not p-GSK3β levels, were independent prognostic factors. Significant mortality risk was found in T stage (III/IV) oral cancer patients with high levels of p-GSK3β (p=0.0006)., Conclusion: GSK3β inactivation is a key event in oral cancer patients and targeting GSK3β might be valuable in treating oral cancer patients., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Expression of cyclo-oxygenase-2 (COX-2) and protein phosphatase 2A (PP2A) deactivation occurs frequently in oral squamous cell carcinoma (OSCC). We initially assessed COX-2 and PP2A protein expression in OSCC specimens using immunohistochemical (IHC) staining and western blot analysis. We found strong COX-2 and phosphorylated PP2A (p-PP2A) expression in OSCC samples. No significant difference in total PP2A expression was observed between cancer and nontumor tissues. The effect of combining COX-2 inhibitor and celecoxib (CXB) with the PP2A inhibitor, calyculin-A (CLA) on the OSCC cell line, HSC3, was evaluated in vitro. We found that a combination of 1 nM CLA and 50 µM CXB significantly inhibited cell viability, and migration and invasion of HSC3 cells. Western blots for AKT, p-AKT, ERK, p-ERK, E-cadherin, vimentin and β-catenin were conducted after treatment with CXB and/or CLA. Increased E-cadherin and decreased β-catenin expression were found in CXB or CLA treated hsc-3 cells, whereas the combined CXB and CLA treatment showed no difference in E-cadherin or β-catenin expression. Our findings suggest that CLA alone was more effective than CXB alone, but not in the combined drug treatment.

A number of genetic variants were suggested to be associated with oral malignancy, few variants can be replicated. The aim of this study was to identify significant variants that enhanced personal risk prediction for oral malignancy. A total of 360 patients diagnosed with oral squamous cell carcinoma, 486 controls and 17 newly diagnosed patients with OPMD including leukoplakia or oral submucous fibrosis were recruited. Fifteen tagSNPs which were derived from somatic mutations were genotyped and examined in associations with the occurrence of oral malignancy. Environmental variables along with the SNPs data were used to developed risk predictive models for oral malignancy occurrence. The stepwise model analysis was conducted to fit the best model in an economically efficient way. Two tagSNPs, rs28647489 in FAT1 gene and rs550675 in COL9A1 gene, were significantly associated with the risk of oral malignancy. The sensitivity and specificity were 85.7% and 85.5%, respectively (area under the receiver operating characteristic curve (AUC) was 0.91) for predicting oral squamous cell carcinoma occurrence with the combined genetic variants, betel-quid, alcohol and age. The AUC for OPMD was only 0.69. The predictive probability of squamous cell carcinoma occurrence for genetic risk score without substance use increased from 10% up to 43%; with substance use increased from 73% up to 92%. Genetic variants with or without substance use may enhance risk prediction for oral malignancy occurrence in male population. The prediction model may be useful as a clinical index for oral malignancy occurrence and its risk assessments., Competing Interests: The authors have declared that no competing interests exist.

Background: Discoidin domain receptors (DDRs), a collagen receptor tyrosine kinase, play a major role in cancer progression. DDR2 has been suggested as a prognostic marker in several cancer types; however, the correlation between DDR2 expression and clinical outcome of oral cancer patients in Taiwan population has not been investigated., Materials and Methods: In the present study we sought to determine the clinical significance of Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2) expression in oral squamous cell carcinoma (OSCC) patients. We examined DDR2 expression in OSCC specimens by immunohistochemistry and then we analyzed the association of DDR2 expression with clinicopathological factors in OSCC., Results: We divided 254 OSCC cases into two groups based on DDR2 expression levels and compared with several clinicopathological factors and their overall survival. The group with high DDR2 expression had significantly higher frequencies of lymph node metastasis (P= 0.0094) and AJCC stage (P= 0.0058) compared to the group with low DDR2 expression. Furthermore, the lymph node metastasis oral cancer patients with high DDR2 expression had low survival rate than low DDR2 group (P= 0.0458)., Conclusions: Our data indicate that DDR2 is a potent biomarker that can be used as an effective therapeutic target for treating OSCC patients with lymph node metastasis.

Overexpression of cyclooxygenase-2 in oral cancer increases lymph node metastasis and is associated with a poor prognosis. The potential of celecoxib (CXB) use is reported in cancer treatment by inhibiting proliferation through apoptosis, but the effects on the epithelial-mesenchymal transition (EMT) and cancer cell mobility remain unclear. We performed a preclinical study and population-based study to evaluate CXB use in the prevention of oral cancer progression and occurrence. The in-vitro findings showed that CXB is involved in the inhibition of EMT and cell mobility through blocking transcription factors (Slug, Snail and ZEB1), cytoplasmic mediators (focal adhesion kinase (FAK), vimentin and β-catenin), cell adhesion molecules (cadherins and integrins), and surface receptors (AMFR and EGFR). The murine xenograft model showed a 65% inhibition in tumour growth after a 5-week treatment of CXB compared to placebo. Xenograft tumours in placebo-treated mice displayed a well-to-moderate/moderate differentiated SCC grade, while those from CXB-treated mice were well differentiated. The expression levels of membrane EGFR, and nuclear FAK, Slug and ZEB1 were decreased in the xenograft tumours of CXB-treated mice. A retrospective cohort study showed that increasing the daily dose and medication time of CXB was associated with oral cancer prevention. The findings provide an alternative prevention strategy for oral cancer development with CXB use.

We integrated genetic risk scores (GRS) and environmental factors for identifying high-risk subjects for oral squamous cell carcinoma (OSCC) occurrence by using case-control study. A total of 447 patients diagnosed with OSCC and 580 unrelated subjects were recruited from two medical centers in Taiwan. A multinomial logistic regression model was conducted to access interaction between GRS and betel quid (BQ) chewing. We employed ROC curve to compare the accuracy of OSCC occurrence. Four tag SNPs were found in NOTCH1, BRCA1, COL9A1 , and HSPA13 genes that were significantly associated with OSCC occurrence. GRS was calculated by the four tag SNP risk alleles. The higher GRS (scores = 4) remained independently associated with risk of OSCC after adjustment for age, the use of alcohol, BQ, and cigarette: adjusted OR = 4.42 [95% confidence interval (95% CI), 1.34-14.55]. The GRS and BQ chewing interaction showed an increased risk for OSCC occurrence with adjusting for other substance use and age (OR = 70.77; 95% CI, 8.70-575.73). The synergy index was 16.58 (95% CI, 2.27-70.56), suggesting a positive additive interaction between GRS and BQ chewing. The areas under the ROC curves (AUROC) were 0.91 for combined GRS and BQ chewing with sensitivity of 88.6% and specificity of 86.7%. The AUROC of GRS and BQ chewing is above 90%, which may be valuable in identifying high-risk subjects. Early screening can allow the clinician to provide the appropriate intervention and to reduce the OSCC occurrence. Cancer Prev Res; 10(6); 355-62. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Objectives: Several studies suggested that antidepressant use may increase or decrease the risk of cancer occurrence, depending on specific cancer types. The possible carcinogenic effect of antidepressants has received substantial attention; however, evidence remains inconclusive. Here we investigated associations between the use of antidepressants and occurrences of oral cancer (OC)., Methods: Two million samples were randomly collected from the National Health Insurance Research Database in Taiwan, which covers 98% of the total population (23 million). All patients from2000 to 2009 were followed up. We identified 5103 patients newly diagnosed with OC after antidepressants use in addition to 20,412 non-OC matched subjects and 95,452 unmatched non-OC subjects., Results: In nested case control analysis, factors associating with OC, including age [OR = 1.02; 95% confidence interval (CI) = 1.01-1.03) and male (OR = 5.30; 95% CI = 4.92-5.70) were independently associated with increased risk of OC. Based on the functions of antidepressants, antidepressants treatment medications were further classified to investigate risk of OC. Selective serotonin reuptake inhibitors (OR = 0.61; 95% CI = 0.53-0.70) and tricyclic antidepressants (OR = 0.57; 95% CI = 0.52-0.63) were associated with reduced risk of OC. The risk of developing OC among subjects taking antidepressants was less than 26% [hazard ratio (HR) =0.74; 95% CI = 0.68-0.81] in prospective cohort study. The effect of a cumulative duration and dose was a significantly reduced risk of OC., Conclusions: The association between antidepressant use and decreasing OC risk were demonstrated by both prospective and nested case-control studies.