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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, and oral squamous cell carcinoma (OSCC) is one of the most common types. There is strong evidence that ryanodine receptor 2 (RYR2) plays an important role in different types of cancer according to previous studies. Its expression is associated with survival in patients with HNSCC, but it is unknown whether altered RYR2 expression contributes to tumorigenesis. Therefore, we examined how RYR2 polymorphisms affect OSCC susceptibility and clinicopathological characteristics. Five single nucleotide polymorphisms (SNPs) of RYR2, rs12594, rs16835904, rs2779359, rs3765097, and rs3820216, were analyzed in 562 cases of OSCC and 332 healthy controls using real-time PCR. We demonstrated that RYR2 SNP rs12594 was significantly different between the case and control groups, but this difference was not significant after adjusting for personal habits. In contrast, we found that different genotypes of SNP rs2779359 were significantly associated with the characteristics of clinical stage and tumor size in OSCC patients, according to the odds ratios and the adjusted odds ratios; specifically, patients with the T genotype had 1.477-fold (95% CI, 1.043 to 2.091; p = 0.028) and 1.533-fold (95% CI, 1.087–2.162; p = 0.015) increases in clinical stage and tumor size, respectively, compared with patients with the C allele. The results of our study, in which RYR2 SNPs associated with OSCC progression and development were examined for the first time, suggest that clinicopathological characteristics may alter OSCC susceptibility. Finally, RYR2 SNP rs2779359 not only plays a role in both the prognosis and diagnosis of oral cancer but is also likely an important predictive factor for recurrence, response to treatment, and medication toxicity. [ABSTRACT FROM AUTHOR]

Abstract Epigenetic alterations, such as those in chromatin structure and DNA methylation, have been extensively studied in a number of tumor types. But oral cancer, particularly oral adenocarcinoma, has received far less attention. Here, we combined laser-capture microdissection and muti-omics mini-bulk sequencing to systematically characterize the epigenetic landscape of oral cancer, including chromatin architecture, DNA methylation, H3K27me3 modification, and gene expression. In carcinogenesis, tumor cells exhibit reorganized chromatin spatial structures, including compromised compartment structures and altered gene-gene interaction networks. Notably, some structural alterations are observed in phenotypically non-malignant paracancerous but not in normal cells. We developed transformer models to identify the cancer propensity of individual genome loci, thereby determining the carcinogenic status of each sample. Insights into cancer epigenetic landscapes provide evidence that chromatin reorganization is an important hallmark of oral cancer progression, which is also linked with genomic alterations and DNA methylation reprogramming. In particular, regions of frequent copy number alternations in cancer cells are associated with strong spatial insulation in both cancer and normal samples. Aberrant methylation reprogramming in oral squamous cell carcinomas is closely related to chromatin structure and H3K27me3 signals, which are further influenced by intrinsic sequence properties. Our findings indicate that structural changes are both significant and conserved in two distinct types of oral cancer, closely linked to transcriptomic alterations and cancer development. Notably, the structural changes remain markedly evident in oral adenocarcinoma despite the considerably lower incidence of genomic copy number alterations and lesser extent of methylation alterations compared to squamous cell carcinoma. We expect that the comprehensive analysis of epigenetic reprogramming of different types and subtypes of primary oral tumors can provide additional guidance to the design of novel detection and therapy for oral cancer.

Oral Squamous Cell Carcinoma (OSCC) it was reported to be the 6th on the list of human malignant neoplasms responsible for high morbidity and mortality worldwide. We conducted a retrospective study between 2009-2019, investigating 50 such cancers hospitalized and diagnosed during this period in our institution. The purpose of the study was to establish a clinical-morphological profile of this type of cancer developed in the geographical area served by our institution. The epidemiological study highlighted the predominance of cases in men over 50 years old, mainly affecting the tongue, followed by the lips and oral floor. The histopathological study showed the prevalence of conventional cases of OSCC (70%) and the rest of the cases belonging to rarer forms (acantholytic-18%, verrucous-6%, basaloid-4% and sarcomatoid-2%). In terms of the degree of differentiation, the moderately differentiated cases prevailed (64%) and according to the TNM clinical stage, most cases were diagnosed in stage II (36%) and IV (26%). 70% of investigated cases presented muscle invasion and 38% perineural invasion. Our investigation highlighted the existence of particular morpho-clinical profiles depending on the tumor topography. Thus, tumors developed at the tongue level reached the maximum frequency in the 6th decade of life, being absent in the 8th decade and most often associated muscle invasion and perineural invasion, being diagnosed in advanced pTNM stages. [ABSTRACT FROM AUTHOR]

BackgroundH19, a 2.3 kb lncRNA, has been linked to tumor metastasis and progression, but its significance in oral squamous cell carcinoma (OSCC) remains unclear. H19 was initially thought to have a tumor-suppressive function, but recent studies have shown that it possesses both tumor-promoting and suppressive functions. The variation in H19 expression may be due to the influence of tobacco or low basal expression levels. However, there are limited studies available on the association between H19 and its role in the prognosis of OSCC.ObjectiveThe present study analyzes the expression of H19 correlated with clinicopathological parameters, tobacco habit, loco-regional recurrence, and overall survival.MethodsA longitudinal study was undertaken using 96 formalin-fixed paraffin-embedded (FFPE) OSCC tissues and 30 FFPE adjacent normal mucosa (NM) tissues from patients who had surgery between 2015 and 2018. The tissues were subjected to quantitative reverse-transcription PCR (qRT-PCR) to determine H19 expression. The differential expression levels of H19 in OSCC were compared to clinicopathological variables and risk habits using the t-test and ANOVA. H19 expression correlated overall survival was analyzed by drawing the Kaplan–Meier curve followed by the log-rank test. A multivariate Cox proportional hazards regression analysis was performed to determine the ability of H19 to independently predict loco-regional recurrence and overall survival for OSCC.ResultH19 was significantly underexpressed in OSCC compared to NM in both the study cases and the TCGA OSCC database. The lower expression of H19 was significantly associated with the tobacco smoking habit and was not associated with any clinical or pathological features. Multivariate Cox’s proportional hazards regression analysis indicated that low H19 expression and positive lymph node metastasis were independent predictors of overall survival for OSCC. Higher age, higher TNM staging, and low H19 expression were independent predictors of loco-regional recurrence.ConclusionThe findings in the present study indicate that H19 is a novel prognostic marker and may provide a therapeutic strategy for the targeted treatment of OSCC, and tobacco may play a role in the expression of H19.

Objectives: Surgical resection is a key component of the treatment of head and neck cancer and the achievement of free surgical margins are essential for the patients’ outcome in terms of survival. While there is a general recommendation for a free resection range of 5 mm, up to date, there is a lack of investigations on the quality of tumor resection in dependence of affected subsite and tumor stage. In the presented study, predictors for the achieved resection margins in surgically treated oral squamous cell carcinomas were analyzed. Materials and methods: A cohort of 567 patients was included in a retrospective analysis and resection status with exact margin ranges were analysed. Tumor stage, affected subsite and the results of the intraoperative frozen section analysis were assessed. Primary endpoint was the achieved resection margin in mm, secondary endpoints were overall and progression-free survival. Results: The observed mean values of minimal resection margins differed significantly between the investigated subsites (p = 0.042),pathological tumor stages (p < 0.001) and in tumors which demonstrated perineural infiltration (Pn1, p = 0.002). Furthermore, there was a significant impact of the results of the intraoperative frozen section analysis on progression-free and overall survival (p < 0.001). Conclusions: Our data clearly indicate that resection status differs between tumors of different subsites and tumor stages. Clinical relevance: Clinical procedures should be adapted in order to achieve similar certainty in all resections, and, thus to improve patients’ outcome. [ABSTRACT FROM AUTHOR]

Significance: Surgical excision is the main treatment for solid tumors in oral squamous cell carcinomas, where wide local excision (achieving a healthy tissue margin of >5 mm around the excised tumor) is the goal as it results in reduced local recurrence rates and improved overall survival. Aim: No clinical methods are available to assess the complete surgical margin intraoperatively while the patient is still on the operating table; and while recent intraoperative back-bench fluorescence-guided surgery approaches have shown promise for detecting "positive" inadequate margins (<1 mm), they have had limited success in the detection of "close" inadequate margins (1 to 5 mm). Here, a dual aperture fluorescence ratio (dAFR) approach was evaluated as a means of improving detection of close margins. Approach: The approach was evaluated on surgical specimens from patients who were administered a tumor-specific fluorescent imaging agent (cetuximab-800CW) prior to surgery. The dAFR approach was compared directly against standard widefield fluorescence imaging and pathology measurements of margin thickness in specimens from three patients and a total of 12 margin locations (1 positive, 5 close, and 6 clear margins). Results: The area under the receiver operating characteristic curve, representing the ability to detect close compared to clear margins (>5 mm) was found to be 1.0 and 0.57 for dAFR and sAF, respectively. Improvements in dAFR were found to be statistically significant (p < 0.02). Conclusions: These results provide evidence that the dAFR approach potentially improves detection of close surgical margins. [ABSTRACT FROM AUTHOR]

Epidemiological studies have spotlighted the intricate relationship between individual oral bacteria and tumor occurrence. Porphyromonas gingivalis and Fusobacteria nucleatum, which are known periodontal pathogens, have emerged as extensively studied participants with potential pathogenic abilities in carcinogenesis. However, the complex dynamics arising from interactions between these two pathogens were less addressed. This narrative review aims to summarize the current knowledge on the prevalence and mechanism implications of P. gingivalis and F. nucleatum in the carcinogenesis of oral squamous cell carcinoma (OSCC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). In particular, it explores the clinical and experimental evidence on the interplay between P. gingivalis and F. nucleatum in affecting oral and gastrointestinal carcinogenesis. P. gingivalis and F. nucleatum, which are recognized as keystone or bridging bacteria, were identified in multiple clinical studies simultaneously. The prevalence of both bacteria species correlated with cancer development progression, emphasizing the potential impact of the collaboration. Regrettably, there was insufficient experimental evidence to demonstrate the synergistic function. We further propose a hypothesis to elucidate the underlying mechanisms, offering a promising avenue for future research in this dynamic and evolving field. [ABSTRACT FROM AUTHOR]

Oral cancer is a highly prevalent disease affecting millions worldwide. Major risk factors for oral cancer include tobacco and alcohol use, HPV infections, poor nutrition, and genetic susceptibility. The disease progresses through multiple genetic and epigenetic alterations involving tumor suppressors like p53, p16, and FHIT, along with oncogenes like EGFR, c-yc, K-ras, int-2, PRAD-1, and bcl leading to the development of premalignant lesions and subsequent tumors. Surgery, radiation, and chemotherapy are conventional therapies used against oral cancer, though they have numerous side effects. This necessitates the development of alternative therapeutic strategies like targeted drugs, immunotherapies, photodynamic therapy, and delivery systems based on nanotechnology. The paper provides an extensive review of patents pertaining to novel therapeutics, formulations, and treatment methods for oral cancer. Patents encompass siRNA, antibodies, immune checkpoint inhibitors, antimicrobial peptides, natural products like curcumin, nanoparticle drug carriers, and bioadhesive electrospun fibers loaded with drugs. Major routes of administration covered are oral, parenteral, mucoadhesive patch, rectal, topical, etc. Common excipients used are PEG, PLGA, lipids, surfactants, preservatives, salts, permeation enhancers, etc. The review study shows assays like RT-PCR, immunohistochemistry, animal carcinoma models, and cytotoxicity tests to demonstrate anticancer efficacy. The review insights into emerging oral cancer therapies and facilitates further research in this area.

Objective: To evaluate the relation between the expression of PD‐1, PD‐L1, CD3, CD8, Foxp3 and clinicopathological features in patients with oral leukoplakia (OLK) and oral squamous cell carcinomas (OSCC) as well as the malignant outcome in OLK patients, and to study the effect of PD‐1 and PD‐L1 on immune microenvironment in the progression of oral carcinogenesis. Methods: We evaluated the expression of PD‐1/PD‐L1 and composition of CD3+, CD8+and Foxp3+ T lymphocytes in OLK and OSCC samples by immunohistochemical (IHC) staining and analyzed their relation with clinical information and malignant transformation in OLK patients. Results: IHC staining demonstrated that the expression of PD‐1 was significantly increased in the high‐grade OLK group than in the low‐grade OLK group, while PD‐L1 was detected mainly in OSCC. The expression of CD3, CD8, and Foxp3 was found higher in the high‐grade OLK group than in the low‐grade OLK group, and the Foxp3+ cells were found more in the OSCC group than in the high‐grade OLK group. PD‐1 was significantly correlated with CD3 (p < 0.05, R = 0.52), CD8 (p < 0.05, R = 0.46), and Foxp3 (p < 0.05, R = 0.46), and the low PD‐1‐expression group showed a better malignant‐free survival than high PD‐1 expression group in the OLK (p < 0.05). Conclusion: The PD‐1/PD‐L1 may induce immune suppression in OLK and accelerate the progress of malignant transformation. [ABSTRACT FROM AUTHOR]

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Purpose: Oral squamous cell carcinomas (OSCCs) are primary head and neck malignant tumours with a high incidence and mortality. However, the molecular mechanisms involved in OSCC tumorigenesis are not fully understood. Methods: OSCC and paired para-carcinoma samples were collected and used to perform multi-omics study. Transcriptomic analysis was used to reveal significant alterations in inflammatory and immune processes in OSCC. Ingenuity Pathway Analysis (IPA) combined with the LASSO Cox algorithm was used to identify and optimize a crucial gene signature. Metabolomics analysis was performed to identify the important metabolites which linked to the crucial gene signature. The public data TCGA-HNSCC cohort was used to perform the multiple bioinformatic analysis. Results: These findings identified a FN1-mediated crucial network that was composed of immune-relevant genes (FN1, ACP5, CCL5, COL1A1, THBS1, BCAT1, PLAU, IGF2BP3, TNF, CSF2, CXCL1 and CXCL5) associated with immune infiltration and influences the tumour microenvironment, which may contribute to OSCC tumorigenesis and progression. Moreover, we integrated the relevant genes with altered metabolites identified by metabolic profiling and identified 7 crucial metabolites (Glu-Glu-Lys, Ser-Ala, Ser-Ala, N-(octadecanoyl) sphing-4-enine-1-phosphocholine, N-methylnicotinamide, pyrrhoxanthinol and xanthine) as potential downstream targets of the FN1-associated gene signature in OSCC. Importantly, FN1 expression is positively correlated with immune infiltration levels in HNSCC, which was confirmed at the single-cell level. Conclusions: Overall, these results revealed the differential genetic and metabolic patterns associated with OSCC tumorigenesis and identified an essential molecular network that plays an oncogenic role in OSCC by affecting amino acid and purine metabolism. These genes and metabolites might, therefore, serve as predictive biomarkers of survival outcomes and potential targets for therapeutic intervention in OSCC. [ABSTRACT FROM AUTHOR]

Oral cancer is a common malignancy worldwide, accounting for 1.9% to 3.5% of all malignant tumors. Transforming growth factor β (TGF-β), as one of the most important cytokines, is found to play complex and crucial roles in oral cancers. It may act in a pro-tumorigenic and tumor-suppressive manner; activities of the former include cell cycle progression inhibition, tumor microenvironment preparation, apoptosis promotion, stimulation of cancer cell invasion and metastasis, and suppression of immune surveillance. However, the triggering mechanisms of these distinct actions remain unclear. This review summarizes the molecular mechanisms of TGF-β signal transduction, focusing on oral squamous cell and salivary adenoid systemic carcinomas as well as keratocystic odontogenic tumors. Both the supporting and contrary evidence of the roles of TGF-β is discussed. Importantly, the TGF-β pathway has been the target of new drugs developed in the past decade, some having demonstrated promising therapeutic effects in clinical trials. Therefore, the achievements of TGF-β pathway-based therapeutics and their challenges are also assessed. The summarization and discussion of the updated knowledge of TGF-β signaling pathways will provide insight into the design of new strategies for oral cancer treatment, leading to an improvement in oral cancer outcomes. [ABSTRACT FROM AUTHOR]

Epidemiological studies have spotlighted the intricate relationship between individual oral bacteria and tumor occurrence. Porphyromonas gingivalis and Fusobacteria nucleatum, which are known periodontal pathogens, have emerged as extensively studied participants with potential pathogenic abilities in carcinogenesis. However, the complex dynamics arising from interactions between these two pathogens were less addressed. This narrative review aims to summarize the current knowledge on the prevalence and mechanism implications of P. gingivalis and F. nucleatum in the carcinogenesis of oral squamous cell carcinoma (OSCC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). In particular, it explores the clinical and experimental evidence on the interplay between P. gingivalis and F. nucleatum in affecting oral and gastrointestinal carcinogenesis. P. gingivalis and F. nucleatum, which are recognized as keystone or bridging bacteria, were identified in multiple clinical studies simultaneously. The prevalence of both bacteria species correlated with cancer development progression, emphasizing the potential impact of the collaboration. Regrettably, there was insufficient experimental evidence to demonstrate the synergistic function. We further propose a hypothesis to elucidate the underlying mechanisms, offering a promising avenue for future research in this dynamic and evolving field.

A diverse category of malignancies called oral squamous cell carcinomas (OSCCs) develops from the mucosal lining of the oral cavity. The bulk of these malignancies are linked to risky lifestyle behaviors such as smoking, binge drinking, and betel nut chewing. The majority of malignant epithelial tumors of the head and neck are OSCCs, which make up 80%–90% of all malignant tumors of the oral cavity. The fifth to eighth decade of life is when the incidence rate is highest. Less than 40-year-old age groups are an uncommon exception to the OSCC rule. Although it occasionally varies on the population and the habits of the people, the border of the tongue is the most common place for OSCC, followed by the lower lip, the floor of the mouth, the ventral tongue, and the alveolar mucosa/gingiva. There have been noticeably better results on recent improvements in diagnostic and therapy planning. Although the standard of care for OSCC remains surgery, adjuvant radiation, and chemotherapy, advancements in these therapeutic modalities have allowed for better prognoses and the saving of many lives. In the present case report, we evaluated an OSCC in a 53-year-old female patient.

Abstract Background The role and mechanisms of lipid metabolism in oral squamous cell carcinomas (OSCC) metastasis have not been clarified. This study aims to identify lipid metabolism-related genes and transcription factors regulated by metastasis-associated enhancers (MAEs) in OSCC. Methods Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were performed for lipid metabolism enrichment. TCGA data were used to analyze the differentially expressed lipid metabolism-related genes. MAEs were analyzed using GSE120634. Overlapping analysis was used to screen the MAE-regulated lipid metabolism-related genes, and the prognosis of these genes was analyzed. Transcription factor prediction was performed for the MAE-regulated lipid metabolism-related genes with prognostic value. Validation of the metastatic specificity of MAEs at ACAT1, OXSM and VAPA locus was performed using GSE88976 and GSE120634. ChIP-qPCR, qRT-PCR and Western blotting were used to verify the regulation of ACAT1, OXSM and VAPA expression by CBFB. Effects of CBFB knockdown on proliferation, invasion and lipid synthesis in metastatic OSCC cells were analyzed. Results Lipid metabolism was significantly enhanced in metastatic OSCC compared to non-metastatic OSCC. The expression of 276 lipid metabolism-related genes was significantly upregulated in metastatic OSCC, which were functionally related to lipid uptake, triacylglycerols, phospholipids and sterols metabolism. A total of 6782 MAEs and 176 MAE-regulated lipid metabolism-related genes were filtered. Three MAE-regulated lipid metabolism-related genes, ACAT1, OXSM and VAPA, were associated with a poor prognosis in OSCC patients. Enhancers at ACAT1, OXSM and VAPA locus were metastasis-specific enhancers. CBFB regulated ACAT1, OXSM and VAPA expression by binding to the enhancers of these genes. Knockdown of CBFB inhibited proliferation, invasion and lipid synthesis in metastatic OSCC cells. Conclusion The MAE-regulated lipid metabolism-related genes (ACAT1, OXSM and VAPA) and the key transcription factor (CBFB) were identified. CBFB knockdown inhibited proliferation, invasion and lipid synthesis of OSCC cells. These findings provide novel candidates for the development of therapeutic targets for OSCC.

Background/purpose: Cancer stem cells (CSCs) have been known to be implicated in tumorigenesis, metastasis, and drug resistance in oral squamous cell carcinomas (OSCC). In this study, we aimed to investigate whether magnolol, a polyphenolic component derived from Magnolia officinalis, exhibited the anti-CSCs properties. Methods: The cytotoxicity of magnolol was tested using normal gingival epithelioid SG cells and sphere-forming OSCC-CSCs isolated from SAS, OECM1, and GNM cells. Secondary sphere-forming ability, the proportion of ALDH1 positive cells, Transwell migration, and invasion capacities were examined as well. The chemosensitive effects of magnolol were investigated using MTT, secondary sphere-forming, and invasion assays. Results: Magnolol exerted a higher cytotoxicity of OSCC-CSCs and cancer stemness features, including self-renewal ability, the expression CSC marker, migration, and invasion capacities were all downregulated in magnolol-treated OSCC-CSCs. Moreover, administration of magnolol potentiated the effect of cisplatin, including a decrease in cell viability, self-renewal, and invasion activities. In addition, we observed that the secretion of IL-6 and phosphorylation of Stat3 were decreased in OSCC-CSCs treated with magnolol. Conclusion: Our data suggest that magnolol is able to target CSCs and suppress the cancer stemness properties, at least in part, via IL-6/Stat3 signaling. Besides, a dietary supplement of magnolol may function as an adjunct to cisplatin treatment.

Background: The growth of several cancers can be inhibited by naturally occurring medicinal plants. A flavone called Scutellarein found in the perennial herb Scutellaria lateriflora does have a wide range of biological functions. Scutellarein was studied to determine whether it could induce apoptosis and cause cytotoxicity. Methods: On oral squamous cell carcinoma KB cell lines, Scutellarein's cytotoxic activity was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Scutellarein was added to KB cells at concentrations ranging from 25 to 125 g/mL for 24 h. The real-time polymerase chain reaction was also used to investigate apoptotic induction potential in Scutellarein-incubated KB cell lines by analyzing Bcl-2 protein and gene expression. Results: In KB-cell lines treated with scutellarein, cytotoxicity and anticancer effects were observed, as well as inhibit the growth of cancer cells. In comparison to the cells not treated with scutellarein, KB cells that had been exposed to scutellarein displayed reduced Bcl-2 expression. Conclusion: KB cells were treated with scutellarein to induce apoptosis, suggesting its potential as a chemo preventative agent. This activity appears to be mediated through the modulation of Bcl-2, a cytotoxic gene.

Oral squamous cell carcinoma (SCC) is one among the most frequent cancers across the globe. The postoperative overall survival (OS) has not improved over years much despite of advanced surgical techniques and various anticancer drugs. A better and good understanding of molecular mechanisms and identification of potential oncogenes in OSCC may provide new therapeutic decisions such as target therapy in management of these cancer patients. To find whether there is any association between surgical margins and pathological staging with epidermal growth factor receptor expression affecting the prognosis in oral squamous cell carcinomas. A prospective cohort study was performed in 25 patients with biopsy proven oral squamous cell carcinoma who presented to our hospital from July 2017 to June 2019. The data collected from their report were pTNM staging, surgical margins (anterior, posterior, superior and inferior) and scoring of EGFR expression. Surgical margins with EGFR expression was found to have p-value of 0.023 and pTNM staging with EGFR expression was found to have p-value of 0.051 which were statistically significant. This study concludes that there is strong association of EGFR expression with pTNM and surgical margins which may influence the prognosis of the patient. This study helps us to understand the need of adding EGFR targets like cetuximab along with radiation instead of conventional cisplatin therapy. [ABSTRACT FROM AUTHOR]

Background: H19, a 2.3 kb lncRNA, has been linked to tumor metastasis and progression, but its significance in oral squamous cell carcinoma (OSCC) remains unclear. H19 was initially thought to have a tumor-suppressive function, but recent studies have shown that it possesses both tumor-promoting and suppressive functions. The variation in H19 expression may be due to the influence of tobacco or low basal expression levels. However, there are limited studies available on the association between H19 and its role in the prognosis of OSCC., Objective: The present study analyzes the expression of H19 correlated with clinicopathological parameters, tobacco habit, loco-regional recurrence, and overall survival., Methods: A longitudinal study was undertaken using 96 formalin-fixed paraffin-embedded (FFPE) OSCC tissues and 30 FFPE adjacent normal mucosa (NM) tissues from patients who had surgery between 2015 and 2018. The tissues were subjected to quantitative reverse-transcription PCR (qRT-PCR) to determine H19 expression. The differential expression levels of H19 in OSCC were compared to clinicopathological variables and risk habits using the t-test and ANOVA. H19 expression correlated overall survival was analyzed by drawing the Kaplan-Meier curve followed by the log-rank test. A multivariate Cox proportional hazards regression analysis was performed to determine the ability of H19 to independently predict loco-regional recurrence and overall survival for OSCC., Result: H19 was significantly underexpressed in OSCC compared to NM in both the study cases and the TCGA OSCC database. The lower expression of H19 was significantly associated with the tobacco smoking habit and was not associated with any clinical or pathological features. Multivariate Cox's proportional hazards regression analysis indicated that low H19 expression and positive lymph node metastasis were independent predictors of overall survival for OSCC. Higher age, higher TNM staging, and low H19 expression were independent predictors of loco-regional recurrence., Conclusion: The findings in the present study indicate that H19 is a novel prognostic marker and may provide a therapeutic strategy for the targeted treatment of OSCC, and tobacco may play a role in the expression of H19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kumar, Hallikeri, Oli, Radder, Jain, Shilpasree, Dhanapal, Tabnjh and Selvaraj.)

Abstract Background Khat leaves contain the alkaloid cathinone. Research shows that khat might provoke toxicity, mutagenicity, as well as carcinogenicity. Methods Two groups were identified as khat abusers and were categorized by abuse time and diagnosis of oral squamous cell carcinoma (OSCC). Here, 41 participants from Group 2 were short-term khat users, and 42 participants were long-term khat users. The control group included 30 healthy individuals. The coding exons included nine cancer-related genes and were analysed. The histopathological research was conducted with H&E staining along with the TP53 protein expression by implementing immunohistochemical analyses. Results Here, 41 short-term khat users carried seven somatic mutations in four out of nine cancer-related genes: 29/41(70.73%) ARID1A, 24/41(58.53%) MLH1, 34/41(82.92%) PIK3CA and 36/41(87.80%) TP53. The 42 long-term khat users incorporated nine somatic mutations in five out of nin ecancer-related genes: 40/42(95.23%) ARID1A, 36/42(85.71%) ARID2, 29/42(69.04%) PIK3CA, 27/42(64.28%) MLH1, and 35/42(83.33%) TP53. Every khat user had somatic mutations related to OSCC affecting the gingiva and the lower lip. TP53 protein expression was confirmed in all immunohistochemical oral tests. Carcinoma was also positive in the histopathological analysis. Conclusions Khat is a mutagenic and carcinogenic plant that provoked OSCC among short-term khat users (15 years of use).

Dysregulation of non‐coding RNAs (ncRNAs) has been proved to play important roles in oral squamous cell carcinoma (OSCC). This study aimed to determine the combined role of lncRNA TUG1, miR-593-3p, and MAPK signaling in oral squamous cell carcinoma (OSCC) development. Here, we found that TUG1 was up-regulated in OSCC tissues and cell lines. Silencing TUG1 suppressed proliferation migration, invasion and promoted apoptosis of OSCC cells. We also validated that knockdown of TUG1 suppressed MAPK signaling pathway and inhibited EMT process in OSCC cells. Then, a novel LncRNA TUG1/ miR-593-3p/MAPK axis was verified to rescue cell viability in OSCC cells. Mechanistically, miR-593-3p bound to lncRNA TUG1, and lncRNA TUG1 positively regulated MAPK related proteins through acting as RNA sponger for miR-593-3p. Further gain- and loss-of-function experiments evidenced that the protective effects of lncRNA TUG1 knock-down on OSCC cells were abrogated by silencing miRNA-593-3p. The OSCC nude mice model experiments demonstrated that depletion of TUG1 further inhibited tumor growth. In conclusion, appropriate diagnostic biomarkers and therapies for OSCC can be identified by targeting the TUG1/miR-593-3p/MAPK axis. [ABSTRACT FROM AUTHOR]

Background: The role and mechanisms of lipid metabolism in oral squamous cell carcinomas (OSCC) metastasis have not been clarified. This study aims to identify lipid metabolism-related genes and transcription factors regulated by metastasis-associated enhancers (MAEs) in OSCC. Methods: Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were performed for lipid metabolism enrichment. TCGA data were used to analyze the differentially expressed lipid metabolism-related genes. MAEs were analyzed using GSE120634. Overlapping analysis was used to screen the MAE-regulated lipid metabolism-related genes, and the prognosis of these genes was analyzed. Transcription factor prediction was performed for the MAE-regulated lipid metabolism-related genes with prognostic value. Validation of the metastatic specificity of MAEs at ACAT1, OXSM and VAPA locus was performed using GSE88976 and GSE120634. ChIP-qPCR, qRT-PCR and Western blotting were used to verify the regulation of ACAT1, OXSM and VAPA expression by CBFB. Effects of CBFB knockdown on proliferation, invasion and lipid synthesis in metastatic OSCC cells were analyzed. Results: Lipid metabolism was significantly enhanced in metastatic OSCC compared to non-metastatic OSCC. The expression of 276 lipid metabolism-related genes was significantly upregulated in metastatic OSCC, which were functionally related to lipid uptake, triacylglycerols, phospholipids and sterols metabolism. A total of 6782 MAEs and 176 MAE-regulated lipid metabolism-related genes were filtered. Three MAE-regulated lipid metabolism-related genes, ACAT1, OXSM and VAPA, were associated with a poor prognosis in OSCC patients. Enhancers at ACAT1, OXSM and VAPA locus were metastasis-specific enhancers. CBFB regulated ACAT1, OXSM and VAPA expression by binding to the enhancers of these genes. Knockdown of CBFB inhibited proliferation, invasion and lipid synthesis in metastatic OSCC cells. Conclusion: The MAE-regulated lipid metabolism-related genes (ACAT1, OXSM and VAPA) and the key transcription factor (CBFB) were identified. CBFB knockdown inhibited proliferation, invasion and lipid synthesis of OSCC cells. These findings provide novel candidates for the development of therapeutic targets for OSCC. [ABSTRACT FROM AUTHOR]

Introduction: Cyclooxygenase 2 (COX-2) expression in oral potentially malignant disorders (OPMDs) such as oral submucous fibrosis (OSMF) and oral squamous cell carcinomas (OSCCs) has revealed inconclusive reports. Studies on loss of type IV collagen expression in oral epithelial dysplasias (OEDs) and OSCCs were subjective and lacked systemic approach. To evaluate the immunohistochemical (IHC) expression of COX-2 and type IV collagen in OED, OSMF, and OSCC. Materials and methods: IHC expression of COX-2 and type IV collagen on paraffin-embedded tissue section of 10 cases each in normal oral mucosa, mild OED, moderate OED, and severe OED, OSMF, and OSCC were evaluated using mean H score and discontinuity Score (DS) designed grades for every group, respectively. Mean H score of COX-2 was compared within and between the groups using analysis of variance (ANOVA), and DS designed specifically for type IV collagen expression was compared using Kruskal–Wallis ANOVA. Pairwise comparison between the groups were performed using Tukey multiple posthoc procedure and Mann–Whitney U test for COX-2 and type IV collagen, respectively. Results: Mean H scores of COX-2 expression increased significantly (P = 0.0001) as disease progressed from mild OED to severe OED. But COX-2 in OSCC was less than that observed in mild OED (P = 0.0001). Expression of COX-2 in OSMF was more than that observed in moderate OED. Type IV collagen expression decreased as disease progressed from OED to malignancy (P = 0.0001). OSMF indicated a variation in grades of loss of type IV collagen expression. Conclusion: Expression of COX-2 in OED, OSMF, and OSCC and DS for type IV collagen expression in our study could be effectively applied to assess the malignant potential of OPMDs. However, further studies need to be implemented on a larger sample size to conclude the above findings.

Background/purpose: Cancer stem cells (CSCs) have been known to be implicated in tumorigenesis, metastasis, and drug resistance in oral squamous cell carcinomas (OSCC). In this study, we aimed to investigate whether magnolol, a polyphenolic component derived from Magnolia officinalis, exhibited the anti-CSCs properties.Methods: The cytotoxicity of magnolol was tested using normal gingival epithelioid SG cells and sphere-forming OSCC-CSCs isolated from SAS, OECM1, and GNM cells. Secondary sphere-forming ability, the proportion of ALDH1 positive cells, Transwell migration, and invasion capacities were examined as well. The chemosensitive effects of magnolol were investigated using MTT, secondary sphere-forming, and invasion assays.Results: Magnolol exerted a higher cytotoxicity of OSCC-CSCs and cancer stemness features, including self-renewal ability, the expression CSC marker, migration, and invasion capacities were all downregulated in magnolol-treated OSCC-CSCs. Moreover, administration of magnolol potentiated the effect of cisplatin, including a decrease in cell viability, self-renewal, and invasion activities. In addition, we observed that the secretion of IL-6 and phosphorylation of Stat3 were decreased in OSCC-CSCs treated with magnolol.Conclusion: Our data suggest that magnolol is able to target CSCs and suppress the cancer stemness properties, at least in part, via IL-6/Stat3 signaling. Besides, a dietary supplement of magnolol may function as an adjunct to cisplatin treatment. [ABSTRACT FROM AUTHOR]

Background: The growth of several cancers can be inhibited by naturally occurring medicinal plants. A flavone called Scutellarein found in the perennial herb Scutellaria lateriflora does have a wide range of biological functions. Scutellarein was studied to determine whether it could induce apoptosis and cause cytotoxicity. Methods: On oral squamous cell carcinoma KB cell lines, Scutellarein's cytotoxic activity was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Scutellarein was added to KB cells at concentrations ranging from 25 to 125 g/mL for 24 h. The real-time polymerase chain reaction was also used to investigate apoptotic induction potential in Scutellarein-incubated KB cell lines by analyzing Bcl-2 protein and gene expression. Results: In KB-cell lines treated with scutellarein, cytotoxicity and anticancer effects were observed, as well as inhibit the growth of cancer cells. In comparison to the cells not treated with scutellarein, KB cells that had been exposed to scutellarein displayed reduced Bcl-2 expression. Conclusion: KB cells were treated with scutellarein to induce apoptosis, suggesting its potential as a chemo preventative agent. This activity appears to be mediated through the modulation of Bcl-2, a cytotoxic gene. [ABSTRACT FROM AUTHOR]

The management of oral squamous cell carcinoma (OSCC) poses significant challenges, leading to organ impairment and ineffective treatment of deep-seated tumors, adversely affecting patient prognosis. A cascade nanoreactor that integrates photodynamic therapy (PDT) and chemodynamic therapy (CDT) for comprehensive multimodal OSCC treatment is introduced. Utilizing iron oxide and mesoporous silica, the FMMSH drug delivery system, encapsulating the photosensitizer prodrug δ-aminolevulinic acid (δ-ALA), is developed. Triphenylphosphine (TPP) modification facilitates mitochondrial targeting, while tumor cell membrane (TCM) coating provides homotypic targeting. The dual-targeting δ-ALA@FMMSH-TPP-TCM demonstrate efficacy in eradicating both superficial and deep tumors through synergistic PDT/CDT. Esterase overexpression in OSCC cells triggers δ-ALA release, and excessive hydrogen peroxide in tumor mitochondria undergoes Fenton chemistry for CDT. The synergistic interaction of PDT and CDT increases cytotoxic ROS levels, intensifying oxidative stress and enhancing apoptotic mechanisms, ultimately leading to tumor cell death. PDT/CDT-induced apoptosis generates δ-ALA-containing apoptotic bodies, enhancing antitumor efficacy in deep tumor cells. The anatomical accessibility of oral cancer emphasizes the potential of intratumoral injection for precise and localized treatment delivery, ensuring focused therapeutic agent delivery to maximize efficacy while minimizing side effects. Thus, δ-ALA@FMMSH-TPP-TCM, tailored for intratumoral injection, emerges as a transformative modality in OSCC treatment., (© 2024 Wiley‐VCH GmbH.)

Background: Khat leaves contain the alkaloid cathinone. Research shows that khat might provoke toxicity, mutagenicity, as well as carcinogenicity. Methods: Two groups were identified as khat abusers and were categorized by abuse time and diagnosis of oral squamous cell carcinoma (OSCC). Here, 41 participants from Group 2 were short-term khat users, and 42 participants were long-term khat users. The control group included 30 healthy individuals. The coding exons included nine cancer-related genes and were analysed. The histopathological research was conducted with H&E staining along with the TP53 protein expression by implementing immunohistochemical analyses. Results: Here, 41 short-term khat users carried seven somatic mutations in four out of nine cancer-related genes: 29/41(70.73%) ARID1A, 24/41(58.53%) MLH1, 34/41(82.92%) PIK3CA and 36/41(87.80%) TP53. The 42 long-term khat users incorporated nine somatic mutations in five out of nin ecancer-related genes: 40/42(95.23%) ARID1A, 36/42(85.71%) ARID2, 29/42(69.04%) PIK3CA, 27/42(64.28%) MLH1, and 35/42(83.33%) TP53. Every khat user had somatic mutations related to OSCC affecting the gingiva and the lower lip. TP53 protein expression was confirmed in all immunohistochemical oral tests. Carcinoma was also positive in the histopathological analysis. Conclusions: Khat is a mutagenic and carcinogenic plant that provoked OSCC among short-term khat users (<15 years of use) and long-term users (>15 years of use). [ABSTRACT FROM AUTHOR]

Introduction: Nodal metastasis reduces the survival by 50% in head-and-neck squamous cell carcinomas. The presence of nodal extension/extracapsular spread (ECS) further reduces survival. Current literature favors a selective level IIb sparing neck dissection in clinically N0 neck. Studies have evaluated the role of primary tumour size, number of lymph nodes, and depth of invasion (DOI) with the occurrence of extranodal extension (ENE). Patients and Methods: Patients were retrospectively reviewed who presented with oral cavity carcinomas and clinically N0 neck. Relationship was sought between tumour site, size, histological grading, DOI, and the occurrence of level IIb metastasis and ECS. A P < 0.05 was considered statistically significant. Results: The relationship showed insignificant correlation with P values (0.6643, 0.6704, 0.6779, and 0.6779) between site, size, grading, DOI, and level IIb and ENE. Discussion: Previous studies have shown DOI >5 mm and lymph node size 15 mm and multiple lymph nodes predict ECS. DOI and primary site with more than 20% for occult metastasis predicts elective neck treatment. However, in our study, no correlation was found between primary tumour characteristics and ECS or level IIb metastasis. Elective neck dissection is the standard surgical protocol from both diagnostic and therapeutic viewpoints. The only criterion for level IIb dissection is concomitant presence of level IIa involvement intraoperatively. Since ENE can occur early in the disease process, elective neck dissection remains the standard of care. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) is the most common head and neck malignant tumor. Periodontitis, a common chronic inflammatory disease, has been proven to increase the risk of oral cancers. Porphyromonas gingivalis (P. gingivalis), the major pathogen in periodontal disease, was recently shown to promote the development of OSCC. However, the underlying mechanisms have not been defined. Emerging evidence suggests that P. gingivalis outer membrane vesicles (OMVs) contain different packaged small RNAs (sRNAs) with the potential to target host mRNA function and/or stability. In this study, we found that P. gingivalis OMVs promote the invasion and migration of OSCC cells in vitro. Further research showed that sRNA23392 was abundant in P. gingivalis OMVs and it promoted the invasion and migration of OSCC cells by targeting desmocollin-2 (DSC2). DSC2, a desmosomal cadherin family member, has been found to be involved in tumor progression. sRNA23392 inhibitors attenuated P. gingivalis OMV-induced migration and invasion of OSCC cells. Collectively, these findings are consistent with the hypothesis that sRNA23392 in P. gingivalis OMVs is a novel mechanism of the host-pathogen interaction, whereby P. gingivalis promotes the invasion and migration of OSCC. [ABSTRACT FROM AUTHOR]

Objectives: To correlate CK-19 with different histopathological gradings of oral squamous cell carcinomas (OSCCs). Methods: Study Design: Descriptive study. Setting: Department of Outpatient, ISRA Dental College Hospital. Period: January 2014 to November 2019. Material & Methods: In current study 60 suspected patients of oral squamous cell carcinomas were enrolled for cancer diagnosis and histopathological evaluation. Incisional biopsy method was opted for tissue sample collection. Patients from both genders were tested for CK-19 at different histopathological gradings. Ethical approval was properly taken from Institutional review board and patients’ willingness to participate in the study was ensured. For statistical data analysis SPSS version 21.0 and Revman5.30 multiple tools were used. Results: Histopathological grading of sixty suspected cases of OSCCs was done into four different gradings which include, poorly differentiated, moderately differentiated, well differentiated and undifferentiated OSCCs. Fifty-two (87 %) of the included subjects were male, where only 8 patients were female. The mean age of female to male was (36.14 vs. 43.21 years). Out of 12 positive cases of OSCCs. CK-19 was found positive in 10 cases (83.3%) in well differentiated Oral Squamous cell carcinomas, where only 2 cases (16 %) of moderately differentiated OSCCs were positive against CK-19. Conclusion: Our outcomes suggest CK-19 has strong association with well differentiated and moderately differentiated Oral Squamous cell carcinomas. We highly recommend further research standardizing CK-19 as a promising histopathological grading marker. [ABSTRACT FROM AUTHOR]

Introduction: Human papillomavirus (HPV) are now being increasingly associated as a cause of oral squamous cell carcinomas (OSCC). This study was designed to evaluate the prevalence of HPV in Pelizaeus-Merzbacher disease (PMD) and OSCC using polymerase chain reaction that might help in better understanding of the role played by this virus in the oncogenic process even from its evolution stage. Materials and Methods: Formalin-fixed paraffin-embedded tissue samples (n = 40) of OSCC and mild, moderate, and severe dysplasia were used for this study. DNA was quantified and checked for purity spectrophotometrically. Statistical analysis was performed using SPSS software and statistical significance was assessed using Fischer's exact test (p < 0.05 was considered significant). Results: High-risk (HR)-HPV-16 was found to be positive in 35% of OSCC cases which showed a statistically significant association of HPV 16 with OSCC. Verrucous carcinoma had predominant HPV 16 infection (60%), followed by SCC with 40%. However, this association was not statistically significant. None of the OSCC samples were infected with HPV 18. Among the PMD, we found only 5% showing HR-HPV 16 infection which was not significant. Discussion: Although OSCC is attributed to tobacco and alcohol consumption, a significant proportion of OSCC cases have been demonstrated to contain HPV types. The high-risk HPV type 16 tends to be the most predominant type detected in cases of OSCC. [ABSTRACT FROM AUTHOR]

The lack of clinical biomarkers for head and neck cancer subtypes limits early diagnosis and monitoring of disease progression. This study investigates genetic alterations in clinically identical tumor, tumor-adjacent dysplastic epithelium (TADE) and normal epithelium (NE) in five oral cancer patients to identify differences and commonalities between oral cancer, TADE and NE. A VELscope®Vx device was used to identify TADE and NE surrounding a clinical tumor for analysis of genetic alterations using the OncoScan® assay. One of the tumor samples examined was an “M” class tumor with a high confidence BRAF:p.G469A:c.1406G>C somatic mutation, which is the first to be reported in oral cancer. Another tumor showed mosaicism in genetic alterations, indicating the presence of multiple clones. Overall, each patient's tumor, TADE and NE showed a distinct genetic profile which indicates intertumoral clonal/genetic diversity. Interestingly, four tumors showed gain of 3q26.2, 5q14.3, 8q24.3, 8q22.3, 14q32.33 and loss/LOH in 9p21.3 while all TADE had LOH on 22q11.23. In addition, some genetic alterations progressed from NE through TADE into tumor in individual patients. Furthermore, no molecular event was identified that is common to all NE and/or TADE that progressed into tumor. This pilot study demonstrates the presence of genetic heterogeneity in oral tumorigenesis, and suggests that there might exist some common genetic alterations between tumors and TADE. However, this observation would need to be further investigated and validated in a larger cohort of oral cancer patients for its potential role in oral tumorigenesis.

BackgroundOral squamous cell carcinoma (OSCC) is a solid tumor, which originates from squamous epithelium, with about 400,000 new-cases/year worldwidely. Presently, chemoradiotherapy is the most important adjuvant treatment for OSCC, mostly in advanced tumors. However, clinical resistance to chemotherapy still leads to poor prognosis of OSCC patients. Via high-throughput analysis of gene expression database of OSCC, we investigated the molecular mechanisms underlying cisplatin resistance in OSCC, analyzing the differentially expressed genes (DEGs) and their regulatory relationship, to clarify the molecular basis of OSCC chemotherapy resistance and provide a theoretical foundation for the treatment of patients with OSCC and individualized therapeutic targets accurately.MethodsDatasets related to “OSCC” and “cisplatin resistance” (GSE111585 and GSE115119) were downloaded from the GEO database and analyzed by GEO2R. Venn diagram was used to obtain drug-resistance-related DEGs. Functional enrichment analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were performed on DEGs using The Database for Annotation, Visualization and Integrated Discovery (DAVID) software. Protein–protein interaction (PPI) network was constructed by STRING (search tool for recurring instances of neighbouring genes) database. Potential target genes of miRNA were predicted via miRDB, and cBioportal was used to analyze the function and survival of the potential functional genes.ResultsForty-eight upregulated DEGs and 49 downregulated DEGs were obtained from the datasets, with cutoff as p < 0.01 and |log FC| > 1. The DEGs in OSCC mainly enriched in cell proliferation regulation, and chemokine activity. In PPI network with hub score > 300, the hub genes were identified as NOTCH1, JUN, CTNNB1, CEBPA, and ETS1. Among miRNA–mRNA targeting regulatory network, hsa-mir-200c-3p, hsa-mir-200b-3p, hsa-mir-429, and hsa-mir-139-5p were found to simultaneously regulate multiple hub genes. Survival analysis showed that patients with high CTNNB1 or low CEBPA expression had poor outcome.ConclusionsIn the OSCC cisplatin-resistant cell lines, NOTCH1, JUN, CTNNB1, CEBPA, and ETS1 were found as the hub genes involved in regulating the cisplatin resistance of OSCC. Members of the miR-200 family may reverse drug resistance of OSCC cells by regulating the hub genes, which can act as potential targets for the treatment of OSCC patients with cisplatin resistance.

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Background: Cyclin D1 is derived from PRAD1 or CCND1 gene located on chromosome 11q13 and it acts as a positive regulator of the cell cycle. In normal cells, cyclin D1 promotes progression through the G1 phase of the cell cycle. Over expression of cyclin D1 may lead to shortening of G1 phase, increased cell proliferation and reduced dependency on growth factors. Over expression of cyclin D1 has been reported in various tumors like esophageal carcinoma, hepatocellular carcinoma, lung carcinoma, and head and neck carcinoma. Aims and Objectives: The study was carried out to evaluate and compare the expression of Cyclin D1 in premalignant lesion and different grades of oral squamous cell carcinoma. Materials and Methods: A total 75 histopathologically diagnosed cases of oral squamous cell carcinoma and oral premalignant lesions cases were evaluated immunohistochemically for cyclin D1 expression. Results: We found that cyclin D1 protein expression was significantly altered from epithelial dysplasia to oral squamous cell carcinomas. Conclusion: Thus we can conclude that cyclin D1 may be a useful marker in the cases of oral precancer and cancer. It can also act as a potential target for molecular intervention studies in future. [ABSTRACT FROM AUTHOR]

The lack of clinical biomarkers for head and neck cancer subtypes limits early diagnosis and monitoring of disease progression. This study investigates genetic alterations in clinically identical tumor, tumor-adjacent dysplastic epithelium (TADE) and normal epithelium (NE) in five oral cancer patients to identify differences and commonalities between oral cancer, TADE and NE. A VELscope®Vx device was used to identify TADE and NE surrounding a clinical tumor for analysis of genetic alterations using the OncoScan® assay. One of the tumor samples examined was an "M" class tumor with a high confidence BRAF :p.G469A:c.1406G>C somatic mutation, which is the first to be reported in oral cancer. Another tumor showed mosaicism in genetic alterations, indicating the presence of multiple clones. Overall, each patient's tumor, TADE and NE showed a distinct genetic profile which indicates intertumoral clonal/genetic diversity. Interestingly, four tumors showed gain of 3q26.2, 5q14.3, 8q24.3, 8q22.3, 14q32.33 and loss/LOH in 9p21.3 while all TADE had LOH on 22q11.23. In addition, some genetic alterations progressed from NE through TADE into tumor in individual patients. Furthermore, no molecular event was identified that is common to all NE and/or TADE that progressed into tumor. This pilot study demonstrates the presence of genetic heterogeneity in oral tumorigenesis, and suggests that there might exist some common genetic alterations between tumors and TADE. However, this observation would need to be further investigated and validated in a larger cohort of oral cancer patients for its potential role in oral tumorigenesis. [ABSTRACT FROM AUTHOR]

Background: Oral squamous cell carcinoma (OSCC) is a solid tumor, which originates from squamous epithelium, with about 400,000 new-cases/year worldwidely. Presently, chemoradiotherapy is the most important adjuvant treatment for OSCC, mostly in advanced tumors. However, clinical resistance to chemotherapy still leads to poor prognosis of OSCC patients. Via high-throughput analysis of gene expression database of OSCC, we investigated the molecular mechanisms underlying cisplatin resistance in OSCC, analyzing the differentially expressed genes (DEGs) and their regulatory relationship, to clarify the molecular basis of OSCC chemotherapy resistance and provide a theoretical foundation for the treatment of patients with OSCC and individualized therapeutic targets accurately. Methods: Datasets related to "OSCC" and "cisplatin resistance" (GSE111585 and GSE115119) were downloaded from the GEO database and analyzed by GEO2R. Venn diagram was used to obtain drug-resistance-related DEGs. Functional enrichment analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were performed on DEGs using The Database for Annotation, Visualization and Integrated Discovery (DAVID) software. Protein–protein interaction (PPI) network was constructed by STRING (search tool for recurring instances of neighbouring genes) database. Potential target genes of miRNA were predicted via miRDB, and cBioportal was used to analyze the function and survival of the potential functional genes. Results: Forty-eight upregulated DEGs and 49 downregulated DEGs were obtained from the datasets, with cutoff as p < 0.01 and |log FC| > 1. The DEGs in OSCC mainly enriched in cell proliferation regulation, and chemokine activity. In PPI network with hub score > 300, the hub genes were identified as NOTCH1 , JUN , CTNNB1 , CEBPA , and ETS1. Among miRNA–mRNA targeting regulatory network, hsa-mir-200c-3p, hsa-mir-200b-3p, hsa-mir-429, and hsa-mir-139-5p were found to simultaneously regulate multiple hub genes. Survival analysis showed that patients with high CTNNB 1 or low CEBPA expression had poor outcome. Conclusions: In the OSCC cisplatin-resistant cell lines, NOTCH1 , JUN , CTNNB1 , CEBPA , and ETS1 were found as the hub genes involved in regulating the cisplatin resistance of OSCC. Members of the miR-200 family may reverse drug resistance of OSCC cells by regulating the hub genes, which can act as potential targets for the treatment of OSCC patients with cisplatin resistance. [ABSTRACT FROM AUTHOR]

Background: Oral squamous cell carcinoma (OSCC) is an aggressive malignancy worldwide. Icariin (ICA), an active ingredient of flavonoids, has been demonstrated to possess antitumor activity in diverse cancers. Whereas, the role of ICAin OSCC is still unclear. Methods: Herein, we investigated the anti-tumor effects of ICA in vitro and in vivo. CCK-8, colony formation and trans-well assay were used to examined viability, proliferation and invasion in SCC-9 and SCC-15 cell lines, respectively. Next, we tested the expression of toll-like receptor 4 (TLR4) and NF-κB P65 by western blot or immunofluorescence staining. Finally, we constructed a xenograft mice model to investigate the effect of ICA in vivo. Results: In vitro, ICA decreased the human oral squamous cells viability, proliferation and invasion in a concentration-dependent manner. Besides, ICA decreased the phosphorylation level of P65 and down-regulated TLR4 protein. In vivo, compared with control, ICA significantly suppressed the tumor size and weight. In addition, ICA downregulated the levels of Ki67 and VEGF markedly. Dramatically, ICA decreased the phosphorylation level of P65 in tumor tissues. Conclusion: Taken together, ICA could act as a anticancer drug against OSCC to mitigate the growth and invasion ability, the underlying mechanism may due to the down-regulation of TLR4/NF-κB signaling. [ABSTRACT FROM AUTHOR]

Cumulative evidence suggest that microRNAs (miRNAs) function as biosignatures of oral squamous cell carcinomas (OSCC). However, the functional roles of miR-1 as well as its downstream targets in the regulation of tumorigenicity in OSCC remain unclear. Methods: miRNAs RT-PCR analysis was performed to identify miR-1 as a putative candidate on mediating invasiveness of OSCC cells. Consequently, we elucidated the tumorigenicity of OSCC cells with miR-1 downregulation or overexpression, respectively. Finally, miR-1 on OSCC tumor tissues was examined. Results: miR-1 levels were significantly downregulated in the malignant OSCC cells. Overexpression of miR-1 significantly reduced migration/invasiveness of OSCC cells. In addition, overexpression of miR-1 decreased cancer stem cells properties. Conversely, downregulation of miR-1 promotes migration and invasiveness in OSCC cells. We have shown that miR-1 is able to target Slug, suppressing their expression. Clinically, lower miR-1 expression was found in patients with advanced nodal metastasis OSCC. Conclusion: miR-1 as novel biosignatures in OSCC lymph node metastatic patients, supporting the development of novel strategies for OSCC treatment.

Background/Purpose: Cancer stem cells (CSCs) are deemed as the driving force of tumorigenesis in oral squamous cell carcinomas (OSCCs). In this study, we investigated the chemotherapeutic effect of sulforaphane, a dietary component from broccoli sprouts, on targeting OSCC-CSCs. Methods: The effect of sulforaphane on normal oral epithelial cells (SG) and sphere-forming OSCC-CSCs isolated from SAS and GNM cells was examined. ALDH1 activity and CD44 positivity of OSCC-CSCs with sulforaphane treatment was assessed by flow cytometry analysis. In vitro and in vivo tumorigenicity assays of OSCC-CSCs with sulforaphane treatment were presented. Results: We observed that the sulforaphane dose-dependently eliminated the proliferation rate of OSCC-CSCs, whereas the inhibition on SG cells proliferation was limited. Cancer stemness properties including self-renewal, CD44 positivity, and ALDH1 activity were also decreased in OSCC-CSCs with different doses of sulforaphane treatment. Moreover, sulforaphane treatment of OSCC-CSCs decreased the migration, invasion, clonogenicity, and in vivo tumorigenicity of xenograghts. Sulforaphane treatment resulted in a dose-dependent increase in the levels of tumor suppressive miR200c. Conclusion: These lines of evidence suggest that sulforaphane can suppress the cancer stemness and tumor-initiating properties in OSCC-CSCs both in vitro and in vivo.

Summary: Currently, immune checkpoint inhibitors have been shown to extend the survival of many cancer patients. However, few studies have focused on immune checkpoint inhibition for the treatment of patients with oral squamous cell carcinoma (OSCC). Here, by screening at an early stage, we obtained a strain of anti-PD-1 monoclonal antibody (mAb) that targets programmed cell death-1 (PD-1) does not contain the CH1 and CL fragment. In this study, the role of our novel mAb was tested in the treatment of OSCC in vitro and in vivo. We found that our novel mAb can significantly augment T cell mediated cytokine secretion, target cellular lytic and apoptotic abilities, and inhibit tumor growth and inflammation in vivo. The PD-L1 blockade was accompanied by the inhibition of AKT and ERK1/2, thus suggesting that the PD-L1/PD-1 signaling pathway may play an important immunopreventive role in the tumorigenic properties of OSCC cells by modulating the AKT and ERK1/2 pathways. Additionally, PD-L1 staining was observed both in human OSCC tissues and normal oral mucous tissue adjacent to the tumor, which occurred at different rates. Taken together, these results indicated that our novel anti-PD-1 mAb may be used as a clinical therapy in human OSCC development and progression. [ABSTRACT FROM AUTHOR]

Background: This study investigated the hypothesis that phosphoinositide 3‐kinase (PI3‐kinase) pathway dysregulation in either head and neck cancer cells and/or tumor infiltrating immune cells would influence outcomes of patients with surgically treated oral tongue squamous cell carcinomas (SCC). Methods: We constructed tissue microarrays containing 123 oral tongue SCC samples and performed immunohistochemistry using antibodies against 7 PI3‐kinase pathway markers: phosphatase and tensin homolog (PTEN), Akt, p‐Akt, mammalian target of rapamycin (mTOR), phosphorylated‐mammalian target of rapamycin (p‐mTOR), survivin, and Ki‐67). Expression levels in cancer cells or tumor infiltrating immune cells were correlated with outcomes. Results: Higher levels of PTEN expression in immune cells were significantly associated with improved recurrence‐free survival (heart rate (HR) = 0.45, 95% confidence interval (CI) 0.23‐0.90, P = .03), and overall survival (HR = 0.34, 95% CI 0.15‐0.76, P = .01) on univariate and multicovariate models. Conclusions: We identified a novel, negative prognostic role of PI3‐kinase activation (as determined by PTEN loss) in oral SCC infiltrating immune cells. These findings could be relevant for clinical development of PI‐3 kinase inhibitors for this disease. [ABSTRACT FROM AUTHOR]

Introduction and Importance: Ablative surgery for oral cancer, irrespective of the histological subtype, causes large tissue defects, functional and aesthetic damage. Microsurgical free flaps have been widely used in reconstruction after resection, with satisfactory success rates in conjunction with adjuvant radiotherapy (RT). This study aims to describe our clinical institutional experience based on the multimodal treatment performed in four cases diagnosed with oral squamous cell carcinoma with the use of different microvascular free flaps and RT., Case Series Presentation: Four patients underwent reconstructive microsurgery after surgical resection of oral cancer, using three types of free flap: radial forearm fasciocutaneous, osteomyocutaneous fibular, and anterolateral thigh musculocutaneous flaps; RT was performed in Case 2 and Case 3. In the period of 3 years after microsurgical reconstruction and RT, flaps remain clinically stable without failure signs in full patients submitted to multimodal treatment., Clinical Discussion: After resection of oral carcinomas, extensive tissue defects can be successfully treated with reconstructive microsurgery using different types of microvascular free flaps. RT for locoregional control is a feasible option and did not seem to interfere with the survival of flaps., Conclusion: An enhance long-term follow-up to assess overall and disease-free survival rates and quality of life must be carried out; however, cohort studies would be necessary for better understanding of the role of each treatment in the multimodal scheme., Competing Interests: There are no conflicts of interest to declare in relation to this article., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Macrophage migration inhibitory factor (MIF) is considered a pro-tumour factor. However, its clinical relevance in oral squamous cell carcinoma (OSCC) remains unclear. The objective of this study was to investigate the expression of MIF and its receptor CD74 in OSCC tissues, and to study the function of MIF in OSCC cells. Tissues of 90 patients with OSCC from the School of Stomatology, China Medical University were collected, and immunohistochemical staining and quantitative reverse transcription polymerase chain reaction were performed for MIF and CD74. The possible correlations between MIF and CD74 and clinical characteristics were analysed. The Kaplan-Meier analysis was used to determine the survival rates of patients. In addition, the proliferation and invasion of OSCC cells were evaluated after transfection with siRNA against MIF. MIF and CD74 levels were significantly higher in tissues of patients with OSCC than in control tissues. Moreover, MIF levels in patients with OSCC were significantly associated with cell differentiation and TNM classification. MIF expression was closely related to CD74 expression. Kaplan-Meier analysis indicated that OSCC patients with high MIF levels showed reduced overall survival and recurrenc-free survival. Furthermore, MIF expression promoted proliferation and invasion of OSCC cells. Collectively, our results reveal that MIF expression is a significant independent prognostic factor for patients with OSCC and may be a novel prognostic marker for OSCC. [ABSTRACT FROM AUTHOR]

Background: The let-7 family of microRNAs has been considered as tumor suppressors in various cancers; however, the role of let-7c in oral squamous cell carcinoma has not been determined yet.Methods: In this study, phenotypical behaviors and the radio/chemoresistance were examined subsequent to overexpression of let-7c. In addition, the expression of let-7c in cancer stem cells (CSCs) was evaluated and the effect of let-7c on stemness characteristics was assessed. Also, luciferase activity assays were performed to test whether interleukin (IL)-8 was a putative target of let-7c.Results: Our results confirmed that the expression of let-7c in CSCs was reduced, while overexpression of let-7c attenuated the oncogenicity. Moreover, ectopic expression of let-7c in CSCs downregulated the stemness hallmarks and the radio/chemoresistance. Expression and secretion of IL-8 in oral CSCs were both reduced following overexpression of let-7c. Besides, the inhibitory effect of let-7c on various stemness phenotypes was reverted by IL-8, indicating that lower expression of let-7c may confer higher cancer stemness through a failure to downregulate IL-8.Conclusion: These findings revealed the significance of let-7c in the contribution of oral cancer stemness and radio/chemoresistance. Targeting let-7c and its downstream IL-8 may be beneficial to prevent cancer recurrence and metastasis of oral squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Background: Oral cancer is a leading cause of cancer in India and contributes to 12% deaths worldwide. The identification of high-risk oral premalignant lesions such as leukoplakia and intervention at premalignant stages could result in significant loss of mortality and morbidity among these patients. The most frequently observed genetic aberrations in these lesions are of mutations in p53, c-erbB2, and epidermal growth factor receptor (EGFR). No specific tumor markers have been identified consistently in oral leukoplakias and the available studies show wide variations in their expression. Materials and Methods: A total of eighty cases were taken up for study which included forty cases of leukoplakia and forty cases of squamous cell carcinomas (SCCs). Results: There was a significant correlation between the expression of markers p53 and EGFR in leukoplakia and SCC. The expression of p53 was correlated between leukoplakia, SCC, and control and was found to be significant ( P - 0.001). Similarly, EGFR expression was significant ( P - 0.001) between cases of leukoplakia, SCCs, and controls. c-erbB2 was found to be negative though cytoplasmic positivity was observed in a few cases. Similarly, in SCCs, it was observed that lesser the differentiation, more is the expression of both p53 and EGFR. Similarly, a definite correlation was observed between p53 and EGFR ( P - 0.001) but not with c-erbB2 ( P - 1.000). Conclusion: Thus, the author concludes that p53 and EGFR are useful biomarkers for the diagnosis of leukoplakia and their risk of malignant transformation. [ABSTRACT FROM AUTHOR]