Comprehensive insights into oral squamous cell carcinoma: Diagnosis, pathogenesis, and therapeutic advances.

Oral squamous cell carcinoma (OSCC) is considered the most common type of head and neck squamous cell carcinoma (HNSCC) as it holds 90 % of HNSCC cases that arise from multiple locations in the oral cavity. The last three decades witnessed little progress in the diagnosis and treatment of OSCC the aggressive tumor. However, in-depth knowledge about OSCC's pathogenesis, staging & grading, hallmarks, and causative factors is a prime requirement in advanced diagnosis and treatment for OSCC patients. Therefore present review was intended to comprehend the OSCCs' prevalence, staging & grading, molecular pathogenesis including premalignant stages, various hallmarks, etiology, diagnostic methods, treatment (including FDA-approved drugs with the mechanism of action and side effects), and theranostic agents. The current review updates that for a better understanding of OSCC progress tumor-promoting inflammation, sustained proliferative signaling, and growth-suppressive signals/apoptosis capacity evasion are the three most important hallmarks to be considered. This review suggests that among all the etiology factors the consumption of tobacco is the major contributor to the high incidence rate of OSCC. In OSCC diagnosis biopsy is considered the gold standard, however, toluidine blue staining is the easiest and non-invasive method with high accuracy. Although there are various therapeutic agents available for cancer treatment, however, a few only are approved by the FDA specifically for OSCC treatment. The present review recommends that among all available OSCC treatments, the antibody-based CAR-NK is a promising therapeutic approach for future cancer treatment. Presently review also suggests that theranostics have boosted the advancement of cancer diagnosis and treatment, however, additional work is required to refine the role of theranostics in combination with different modalities in cancer treatment.

Wnt pathway in oral cancer: A review update.

The Wnt signalling pathway involves in the pathogenesis of human diseases and one of the pathways that contribute to embryogenic development. Studies about the Wnt pathway have unfolded its regulation in many cancer cell mechanisms such as cell survival, migration, polarity, and cell multiplication. Moreover, the Wnt pathway has a significant role in cell fate determination and self-renewal in stem cells. Oral cancer shares significant concern among clinicians and researchers. However, there are only a few studies done on oral cancer and its correlation with the Wnt pathway. The expression of Wnt gene members in many malignancy diseases which included oral cancer has proven a high inverse correlation with malignancy diseases and malignancy progression. Metastasis which predominantly occurred through the lymphatic system has been the principal cause of mortality in oral cancer and affected to cancer stage, main tumour site, cancer cell differentiation and cancer cell adhesion potency. With intention of contributing to oral pathology and oral medicine research and knowledge advancement, particularly in the oral cancer area, this article presents current findings regarding the Wnt pathway and its multiple mechanisms associated with the treatment of oral carcinogenesis through Wnt pathway signalling.

Involvement of CELSR3 Hypermethylation in Primary Oral Squamous Cell Carcinoma.

BACKGROUND: Promoter hypermethylation is a frequent epigenetic mechanism for gene transcription repression in cancer and is one of the hallmarks of the disease. Cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3) contributes to cell contact-mediated communication. Dysregulation of promoter methylation has been reported in various cancers. OBJECTIVES: The objectives of this study were to investigate the CELSR3 hypermethylation level in oral squamous cell carcinomas (OSCCs) using methylation-sensitive high-resolution melting analysis (MS-HRM) and to correlate CELSR3 methylation with patient demographic and clinicopathological parameters. MATERIALS AND METHODS: Frozen tissue samples of healthy subjects' normal mucosa and OSCCs were examined with regard to their methylation levels of the CELSR3 gene using MS-HRM. RESULTS: MS-HRM analysis revealed a high methylation level of CELSR3 in 86% of OSCC cases. Significant correlations were found between CELSR3 quantitative methylation levels with patient ethnicity (P=0.005), age (P=0.024) and pathological stages (P=0.004). A moderate positive correlation between CELSR3 and patient age was also evident (R=0.444, P=0.001). CONCLUSIONS: CELSR3 promoter hypermethylation may be an important mechanism involved in oral carcinogenesis. It may thus be used as a biomarker in OSCC prognostication.

Screening of differential promoter hypermethylated genes in primary oral squamous cell carcinoma.

BACKGROUND: Promoter hypermethylation leads to altered gene functions and may result in malignant cellular transformation. Thus, identification of biomarkers for hypermethylated genes could be useful for diagnosis, prognosis, and therapeutic treatment of oral squamous cell carcinoma (OSCC). OBJECTIVES: To screen hypermethylated genes with a microarray approach and to validate selected hypermethylated genes with the methylation-specific polymerase chain reaction (MSPCR). MATERIALS AND METHODS: Genome-wide analysis of normal oral mucosa and OSCC tissues was conducted using the Illumina methylation microarray. The specified differential genes were selected and hypermethylation status was further verified with an independent cohort sample of OSCC samples. Candidate genes were screened using microarray assay and run by MSPCR analysis. RESULTS: TP73, PIK3R5, and CELSR3 demonstrated high percentages of differential hypermethylation status. CONCLUSIONS: Our microarray screening and MSPCR approaches revealed that the signature candidates of differentially hypermethylated genes may possibly become potential biomarkers which would be useful for diagnostic, prognostic and therapeutic targets of OSCC in the near future.

Overexpression of MMP13 is associated with clinical outcomes and poor prognosis in oral squamous cell carcinoma.

Matrix metalloproteinase 13 (MMP13) plays a central role in the MMP activation cascade that enables degradation of the extracellular matrix and basement membranes, and it is identified as a potential driver in oral carcinogenesis. Therefore, this study aims to determine the copy number, mRNA, and protein expression of MMP13 in oral squamous cell carcinoma (OSCC) and to associate these expressions with clinicopathological parameters. Copy number, mRNA, and protein expression analysis of MMP13 were determined using real-time quantitative PCR and immunohistochemistry methods in OSCC samples. The correlations between MMP13 expressions and clinicopathological parameters were evaluated, and the significance of MMP13 as a prognostic factor was determined. Despite discrepancies between gene amplification and mRNA and protein overexpression rates, OSCC cases showed high amplification of MMP13 and overexpression of MMP13 at both mRNA and protein levels. High level of MMP13 protein expression showed a significant correlation with lymph node metastasis (P = 0.011) and tumor staging (P = 0.002). Multivariate Cox regression model analysis revealed that high level of mRNA and protein expression of MMP13 were significantly associated with poor prognosis (P < 0.050). Taken together, these observations indicate that the MMP13 protein overexpression could be considered as a prognostic marker of OSCC.

DNA methylation profiling revealed promoter hypermethylation-induced silencing of p16, DDAH2 and DUSP1 in primary oral squamous cell carcinoma.

BACKGROUND: Hypermethylation in promoter regions of genes might lead to altered gene functions and result in malignant cellular transformation. Thus, biomarker identification for hypermethylated genes would be very useful for early diagnosis, prognosis, and therapeutic treatment of oral squamous cell carcinoma (OSCC). The objectives of this study were to screen and validate differentially hypermethylated genes in OSCC and correlate the hypermethylation-induced genes with demographic, clinocopathological characteristics and survival rate of OSCC. METHODS: DNA methylation profiling was utilized to screen the differentially hypermethylated genes in OSCC. Three selected differentially-hypermethylated genes of p16, DDAH2 and DUSP1 were further validated for methylation status and protein expression. The correlation between demographic, clinicopathological characteristics, and survival rate of OSCC patients with hypermethylation of p16, DDAH2 and DUSP1 genes were analysed in the study. RESULTS: Methylation profiling demonstrated 33 promoter hypermethylated genes in OSCC. The differentially-hypermethylated genes of p16, DDAH2 and DUSP1 revealed positivity of 78%, 80% and 88% in methylation-specific polymerase chain reaction and 24% and 22% of immunoreactivity in DDAH2 and DUSP1 genes, respectively. Promoter hypermethylation of p16 gene was found significantly associated with tumour site of buccal, gum, tongue and lip (P=0.001). In addition, DDAH2 methylation level was correlated significantly with patients' age (P=0.050). In this study, overall five-year survival rate was 38.1% for OSCC patients and was influenced by sex difference. CONCLUSIONS: The study has identified 33 promoter hypermethylated genes that were significantly silenced in OSCC, which might be involved in an important mechanism in oral carcinogenesis. Our approaches revealed signature candidates of differentially hypermethylated genes of DDAH2 and DUSP1 which can be further developed as potential biomarkers for OSCC as diagnostic, prognostic and therapeutic targets in the future.