Oral Oral Squamous Cell Carcinoma Research Articles

Effect and mechanism of resveratrol on ferroptosis mediated by p53/SLC7A11 in oral squamous cell carcinoma

ObjectiveResveratrol (Res) is a natural phytoestrogen with antitumor activity. This study sought to investigate the role of Res in ferroptosis in oral squamous cell carcinoma (OSCC).MethodsNormal human oral keratinocyte (HOK)/oral OSCC (CAL-27/SCC-9) cell lines were treated with different doses of Res. Res toxicity was determined by MTT assay, with half maximal inhibitory concentration values of Res on CAL-27 and SCC-9 cells calculated. Cell viability/colony formation efficiency/migration/invasion/cycle were assessed by CCK-8/colony formation assay/transwell assay/flow cytometry. The expression of p53 protein in the nucleus and cytoplasm, glutathione peroxidase 4 (GPX4) expression, and SLC7A11 messenger RNA (mRNA) and protein expression levels were determined by Western blot and RT-qPCR. Fe2+ content, reactive oxygen species (ROS) level, reduced glutathione (GSH), and lactate dehydrogenase (LDH) release were assessed.ResultsMedium- to low-dose Res had no toxic effect on HOK cells, while high-dose Res markedly reduced HOK cell viability. Res significantly suppressed the viability of OSCC cells (CAL-27 and SCC-9). Res inhibited OSCC cell colony formation/migration/invasion, and induced G1 phase arrest. Res caused the translocation of p53 protein to the nucleus, obviously increased Fe2+ content, ROS level and LDH release, decreased GSH content and GPX4 protein expression, and induced ferroptosis. Down-regulation of p53 partially reversed the inhibitory effects of Res on CAL-27 cell malignant behaviors. Res inhibited SLC7A11 transcription by promoting p53 entry into the nucleus. SLC7A11 overexpression negated the the regulatory effects of p53 knockout on the role of Res in OSCC cell malignant behaviors and ferroptosis.ConclusionRes accelerated ferroptosis and inhibited malignant behaviors in OSCC cells by regulating p53/SLC7A11.

Salivary metabolomic identification of biomarker candidates for oral melanoma and oral squamous cell carcinoma in dogs.

Oral melanoma (OM) and oral squamous cell carcinoma (OSCC) are frequently diagnosed in dogs, presenting a challenge in distinguishing them from benign oral tumors (BN). Salivary metabolomic biomarkers offer a practical solution because of saliva's direct contact with tumors and the noninvasive nature of collection. Assess the diversity and abundance of the salivary metabolome in dogs with BN, OM, and OSCC using amine/phenol submetabolome analysis and high-performance chemical isotope labeling liquid chromatography-mass spectrometry (CIL LC-MS). Study included 11 BN, 24 OM, 10 OSCC, and 20 healthy control dogs. Case-control cross-sectional study was conducted to assess salivary submetabolic profiles in dogs with BN, OM, and OSCC and healthy dogs. Samples were labeled with 12C-dansyl chloride and analyzed using CIL LC-MS targeted to amine- and phenol-containing metabolites for amine/phenol submetabolome analysis. Distinct clusters and significant differences in metabolite concentrations were observed among the oral cancer, BN, and control groups. A total of 154 and 66 metabolites showed significantly altered concentrations, particularly in OM and OSCC, respectively, when compared with BN (Padj < .05). Potential metabolic biomarkers were identified for each cancer, including decreased concentrations of seryl-arginine and sarcosine in OSCC. Moreover, high-confidence putative metabolites were identified, including an increase in tryptophyl-threonine and a decrease in 1,2-dihydroxynapthalene-6-sulfonic acid and hydroxyprolyl-hydroxyproline for OM. We identified high coverage of the amine/phenol submetabolome, including seryl-arginine, and sarcosine, in OSCC. Our findings emphasize the potential of these biomarkers for distinguishing between oral OSCC and BN in dogs.

Expression of Ki-67, Cyclin D1, P53, and P16 in patients with oral leukoplakia and leukoplakia cancerization with spicy diet in Chengdu.

To investigate the expression of Ki-67, Cyclin D1, P53, and P16 in patients with oral leukoplakia (OLK) and OLK cancerization who have aspicy diet in Chengdu. Thirtypatients with OLK andspicy diet and 15 patients with OLK without spicy diet in Chengdu were divided into three groups: hyperplastic OLK (OLK-), OLK with mild to moderate dysplasia (OLK+), and severe dysplastic OLK or oral squamous cell carcinoma (OSCC) transforming from OLK (OLK++/OSCC). The expression of Ki-67, Cyclin D1, P53, and P16 were detected by immunohistochemistry and statistically analyzed. The expression of Ki-67 and P53 in patients with or without spicy diet in the OLK+and OLK++/OSCC groups were stronger than that of the OLK- group (P<0.05). The OLK++/OSCC group showed a higher expression of Cyclin D1 and lower expression of P16 than the OLK- group (P<0.05). The expression of Ki-67, Cyclin D1, P53, and P16 in patients with spicy diet and without spicy diet had no substantial difference. The expression of Ki-67 and Cyclin D1 showed a positive correlation (r=0.439, P=0.015). Spicy diet did not have an influence on the expression of Ki-67, Cyclin D1, P53, and P16 in patients with OLK and OSCC. The expression of Ki-67, Cyclin D1, and P53 increased with the development of OLK, whereas P16 showed opposite expression trend.

Comparison of Estimation Method in Diagnostic Meta-Analysis: An Application in Dentistry

In this study, the objective was to compare different estimation methods in diagnostic meta-analysis. In this scope, DerSimonian and Laird (DL), Restricted Maximum Likelihood (REML), Sidik and Jonkman (SJ), Hedges and Olkin (HO), Maximum Likelihood (ML), Paule and Mandel (PM) estimation methods were examined. In the implementation part, effectiveness of Clinical Oral Examination (COE) in predicting the diagnosis of histological dysplasia or Oral Squamous Cell Carcinoma (OSCC) was studied.

From the Matrix to the Nucleus and Back: Mechanobiology in the Light of Health, Pathologies, and Regeneration of Oral Periodontal Tissues.

Among oral tissues, the periodontium is permanently subjected to mechanical forces resulting from chewing, mastication, or orthodontic appliances. Molecularly, these movements induce a series of subsequent signaling processes, which are embedded in the biological concept of cellular mechanotransduction (MT). Cell and tissue structures, ranging from the extracellular matrix (ECM) to the plasma membrane, the cytosol and the nucleus, are involved in MT. Dysregulation of the diverse, fine-tuned interaction of molecular players responsible for transmitting biophysical environmental information into the cell’s inner milieu can lead to and promote serious diseases, such as periodontitis or oral squamous cell carcinoma (OSCC). Therefore, periodontal integrity and regeneration is highly dependent on the proper integration and regulation of mechanobiological signals in the context of cell behavior. Recent experimental findings have increased the understanding of classical cellular mechanosensing mechanisms by both integrating exogenic factors such as bacterial gingipain proteases and newly discovered cell-inherent functions of mechanoresponsive co-transcriptional regulators such as the Yes-associated protein 1 (YAP1) or the nuclear cytoskeleton. Regarding periodontal MT research, this review offers insights into the current trends and open aspects. Concerning oral regenerative medicine or weakening of periodontal tissue diseases, perspectives on future applications of mechanobiological principles are discussed.

Single nucleotide polymorphisms and serologic levels of hypoxia-inducible factor1 α and vascular endothelial growth factor are associated with increased risk of oral submucous fibrosis in gutka users among a North Indian population

Tissue hypoxia in oral submucous fibrosis (OSMF) induces hypoxia-inducible factor (HIF)-1 α and vascular endothelial growth factor (VEGF), causing angiogenesis. Single nucleotide polymorphisms (SNPs) may predict susceptibility to environmental carcinogens and to development of OSMF, as well as its severity and malignant transformation. This study aimed to determine the serologic levels and frequencies of SNPs of HIF-1 α and VEGF in OSMF. In this prospective pilot study, the frequencies of SNPs of HIF-1 α (C1772 T, G1790 A); VEGF-A 936 C/T; and VEGF-C (rs7664413, rs1485766) in patients with OSMF or oral squamous cell carcinoma (OSCC) and in healthy controls were determined by using polymerase chain reaction (PCR) (n=100 each), and serologic levels were determined by using enzyme-linked immunosorbent assay (ELISA (n=50 each), in a North Indian population. Heterozygous forms of HIF-1 α C1772 T (CT: odds ratio [OR] 5.0; 95% confidence interval [CI] 2.24-11.16; P < .001); HIF-1 α G1790 A (GA: OR 2.8; 95% CI 1.62-5.16; P < .001); and VEGF-C rs1485766 (AC: OR 2.18; 95% CI 1.19-3.99; P < .05) were associated with OSMF. The mean serologic levels of HIF-1 α, VEGF-A, and VEGF-C were significantly raised in patients with OSMF compared with healthy controls (P < .001). The SNPs of HIF-1 α, VEGF-A, and VEGF-C and their serologic levels can act as prognostic biomarkers and aid in the development of specialized anti-HIF-1 α or anti-VEGF drugs for the management and prevention of OSCC in patients with OSMF.

CDK4, CDK6, cyclin D1 and Notch1 immunocytochemical expression of oral brush liquid-based cytology for the diagnosis of oral leukoplakia and oral cancer.

This study aimed to investigate the feasibility of using oral liquid-based brush cytology (OLBC) coupled with immunocytochemistry as a minimally invasive approach to stratify the cancer risk in patients with oral leukoplakia. Fifty-five patients diagnosed with either oral leukoplakia (OLK) or oral squamous cell carcinoma (OSCC) were recruited. All patients underwent oral brush biopsy followed by surgical biopsy. 275 liquid-based cytology preparations were made. Pap-stained OLBC slides were assessed using the modified 2014 Bethesda Cytology system. The expression of CDK4, CDK6, cyclin D1, and Notch 1 was immunocytochemically analysed and compared against the histopathological diagnosis. A combined index score of OLBC grading and protein expression was calculated. A significant association was found between the definitive histopathological diagnosis and the cytological interpretation (P=0.0005). The index scores of CDK4, CDK6, and cyclin D1 were significantly associated with the development of disease from non-dysplastic epithelium to OSCC. No significant association was observed between the Notch 1 index score and disease stage. The diagnostic accuracy of OLBC showed the highest values of sensitivity, specificity, positive predictive value, negative predictive value, and accuracy: 84.6%, 70.4%, 73.3%, 82.6%, and 78.8%, respectively, compared with the cumulative protein index, CDK4/6 index, and the combined OLBC grading and CDK4/6 index. This study has also demonstrated the efficacy of the use of OLBC in the detection of OED and OSCC, and showed that the use of CDK4, CDK6, cyclin D1, and Notch 1 immunocytochemistry failed to improve the diagnostic accuracy of OLBC suggesting they are not useful in the early detection of OSCC.

The length of patient and primary care time interval in the pathways to treatment in symptomatic oral cancer. A quantitative systematic review.

To examine the relative length of the patient and primary care intervals in symptomatic oral cancer. Quantitative systematic review. Oral cancer OR oral squamous cell carcinoma OR oropharyngeal cancer AND time interval OR diagnostic delay. Primary and secondary care. Oral and oropharyngeal cancer patients. We computed five measures (patient, primary care, diagnosis, total diagnosis and total treatment intervals). Most studies did not provide any dispersion measure. We then used the sample size of each study to compute a weighted average of the mean intervals. When the median was provided, we assumed normality of the distribution of the means and used the median as a proxy of the mean. A total of 1089 articles were identified, and 22 met the inclusion criteria, reporting on 2710 patients from Europe, USA, India, Australia, Japan, Argentina and Iran. The weighted average of patient interval was 80.3days. Primary care interval was five times shorter: 15.8days. The diagnostic interval was appreciably shorter (47.9days) when compared with the patient interval during symptomatic period. Patient interval represents the major component of waiting times since the detection of the first signs/symptoms to the definitive diagnosis of oral cancer. Thus, strategies focused on high-risk patients should be prioritised. Interventions aimed at optimising the health systems should be implemented by monitoring and facilitating diagnostic and treatment pathways of patients with oral cancer.

Oral Health-Related Quality of Life of Patients With Oral Lichen Planus, Oral Leukoplakia, or Oral Squamous Cell Carcinoma

To compare oral health-related quality of life (OHRQoL) of patients with oral lichen planus (OLP), oral leukoplakia (OL), or oral squamous cell carcinoma (OSCC). Seventy-three patients with OLP, 44 with OL, and 37 with OSCC participated in this prospective study. The German version of the 14-item Oral Health Impact Profile (OHIP-G 14) was used to measure OHRQoL. Descriptive statistics and multivariate analysis of clinical forms, age, gender, alcohol consumption, and smoking habits were evaluated. No association to cumulative OHIP-14 score (P = .086) among the 3 groups was found. However, patients with OLP showed a higher "physical pain" score and a lower "social disability" score (P = .026) than patients with OSCC, followed by patients with OL. Women with OLP had a lower OHRQoL than men. After differentiation of clinical forms of OLP (symptomatic vs asymptomatic), an impact on these patients' OHRQoL in the dimensions "physical pain" and "physical disability" was found. Patients with OLP or OSCC and high OHIP-G 14 scores reported physical pain, which emphasizes the need for physical therapy. For improved OHRQoL, patients with symptomatic forms of OLP would gain more from a treatment compared with those with asymptomatic forms. In contrast, patients with asymptomatic OLP or OL and thus with a minimal impact on their OHRQoL might be at risk of delayed consultation, diagnosis, and treatment of their condition.

The FGFR1 inhibitor PD173074 induces mesenchymal–epithelial transition through the transcription factor AP-1

Background:Epithelial–mesenchymal transition (EMT) is a crucial process in cancer progression that provides cancer cells with the ability to escape from the primary focus, invade stromal tissues and migrate to distant regions. Cell lines that lack E-cadherin show increased tumorigenesis and metastasis, and the expression levels of E-cadherin and Snail correlate inversely with the prognosis of patients suffering from breast cancer or oral squamous cell carcinoma (OSCC). Moreover, recent studies have shown that most EMT cases are regulated by soluble growth factors or cytokines. Among these factors, fibroblast growth factors (FGFs) execute diverse functions by binding to and activating members of the FGF receptor (FGFR) family, including FGFR1–4. Fibroblast growth factor receptor 1 is an oncoprotein that is involved in tumorigenesis, and PD173074 is known to be a selective inhibitor of FGFR1. However, the roles of FGFR1 and FGFR1 inhibitors have not yet been examined in detail.Methods:Here, we investigated the expression of FGFR1 in head and neck squamous cell carcinoma (HNSCC) and the role of the FGFR1 inhibitor PD173074 in carcinogenesis and the EMT process.Results:Fibroblast growth factor receptor 1 was highly expressed in 54% of HNSCC cases and was significantly correlated with malignant behaviours. Nuclear FGFR1 expression was also observed and correlated well with histological differentiation, the pattern of invasion and abundant nuclear polymorphism. Fibroblast growth factor receptor 1 was also overexpressed in EMT cell lines compared with non-EMT cell lines. Furthermore, treatment of HOC313 cells with PD173074 suppressed cellular proliferation and invasion and reduced ERK1/2 and p38 activation. These cells also demonstrated morphological changes, transforming from spindle- to cobble stone-like in shape. In addition, the expression levels of certain matrix metalloproteinases (MMPs), whose genes contain activator protein-1 (AP-1) promoter sites, as well as Snail1 and Snail2 were reduced following PD173074 treatment.Conclusion:Taken together, these data suggest that PD173074 inhibits the MAPK pathway, which regulates the activity of AP-1 and induces MET. Furthermore, this induction of MET likely suppresses cancer cell growth and invasion.

PP064: Wnt5a stimulates migration and invasion in OSCC

Purpose Wnt5a is the most important Wnt protein activating the non-canonical Wnt pathway. It regulates proliferation, differentiation, migration, adhesion and polarity of the cell. Clinical studies have shown that Wnt5a could act as a prognostic marker in various cancers. It seems that Wnt5a acts both as a tumor suppressor (breast, thyroid, colon and livercancer) and as a tumor promotor (malignant melanoma, pancreatic and gastric cancer). In oral squamous cell carcinoma (OSCC) a number of Wnt and Frizzled genes are expressed, mostly Wnt5a and Frizzled-5 but the role of Wnt5a has not yet been thoroughly elucidated. The aim of this study is to evaluate the role of Wnt5a in oral OSCC and its influence on the cell proliferation, migration and invasion. Material and methods The protein content of Wnt5a in two OSCC cell lines (SCC25 and SCC9) was determined by Western blotting. The influence of rWnt5a and two Wnt5a-derived hexapeptides: Foxy5 (an agonist that mimics Wnt5a activity) and Box5 (an antagonist that inhibits Wnt5a) on the migration and proliferation in OSCC cell lines was studied by a scratch assay and BrdU. Invasion influenced by rWnt5a was studied using Boyden chambers. Results Both cell lines express Wnt5a. Dose–response curves of rWnt5a in SCC9 and SCC25 indicate that Wnt5a increases migration with statistically significant effective concentration at 0.4 μg/ml but has no effect on the proliferation of the two cell lines. To confirm this we used Foxy5 and Box5. Foxy5 increases migration with statistically significant effective concentration at 150 μM while Box5 inhibits Wnt5a effect on the migration. Foxy5 and Box5 have no influence on proliferation. Invasion was increased by rWnt5a. Conclusions The results demonstrate that Wnt5a increases migration and invasion but has no influence on proliferation in OSCC cell lines.

The limitations of the clinical oral examination in detecting dysplastic oral lesions and oral squamous cell carcinoma

The clinical oral examination (COE) is the criterion standard for the initial detection of oral lesions that harbor dysplasia or oral squamous cell carcinoma (OSCC) at an early stage when they are most treatable. The authors conducted a systematic review to assess the effectiveness of the COE in predicting histologic diagnosis of dysplasia or OSCC. The authors conducted automated searches of PubMed, Web of Knowledge and the Cochrane Library from 1966 through 2010 for randomized controlled trials and observational studies that included the terms "oral mucosal lesion screening" and "oral lesions." They determined the quality (sensitivity, specificity, positive predictive value, negative predictive value and diagnostic odds ratio) of selected studies by using the Quality Assessment of Diagnostic Accuracy Studies tool. The overall diagnostic odds ratio was 6.1 (95 percent confidence interval, 2.1-17.6); therefore, the COE was considered to have poor overall performance as a diagnostic method for predicting dysplasia and OSCC. On the basis of the available literature, the authors determined that a COE of mucosal lesions generally is not predictive of histologic diagnosis. The fact that OSCCs often are diagnosed at an advanced stage of disease indicates the need for improving the COE and for developing adjuncts to help detect and diagnose oral mucosal lesions.