Outcome Of Oral Squamous Cell Carcinoma Research Articles

Comparison of mutation landscapes of pretreatment versus recurrent squamous cell carcinoma of the oral cavity: The possible mechanism of resistance to standard treatment.

A high recurrent rate of oral squamous cell carcinoma (OSCC) is a major concern in head and neck cancer treatment. The study of the genetic mutation landscape in recurrent OSCC may provide information on certain mutations associated with the pathobiology and treatment response of the OSCC. We investigated the mutation landscape of matched pretreatment and recurrent tumors to understand the influence of genetic mutations on the pathobiology and clinical outcomes in OSCC. We sequenced 33 formalin-fixed paraffin-embedded (FFPE) recurrent tumors, primary tumors, and primary tumors before recurrence that matched the recurrent tumors collected from Rajavithi Hospital during 2019-2021. We identified recurrent mutations from these samples by the Oncomine Ion Torrent-based next-generation sequencing on the 517 cancer-associated gene panel. From the results, we found that the most commonly mutated gene in the cohort is a histone methyltransferase KMT2D (54.55%), implicating that aberrance in epigenetic regulation may play a role in oral cancer tumorigenesis. Functional protein association network analysis of the gene frequently mutated in the recurrent tumors showed enrichment of genes that regulate the cancer cell cycle, that is, MRE11A, CDKN2A, and CYLD. This finding was confirmed in the primary-recurring matched pair. We found that recurrent tumors possess a small but recurring group of genes, with presumably the subclonal mutations driving the recurrence of the tumor, suggesting that the recurrent disease originated from a small fraction of the cancer cell that survives standard treatment. These genes were absent in the primary tumor with a good response to the standard treatment. On the other hand, we found an enrichment of DNA repair genes, namely ATR, BRCA1, BRCA2, RAD50, and MUTYH, in nonrecurrent tumors suggesting that the mutations in the DNA repair pathway may at least partially explain the different response to the standard treatment. Our pilot study identified pathways of carcinogenesis in oral cancer and specific gene sets that indicate treatment responses and prognoses in this group of patients.

Involvement of ferroptosis‐defensive xCT/GPX4 axis in radioresistance and its impacts on prognosis in oral squamous cell carcinoma

AbstractAimRadiotherapy, the mainstay treatment for patients with advanced oral squamous cell carcinoma (OSCC), has low clinical efficacy, resulting in poor prognosis. Radiation induces ferroptosis, a form of cell death driven by iron‐dependent lipid peroxidation. Since the xCT/glutathione peroxidase 4 (GPX4) axis is predominantly involved in the ferroptosis defense system, targeting this axis may potentiate cancer cell vulnerability to ferroptosis.MethodsWe examined the expression of xCT and GPX4 in the tumor cells of biopsy specimens using immunohistochemistry and evaluated the radiation‐mediated antitumor effects of the ferroptosis inducers, erastin and RSL3, that act by inhibiting xCT and GPX4, respectively.ResultsUnivariate analysis revealed that high immunohistochemical expression of xCT was correlated with shorter survival, and high GPX4 expression was an independent poor prognostic factor, indicating that the xCT/GPX4 axis influences the clinical outcome of OSCC. Analyses using two types of OSCC cell lines revealed that the clonogenic survival of irradiated cells was increased by the ferroptosis inhibitor ferrostatin‐1 and decreased by erastin and RSL3. The enhanced antitumor effects of erastin and RSL3 were accompanied by increased lipid peroxidation, which was suppressed by the iron chelator deferoxamine. Erastin and RSL3 enhance the effects of radiation on OSCC cells in a mouse xenograft model; these effects were associated with increased expression of the lipid peroxidation marker 4‐hydroxynonenal in tumor cells.ConclusionsxCT/GPX4 axis is involved in the tumor resistance against radiation through the inhibition of ferroptosis in OSCC. Furthermore, radiotherapy combined with ferroptosis induction by targeting the xCT/GPX4 axis may improve patient prognosis in advanced OSCC.

Salivary Biomarkers for Oral Cancer Detection: An Exploratory Systematic Review.

Different efforts have been made to find better and less invasive methods for the diagnosis and prediction of oral cancer, such as the study of saliva as a source of biomarkers. The aim of this study was to perform a scoping review about salivary molecules that have been assessed as possible biomarkers for the diagnosis of oral squamous cell carcinoma (OSCC). A search was conducted using EBSCO, PubMed (MEDLINE), Scopus, and Web of Science. The research question was as follows: which molecules present in saliva have utility to be used as biomarkers for the early detection of oral cancer? Sixty-two studies were included. Over 100 molecules were assessed. Most of the markers were oriented towards the early diagnosis of OSCC and were classified based on their ability for detecting OSCC and oral potentially malignant disorders (OPMDs), OSCC outcome prediction, and the prediction of the malignant transformation of OPMDs. TNF-α, IL-1β, IL-6 IL-8, LDH, and MMP-9 were the most studied, with almost all studies reporting high sensitivity and specificity values. TNF-α, IL-1β, IL-6 IL-8, LDH, and MMP-9 are the most promising salivary biomarkers. However, more studies with larger cohorts are needed before translating the use of these biomarkers to clinical settings.

Comprehensive Analysis of Oral Squamous Cell Carcinomas: Clinical, Epidemiological, and Histopathological Insights With a Focus on Prognostic Factors and Survival Time.

Oral squamous cell carcinoma(OSCC) is one of the most common malignancies in the head and neck region. Particularly, high incidence rates are observed in South and Southeast Asia, attributed to the widespread use of the carcinogenic areca nut. This study aimed to investigate the clinical, epidemiological, and histopathological features of OSCC, identify prognostic factors impacting disease-free survival, and determine a post-diagnosis disease-free survival time of OSCC patients. Employing a descriptive cross-sectional design, the study conducted a thorough examination of the clinical, epidemiological, and histopathological aspects of OSCC among patients seeking care at a tertiary healthcare facility. Participants were personally interviewed if available, while information for unreachable or deceased individuals was extracted from archival patient records in the Oral and Maxillofacial Surgery Department, Bakhtawar Amin Medical and Dental College, Multan, Pakistan. Data analysis was performed with a significance level set at p ≤ 0.05. The mean age of the patients was 54.16 ± 11.1, with a notable concentration in the 41 years and above age group, indicating a significant prevalence of OSCC in this population. The data revealed a gender bias towardmales, and a substantial proportion of patients, particularly those aged 41 years and above, had unfortunately passed away. Statistical analysis using the Fisher exact test showed a significant association between age groups and patients' current living status (p-value < 0.05). Histopathologically, moderately differentiated OSCC was the most frequently encountered grade, and surgery emerged as the predominant treatment modality. The majority of patients studied had a survival period of three years or less, emphasizing the need for further exploration of factors influencing prognosis and treatment outcomes in OSCC.

Upregulation of miRNA-196a and miRNA-196b correlates with Bryne’s prognostic score in oral squamous cell carcinoma

BackgroundmicroRNA(miRNA)-196a and miRNA-196b expression has been found to be dysregulated and involved in tumorigenesis and tumor progression in array of cancers through different targets. The role of these miRNAs together in clinical application is not always consistent and, its prognostic value in oral squamous cell carcinoma (OSCC) is still elusive. This study was performed to investigate the correlation of these miRNAs expression with histological grades of OSCC according to Bryne's histological grading system, to predict prognosis and to evaluate their relationship with clinico-pathological data. MethodsReal-time quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) was done to evaluate the expression levels of miRNA-196a and miRNA-196b in 75 pairs of OSCC tissue matched with adjacent normal mucosa, used as a control. ResultsmiRNA-196a and 196b expression in OSCC was significantly higher than that in corresponding adjacent normal tissues (p > 0.001). Also, a significant differential correlation was found in between the expression levels of these two miRNAs (Pearson correlation test r = 0.676, p-value<0.0001). The increased expression of these miRNAs was more frequently observed in OSCC tissues with advanced clinical and pathological TNM stages (IVa and IVb, pIVb respectively, p-value<0.0001). Significant correlation was found between miRNA-196a upregulation and moderate prognostic score (p-value<0.0001) in comparison with good and poor prognostic score of histological grades of OSCC. Sensitivity and specificity for miRNA-196a were 95 % and 85 %, respectively (AUC = 1, 95 % CI = 0.617–0.850; p 0.001), while for miRNA-196b were 94 % and 86 %, respectively (AUC = 0.808, 95 % CI = 0.701–0.916; p0.0001). ConclusionsThese findings suggest that the increased expression of miRNA-196a and 196b may play an important role in tumor progression in OSCC. miRNA-196a might be a useful marker for predicting the clinical outcome of OSCC, especially for advanced stages. In conclusion, our data demonstrate for the first time that these miRNAs may serve as a potent prognostic marker for tumor progression. We further highlight miRNA-196a and miRNA-196b as a promising predictor of prognostic assessment in OSCC.

Role of DNA methylation-based mitotic ageing indices in oral cancer development and recurrence.

DNA methylation data can be used to derive mitotic indices from complex tissues. Here, we assessed if the DNA methylation-derived mitotic ageing indices are associated with oral squamous cell carcinoma (OSCC) development and recurrence-free survival (RFS). DNA methylation-based mitotic indices (MitoticAge, TNSC and hypoSC) were derived using algorithms "MitoticAge" and "epiTOC2" for the discovery [non-malignant (n = 22), premalignant (n = 22) and OSCC (n = 68) tissues] and validation datasets (GSE87053, GSE136704 and TCGA-HNSCC). Differences in mitotic indices between non-malignant, premalignant and OSCC tissues were assessed. Finally, the association between estimated mitotic indices and RFS was evaluated in OSCCs. In the discovery and validation datasets, increased mitotic ageing was observed in OSCC compared to non-malignant and premalignant oral tissues. HPV-positive HNSCCs had higher mitotic index TNSC. Mitotic age index hypoSC was associated with RFS in OSCC (p = 0.011, HR 2.61, 95% CI 1.24-5.48). DNA methylation-derived mitotic indices are associated with OSCC development and RFS. Thus, DNA methylation-derived mitotic indices may be a valuable research tool to reliably estimate the cumulative number of stem cell divisions in malignant and non-malignant oral tissues. Future research utilizing mitotic indices for predicting clinical outcomes in OSCC is warranted.

Unidirectional alteration of methylation and hydroxymethylation at the promoters and differential gene expression in oral squamous cell carcinoma.

Background: Oral squamous cell carcinoma (OSCC) is one of the most common types of cancer worldwide. Although overall losses of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) have been previously observed, a genome-wide, single-base-resolution, and simultaneous mapping of 5mC and 5hmC in OSCC is still unaccomplished. Similarly, the mechanism of how 5mC and 5hmC collectively lead to abnormal gene expression in OSCC is largely unexplored. Using parallel whole-genome bisulfite sequencing (WGBS) and whole-genome oxidative bisulfite sequencing (oxWGBS), we characterized 5mC- and 5hmC-profiles at single-nucleotide resolution in paired primary OSCC samples and their normal adjacent tissues (NATs). We also analyzed the effect of 5mC- and 5hmC-modifications on differential gene expression in OSCC using multi-omics analysis. Results: An overall reduction of both 5mC and 5hmC in various genomic regions have been observed in OSCC samples. At promoter regions, a total of 6,921 differentially methylated regions and 1,024 differentially hydroxymethylated regions were identified in OSCC. Interestingly, compared to bidirectional modification with 5mC and 5hmC, unidirectional modification with 5mC and 5hmC at the promoters is associated with bigger change in the gene expression. Additionally, genes bearing unidirectional modification with 5mC and 5hmC at the promoters are enriched in signaling pathways like cell proliferation, cell differentiation, and receptor tyrosine kinase pathway that are essential for the tumorigenesis. Finally, the grouped expression signature of top 20 genes bearing promoter-unidirectional-modification with 5mC and 5hmC tends to correlate with the clinical outcome of certain subtypes of head and neck squamous cell carcinoma. Conclusion: Using parallel WGBS and oxWGBS analyses, we observed an overall reduction of 5mC- and 5hmC-modifications at various genomic regions in OSCC. Unidirectional modification with 5mC and 5hmC at the promoters is associated with enhanced changes in gene expression in OSCC tissues. Furthermore, such differentially expressed genes bearing unidirectional modifications with 5mC and 5hmC at the promoters might have clinical relevance to the outcome of OSCC.

A Targeted and pH-Responsive Nano-Graphene Oxide Nanoparticle Loaded with Doxorubicin for Synergetic Chemo-Photothermal Therapy of Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is a malignant disease with serious impacts on human health and quality of life worldwide. This disease is traditionally treated through a combination of surgery, radiotherapy, and chemotherapy. However, the efficacy of traditional treatments is hindered by systemic toxicity, limited therapeutic effects, and drug resistance. Fibroblast activation protein (FAP) is a membrane-bound protease. Although FAP has limited expression in normal adult tissues, it is highly expressed in the tumor microenvironment of many solid cancers - a characteristic that makes it an ideal target for anticancer therapy. In this study, we constructed a nano-drug delivery system (NPF@DOX) targeting FAP to increase the therapeutic efficiency of synergistic chemo-photothermal therapy against OSCC. We utilized PEGylated nano-graphene oxide (NGO) to link doxorubicin (DOX) and fluorescently-labeled, FAP-targeted peptide chains via hydrogen bonding and π-π bonding to enhance the targeting capability of NPF@DOX. The synthesis of NPF@DOX was analyzed using UV-Vis and FT-IR spectroscopy and its morphology using transmission electron microscopy (TEM). Additionally, the drug uptake efficiency in vitro, photo-thermal properties, release performance, and anti-tumor effects of NPF@DOX were evaluated and further demonstrated in vivo. Data derived from FT-IR, UV-Vis, and TEM implied successful construction of the NPF@DOX nano-drug delivery system. Confocal laser scanning microscopy images and in vivo experiments demonstrated the targeting effects of FAP on OSCC. Furthermore, NPF@DOX exhibited a high photothermal conversion efficiency (52.48%) under near-infrared radiation. The thermogenic effect of NPF@DOX simultaneously promoted local release of DOX and apoptosis based on a pH-stimulated effect. Importantly, FAP-targeted NPF@DOX in combination with PTT showed better tumor suppression performance in vivo and in vitro than did either therapy individually. NPF@DOX can precisely target OSCC, and combined treatment with chemical and photothermal therapy can improve the therapeutic outcomes of OSCC. This method serves as an efficient therapeutic strategy for the development of synergistic anti-tumor research.

Chrysin promotes Cisplatin-induced apoptosis via oxidative DNA damage in oral squamous cell carcinoma

Chrysin is an apigenin analog with high therapeutic potential by modulation of apoptotic signaling pathways, improving conventional chemotherapy's effectiveness. In this study, we introduced novel evidence that the Chrysin effect with Cisplatin intensely induced cell death through DNA damage in SCC-25 and CAL-27 of oral squamous cell carcinoma (OSCC). The result of Chrysin and Cisplatin alone or in combination with cell proliferation was assessed using the MTT assay. The expression levels of 8-Hydroxy-2′-deoxyguanosine (8-OXO-dG) were analyzed using an enzyme-linked immunosorbent assay (ELISA). DCFH-DA fluorescence dye was utilized to measure reactive oxygen species (ROS) formation. ELISA cell death and caspase 8 activity assays were used to measure the apoptosis rate in these cells. Chrysin significantly stimulates the cytotoxic activity of Cisplatin. Besides, the co-treatment of Chrysin plus Cisplatin significantly increased the expression levels γ-H2AX in both cell lines. Besides, this combined treatment considerably improved ROS levels and significantly down-regulated the antioxidant enzyme expression. Moreover, Chrysin treatment led to the enhancement of Cisplatin-induced apoptosis in OSCC cell lines when compared to either Chrysin or Cisplatin treated cells. Chrysin and Cisplatin co-treatment improved cytotoxicity via the increased levels of ROS production, which results in oxidative DNA damage and leads to potent apoptosis induction in tumor cells. Generally, this co-treatment could propose a therapeutic approach that hopefully promotes patients' clinical outcomes of OSCC. These data confirm the chemo-sensitizer effect of Chrysin in OSCC cells.

The obesity paradox - Is BMI associated with advanced stage in oral cancer?

Background: Recent studies have shown that cancer patients with low BMI have poor outcomes. Their results suggest, obesity have some protective effect in cancer termed as “obesity paradox”. Aim: To examine the association of BMI with prognostic indicators of oral squamous cell carcinoma (OSCC). Methodology: This multicenter cross-sectional study was conducted during the year 2020 and 2021. 126 patients recently diagnosed with OSCC were randomly selected from three different tertiary care setup in Karachi. Height and weight of each subject was recorded to calculate BMI and clinicopathological data was obtained. The BMI indices were categorized into low, normal and high strata according to WHO guidelines. Statistical analysis was done for association of independent factors with BMI strata. Results: We found 81(64.3%) participants were underweight compared to 32(25.4%) normal-weight and 13(10.3%) overweight cases. A strong statistical association was observed between low BMI (83.1% underweight) and advanced tumor stage i.e., Stage IV (P= 0.001) while among risk factors of OSCC, only smokeless tobacco showed significant association (P= 0.002) with reduced BMI. This research brings attention to the importance of BMI in cancer and add to the growing literature in the field of oncology. Our findings about the impact of BMI on OSCC outcome will help in the intervention and development of prevention strategies for one of the most prevalent cancers in Pakistan. This present research will help to answer the complex question of “optimum” BMI in cancer and will help to improve the prognosis of OSCC. Conclusion: Our findings suggested that low BMI could be an indicator of poor clinical outcomes in OSCC. We thus recommend monitoring of BMI in OSCC patients in order to optimize treatment strategies. However, we encourage further studies to examine other body composition metrics for individualized treatments and intervention strategies. Keywords: Adiposity, Obesity paradox, Squamous cells, carcinoma, BMI

Circulating Long Non-Coding RNAs Could Be the Potential Prognostic Biomarker for Liquid Biopsy for the Clinical Management of Oral Squamous Cell Carcinoma.

Long non-coding RNA (lncRNA) have little or no coding potential. These transcripts are longer than 200 nucleotides. Since lncRNAs are master regulators of almost all biological processes, recent evidence proves that aberrantly expressed lncRNAs are pathogenic for oral squamous cell carcinoma (OSCC) and other diseases. LncRNAs influence chromatin modifications, transcriptional modifications, post-transcriptional modifications, genomic imprinting, cell proliferation, invasion, metastasis, and apoptosis. Consequently, they have an impact on the disease transformation, progression, and morbidity in OSCC. Therefore, circulating lncRNAs could be the potential cancer biomarker for the better clinical management (diagnosis, prognosis, and monitoring) of OSCC to provide advanced treatment strategies and clinical decisions. In this review, we report and discuss the recent understandings and perceptions of dysregulated lncRNAs with a focus on their clinical significance in OSCC-disease monitoring and treatment. Evidence clearly indicates that a specific lncRNA expression signature could act as an indicator for the early prediction of diagnosis and prognosis for the initiation, progression, recurrence, metastasis and other clinical prognostic-factors (overall survival, disease-free survival, etc.) in OSCC. The present review demonstrates the current knowledge that all potential lncRNA expression signatures are molecular biomarkers for the early prediction of prognosis in OSCC. Finally, the review provides information about the clinical significance, challenges and limitations of the clinical usage of circulating lncRNAs in a liquid biopsy method in early, pre-symptomatic, sub-clinical, accurate OSCC prognostication. More studies on lncRNA are required to unveil the biology of the inherent mechanisms involved in the process of the development of differential prognostic outcomes in OSCC.

The Emerging Impact of Tumor Budding in Oral Squamous Cell Carcinoma: Main Issues and Clinical Relevance of a New Prognostic Marker.

Simple SummaryThe results of tumor budding are an independent prognostic factor of locoregional recurrences in many solid cancers, including colorectal, nasopharyngeal, esophageal, and lung cancer. Regarding oral squamous cell carcinoma, tumor budding predicts poor survival outcomes regardless of the tumor subsite and the pathological stage. Several detection methods for tumor budding have been proposed in the literature in order to reach an agreement on a standardized scoring system. However, the lack of a standardized assessment method prevents its evaluation in a multidisciplinary setting. In this context, this study aims to critically review the literature data regarding the prognostic role of tumor budding in oral squamous cell carcinoma. The validation of a tumor budding detection method based on tumor stage and site could be relevant to improving risk stratification and planning the clinical management of patients. Moreover, tumor budding could be included in daily pathological practice to better predict the patient’s outcomes.Tumor Budding (TB) represents a single cancer cell or a small cluster of less than five cancer cells on the infiltrative tumor front. Accumulating evidence suggests TB is an independent prognostic factor in oral squamous cell carcinoma (OSCC). However, its exact role is not yet elucidated, and a standardized scoring system is still necessary. The study aims to extensively review the literature data regarding the prognostic role of TB in OSCC. The results of TB are an independent prognostic factor of poor survival outcomes in OSCC. To date, the manual detection of hematoxylin and eosin-staining or pancytokeratin-immunostaining sections are the most commonly used methods. Between the several cut-offs, the two-tier system with five buds/field cut-offs provides better risk stratification. The prognostic role of the BD model in predicting survival outcomes was extensively validated; however, the inclusion of DOI, which is already a staging parameter, encouraged other authors to propose other models, integrating TB count with other adverse risk factors, such as the tumor–stroma ratio and tumor-infiltrated lymphocytes. The prognostic relevance of TB in OSCC highlights its evaluation in daily pathological practice. Therefore, the TB detection method and the TB scoring system should be validated based on tumor stage and site.

Tumor specificity of WNT ligands and receptors reveals universal squamous cell carcinoma oncogenes

BackgroundThe WNT signal pathway has myriad family members, which are broadly involved in embryonic development and human cancer. Over-activation of WNT-β-Catenin signaling promotes cancer cell proliferation and survival. However, how diverse components of WNT signaling specifically engaged in distinct tumor types remains incompletely understood.MethodsWe analyzed the transcriptomic profiling of WNT ligands and receptors/co-receptors among 26 different tumor types to identify their expression pattern, and further verified these results using clinical oral squamous cell carcinoma (OSCC) and lung squamous cell carcinoma (LUSC) samples. At the same time, we also detected WNT7B expression in oral inflammation and carcinoma, and constructed stable WNT7B knockdown OSCC cell lines to study the effects of WNT7B on the cell migration and invasion ability.ResultsWe found a group of tumor-specific WNT members, including a panel of squamous cell carcinomas (SCCs) specific upregulated WNT ligands and receptors, WNT5A, WNT7B, FZD7 and GPC1. We further revealed a significant correlation between these protein expression characteristics and clinical outcomes of OSCC and LUSC patients. Moreover, WNT7B was demonstrated to contribute to the development of oral chronic inflammation and OSCC, partly due to promoting the invasion ability of tumor cells.ConclusionsThese results demonstrate that the function of WNT ligands and receptors in specific tumors depends on the origination of tumor tissue type. Collectively, they support the use of WNT components as a highly specific target for pan-tissue-type originated tumors.

Assessing Gene Expression Related to Cisplatin Resistance in Human Oral Squamous Cell Carcinoma Cell Lines

Cisplatin-based chemotherapy has been effectively used to treat oral cancer, but treatment often fails owing to the development of drug resistance. However, the important gene expression alterations associated with these resistances remain unclear. In this study, we aimed to identify the gene expressions related to cisplatin resistance in oral squamous cell carcinoma (OSCC) cell lines. RNA samples were obtained from three cisplatin-resistant (YD-8/CIS, YD-9/CIS, and YD-38/CIS) and -sensitive (YD-8, YD-9, and YD-38) cell lines. Global gene expression was analyzed using RNA sequencing (RNA-Seq). Differentially expressed genes were determined. Based on the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, functional enrichment and signaling pathways analyses were performed. Candidate genes selected from RNA-Seq analysis were validated by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. The YD-8/CIS and YD-9/CIS samples had very similar expression patterns. qRT-PCR analysis was performed on selected genes commonly expressed between the two samples. The expression levels of 11 genes were changed in cisplatin-resistant samples compared with their parental samples; several of these genes were related to cell adhesion molecules and proteoglycans in cancer pathways. Our data provide candidate genes associated with cisplatin resistance in OSCC, but further study is required to determine which genes have an important role. Nevertheless, these results may provide new ideas to improve the clinical therapeutic outcomes of OSCC.

Implications of Human Antimicrobial Peptide Defensin Beta-1 in Clinical Oral Squamous Cell Carcinoma Patients via an Integrated Bioinformatics Approach.

Background The human antimicrobial peptide defensin beta 1 (DEFB1) has been found to play antimicrobial and anti-inflammatory roles in oral diseases; however, its tumor-regulating role in oral squamous cell carcinoma (OSCC) has not yet been researched by using an integrative bioinformatics approach. Objective To investigate the regulating mechanisms of the DEFB1 gene in OSCC in terms of its expression patterns, prognostic values, biological functions, and implication for tumor immunity. Methods The DEFB1 gene expression pattern and regulatory involvement in OSCC were investigated using publically accessible data from TCGA database. R software tools and public web servers were utilized to conduct statistical analysis of data from cancer and noncancerous samples. Results DEFB1 was found to be significantly downregulated in OSCC tumor samples compared with healthy control oral samples. The DEFB1 gene was found associated with the prognostic outcomes of OSCC, and its upregulation represented better survival outcome. Gene set enrichment analysis (GSEA) results showed that DEFB1-significantly correlated genes were mainly enriched in four signaling pathways mediating the antitumor role of DEFB1 in OSCC, including extracellular matrix-related pathway, RTK/PI3K/AKT/mTOR pathway, keratinization, and cytokine-related pathway. The gene-gene interaction network showed that DEFB1 was closely correlated with several genes, for example, CCR6 (C-C motif chemokine receptor 6), CXCL1 (C-X-C motif chemokine ligand 1), MAP4K2 (mitogen-activated protein kinase kinase kinase kinase 2), PTGER3 (prostaglandin E receptor 3), and MMP7 (matrix metallopeptidase 7). Moreover, DEFB1 was found to be involved in the tumor immunity of OSCC by regulating the function of tumor macrophage cells, mast cells, T cells, and NK cells. Conclusions Given the dysregulation, prognostic value, and tumor progression-related biological pathway alteration, indicating the tumor immune-modulatory role of DEFB1 in OSCC, the DEFB1 gene should be regarded as a potential therapeutic target for treating oral cancer.

Impact of lymph node ratio on survival and recurrence outcomes in oral squamous cell carcinoma

Growing evidence supports the lymph node ratio (LNR) as a prognostic factor for survival in patients with oral squamous cell carcinoma (OSCC). However, there is a lack of data regarding its association with recurrence outcomes. Data on 163 patients with OSCC who underwent primary surgical treatment at a tertiary centre between January 2009 and December 2015 were collected retrospectively and analysed. Receiver operating characteristic curve analysis was performed to determine optimal cut-off values for the survival analyses. Survival endpoints were disease progression/relapse for disease-free time (DFT), freedom from loco-regional recurrence (FLR), and freedom from distant metastasis (FDM), and as death from any cause for overall survival (OS). Patients with a lower LNR were found to have significantly superior DFT (LNR < 14%, P < 0.001), FLR (LNR <14%, P < 0.001), FDM (LNR <16%, P = 0.004), and OS (LNR <7%, P = 0.004) in comparison to patients with a higher LNR. LNR is a good predictor of survival and recurrence outcomes in OSCC.

The Molecular Basis and Therapeutic Aspects of Cisplatin Resistance in Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is a kind of malignant tumors with low survival rate and prone to have early metastasis and recurrence. Cisplatin is an alkylating agent which induces DNA damage through the formation of cisplatin-DNA adducts, leading to cell cycle arrest and apoptosis. In the management of advanced OSCC, cisplatin-based chemotherapy or chemoradiotherapy has been considered as the first-line treatment. Unfortunately, only a portion of OSCC patients can benefit from cisplatin treatment, both inherent resistance and acquired resistance greatly limit the efficacy of cisplatin and even cause treatment failure. Herein, this review outline the underlying mechanisms of cisplatin resistance in OSCC from the aspects of DNA damage and repair, epigenetic regulation, transport processes, programmed cell death and tumor microenvironment. In addition, this review summarizes the strategies applicable to overcome cisplatin resistance, which can provide new ideas to improve the clinical therapeutic outcome of OSCC.

The Hidden Treasures of Preoperative Blood Assessment in Oral Cancer: A Potential Source of Biomarkers.

Simple SummaryIn this study, we assess the prognostic potential of immune and inflammatory elements determined preoperatively in the peripheral blood of patients with oral squamous cell carcinoma (OSCC). Preoperative plasma fibrinogen (Fib) and platelet-to-lymphocyte ratio (PLR) show strong correlations with patients’ outcomes. Analyzed together, in a new parameter named Fibrinogen-PLR Algorithm (FiPLA), predictive power increases significantly. Clinicians can use this new, easy, cost-effective, and globally available tool for risk stratification of patients with OSCC, as early as from the moment of diagnosis.(1) Background: Oral squamous cell carcinoma (OSCC) is a common malignancy, and the impact of immune and inflammatory mechanisms in its development and progression are of major interest. The aim of our study is to assess the prognostic potential of circulating immune and inflammatory elements determined preoperatively in patients with OSCC, as well as the development of a new compound parameter with predictive value. (2) Methods: We assessed preoperative fibrinogen (Fib) and the platelet-to-lymphocyte ratio (PLR) in 111 OSCC patients. Using a mathematic algorithm, we determined a composite parameter with cumulative information from Fib and PLR, named Fibrinogen-PLR Algorithm (FiPLA). Survival analysis, followed by bivariate and multivariate analyses, was subsequently conducted. (3) Results: Increased preoperative Fib and PLR levels were associated with poor outcome in OSCC (p = 0.0001 and p = 0.0015, respectively). Preoperative FiPLA values were also associated with poor patient survival (p < 0.0001). Multivariate analysis confirmed the independent prognostic role for FiPLA only (CI95% 1.232–67.770, p = 0.03), showing the superior predictive value of FiPLA compared to its individual components. (4) Conclusions: Preoperative assessments of circulating immune and inflammatory elements can provide high-quality prognostic information, and they represent valuable tools in clinical practice, facilitating the early risk stratification of patients with OSCC.

A Five-mRNA Expression Signature to Predict Survival in Oral Squamous Cell Carcinoma by Integrated Bioinformatic Analyses.

Objectives: This study was designed to identify a messenger RNA (mRNA) expression signature to predict survival in patients with oral squamous cell carcinoma (OSCC).Methods: mRNA expression profiles were integrated with clinical data from 280 samples, including 19 normal tissues and 261 OSCC tissues in The Cancer Genome Atlas. We identified differentially expressed mRNAs (DEmRNAs) between the OSCC and normal tissue samples and developed a novel mRNA-focused expression signature using a Cox regression analysis and other bioinformatic methods. The prognostic value of this signature was evaluated by Kaplan–Meier analysis, multivariable COX regression, and receiver operating characteristic (ROC) curve analysis. Protein–protein interaction (PPI) network, gene ontology, and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed to predict the function of the DEmRNAs. Signature-related mRNAs were analyzed by gene set enrichment analyses (GSEA) and validated by quantitative real-time polymerase chain reaction (qRT-PCR) in 20 paired OSCC and adjacent healthy tissues.Results: We identified a novel 5-mRNA expression signature (HOXA1, CELSR3, HIST1H3J, ZFP42, and ASCL4) that could predict patient outcomes in OSCC. The risk score based on the signature was able to separate OSCC patients into high- and low-risk groups that showed significantly different overall survival (p < 0.001, log-rank test). The signature was further validated as an effective independent prognostic predictor of OSCC by multivariate Cox regression analysis (hazard ratio = 3.747, confidence interval: 2.279–5.677, p < 0.001) and ROC curve of the third year (area under the curve = 0.733). Functional analysis demonstrated that the key hub genes in the PPI network were mainly enriched in cell division, cell proliferation, and the p53 signaling pathway. GSEA results showed that the 5 mRNAs were significantly enriched in mismatch repair, DNA replication, and the NOTCH signaling pathway. Finally, qRT-PCR results showed that the 5 mRNAs were upregulated in OSCC tissue in agreement with the predictions from our bioinformatics analysis.Conclusions: We identified a novel 5-mRNA signature that could predict the survival of patients with OSCC and may be a promising biomarker for personalized cancer treatments.

Oral Squamous Cell Carcinoma Associated with Precursor Lesions.

Oral squamous cell carcinoma (OSCC) may be associated with precursor lesions known as oral potentially malignant disorders (OPMD). Few studies have reported on how OPMD diagnosis affects early detection and outcome of OSCC. We reviewed a large series of OSCC to determine the proportion that was associated with preceding OPMD and to compare the outcome of OSCC with or without precursor. Cases of oral-oropharyngeal carcinoma diagnosed between 2005 and 2015 were retrieved from the Ontario Cancer Registry (OCR) and matched to records of OPMD between 2001 and 2015 in two large oral pathology diagnostic services and the pathology databases of two hospitals with oral pathology services, to identify cases with precursor. Of 10,987 cancer cases, 378 (3.44%) had a preceding OPMD. Patients living in Central Ontario were more likely to have OPMD diagnosed before carcinoma than those in North Ontario (4.73% vs. 1.63%, P = 0.05). 329 of 5,257 cases of oral cancer were linked to a precursor, compared with 24 of 4,174 cases of oropharyngeal cancer (6.26% vs. 0.57%, P < 0.0001). Oral cancers with precursor were predominantly diagnosed at stage I (49.30%), compared with those without precursor, where stage IV disease predominated (41.28%). Sixty-nine of 309 (22.33%) patients with precursor-associated oral cancer have died of disease, compared with 1,551 of 4,656 (33.31%) patients without a precursor (P = 0.02). We conclude that patients with OSCC associated with a precursor had significantly lower odds of dying from disease. The beneficial effect of precursor lesion diagnosis on outcome is related to a higher proportion of stage I disease. PREVENTION RELEVANCE: OSCC causes significant morbidity and mortality, especially if diagnosed at late stages. Precursor lesions to OSCC can be recognized by clinical examination. Our study shows that early diagnosis of OSCC at the precursor stage can improve the outcome of oral cancer.