Search

Simple Summary: Oral cancer, a malignant neoplasm with invariable poor prognosis in the last 40 years (5-year survival rate of nearly 50%), accounts for a worldwide incidence of 377,713 new cases annually and 177,757 deaths per year. Oral cancer is usually preceded by oral potentially malignant disorders (OPMDs)—such as leukoplakia, oral lichen planus and oral submucous fibrosis—defined by the WHO Collaborating Centre for Oral Cancer as any mucosal abnormality that is associated with a statistical increased risk of developing oral cancer. Unfortunately, there are currently no tools available to accurately predict whether a patient in the early stages of oral carcinogenesis will develop oral cancer, being the presence and severity of epithelial dysplasia the histological marker universally applied for clinical practice. Nevertheless, this system presents relevant limitations related to imprecise and subjective assessments; therefore, emerging molecular biomarkers are under investigation. Among these biomarkers, retinoblastoma protein (pRb) is a well-recognized tumor suppressor in human oncogenesis, with roles linked to evading growth suppressors, a relevant hallmark of cancer. The loss of pRb expression regulates tumor initiation and early progression of neoplasms, and has been hypothesized to exert an oncogenic role during malignant transformation in early stages of oral carcinogenesis. Objective: The aim of this systematic review and meta-analysis was to qualitatively and quantitatively evaluate the current evidence on the significance of the loss of early stages of oral carcinogenesis in lesions diagnosed according to clinical and/or histopathological criteria and their evolution to oral cancer. Materials and Methods: We searched MEDLINE (through PubMed), Embase, Scopus and Web of Science for primary-level studies published before November 2024, designed as prospective or retrospective longitudinal cohorts, and not restricted by language or publication date. The risk of bias was critically assessed using the QUIPS tool. Meta-analyses, heterogeneity exploration, sensitivity and small-study effect analyses were conducted. Results: The inclusion criteria were met by six primary-level studies, which recruited 330 patients with OPMDs with follow-up data. The loss of pRb expression, assessed through immunohistochemistry, was significantly associated with a higher malignant transformation risk of OPMDs (RR = 1.92, 95%CI = 1.25–2.94, p = 0.003). The leukoplakia subgroup retained this significant association (p = 0.006), being the OPMD where the loss of pRb expression showed the best predictive value for malignant transformation (RR = 2.00, 95%CI = 1.22–3.29). Regarding the immunohistochemical technique and scoring methods, better performance and results were achieved by applying a cutoff point > 10% pRb-positive cells with nuclear staining (RR = 2.10, 95%CI = 1.30–3.38, 95%CI = 0.002). Conclussion: The present systematic review and meta-analysis supports that the loss of expression of the tumor suppressor pRb, assessed through immunohistochemistry, is a predictor of the malignant transformation risk of oral leukoplakias. Future studies are needed in other OPMDs following the recommendations provided based on current evidence gaps. [ABSTRACT FROM AUTHOR]

Background: Solitary fibrous tumor (SFT) is a rare mesenchymal lesion that has a wide anatomic distribution. However, this lesion rarely occurs in the oral or maxillofacial region. Methods: A retrospective review was performed to evaluate the clinical symptoms, radiological images, pathology and immunohistochemistry results of 9 patients with SFTs treated between January 2015 to April 2024 in our institute. Surgical tumor resection was administered to all patients. Follow-up for these patients spanned until the conclusion of April 2024. Results: The series contained 3 males and 6 females, with the mean age 50.6 years (range: 25 to 73 years). The tumors were distributed at six different sites, including the tongue, submandibular region, cheek, sublingual gland, mandible, and hard palate. Clinically, the mass grew gradually and usually without obvious clinical symptoms. On imaging examination, the boundaries of all the tumors were clear, except for one patient with a mandibular tumor. Surgical excision was performed in all patients. Histological characteristics and positive immunostaining for STAT6, CD99, CD34 and Bcl-2 were the most important criteria for a final diagnosis. All tumors were positive for CD34 and Bcl-2. Only one tumor was negative for STAT6. While CD99 was negative in one case and weakly positive in two cases. All patients had no local recurrence during the follow-up period ranging from 1 to 100 months (mean 41.4 months). Conclusions: Benign SFTs occurring in the oral and maxillofacial region are rare, and surgery is the primary treatment for this tumor. It usually presents as a distinctly bordered heterogeneous mass on imaging. The tumors can compress surrounding bone tissue leading to bone resorption, and in rare cases, it may exhibit invasive resorption. SFTs should be included in the differential diagnosis of lesions in the oral and maxillofacial region. [ABSTRACT FROM AUTHOR]

Simple Summary: Head and neck cancer (HNC), especially oral squamous cell carcinoma (OSCC), is a common and increasingly prevalent cancer worldwide. OSCC is challenging to treat due to its aggressive nature and resistance to standard therapies like surgery, radiation, and chemotherapy, particularly in advanced stages. Cetuximab, a drug targeting EGFR (a protein that supports cancer cell growth), is often used but has limitations in effectiveness. This study explores a new approach by combining Cetuximab with drugs that target proteins involved in cell division, specifically MPS-1, Aurora-B, and KSP. These proteins help cancer cells progress through the cell cycle and are crucial for tumor survival. By blocking both EGFR and these cell division proteins, the study aimed to increase the effectiveness of Cetuximab in killing OSCC cells. Results showed that targeting MPS-1, Aurora-B, or KSP alongside EGFR led to more cancer cell death, suggesting that this combined approach could reduce treatment resistance. Analysis of patient samples confirmed that these proteins are significant in OSCC. This combined therapy strategy shows promise for improving outcomes in OSCC and potentially other head and neck cancers. Background/Objectives: Head and neck cancer (HNC) is among the most common cancer types globally, with its incidence expected to increase significantly in the coming years. Oral squamous cell carcinoma (OSCC), the predominant subtype, exhibits significant heterogeneity and resistance to treatment. Current therapies, including surgery, radiation, and chemotherapy, often result in poor outcomes for advanced stages. Cetuximab, an EGFR inhibitor, is widely used but faces limitations. This study explores the combined inhibition of EGFR and mitotic proteins to enhance treatment efficacy. Methods: We analyzed the effects of co-treating OSCC cells with small molecules targeting MPS-1 (BAY1217389), Aurora-B (Barasertib), or KSP (Ispinesib), alongside Cetuximab. The rationale is based on targeting EGFR-mediated survival pathways and the mitotic checkpoint, addressing multiple cell cycle phases and reducing resistance. Results: Our findings indicate that inhibiting MPS-1, Aurora-B, or KSP enhances Cetuximab's therapeutic potential, promoting increased cancer cell death. Additionally, we examined EGFR, MPS-1, Aurora-B, and KSP expression in OSCC patient samples, revealing their clinicopathologic significance. Conclusions: This combinatorial approach suggests a promising strategy to improve treatment outcomes in OSCC. [ABSTRACT FROM AUTHOR]

Objective: Carcinoma ex‐pleomorphic adenoma (CEXPA) represents a malignant transformation from a recurrent or primary pleomorphic adenoma (PA), and the immune response may be essential in this process. Therefore, in this study, we aimed to identify and quantify subpopulations of dendritic cells (DCs) in CEXPA, residual PA in CEXPA (rPA), and PA. Materials and Methods: A multicenter study was performed collecting salivary gland tumor (SGT) samples from three Oral and Maxillofacial Pathology Centers. A tissue microarray containing 41 samples of CEXPA and 22 samples of PA was included in this study and submitted to immunohistochemical reactions against CD1a, CD83, CD207, and Ki67 antibodies. Results: Both PA and rPA showed a higher quantification of CD207+ and CD83+ cells when compared to CEXPA (p < 0.001 and p < 0.01, respectively). There was also a difference when comparing the cell proliferation index between PA/rPA and CEXPA using the Ki‐67 marker (p = 0.043). However, there was no difference in the DC population regarding clinical parameters such as sex, anatomical location, size, and metastases (p > 0.06). Conclusions: Immunohistochemical profile of DC subpopulations and cell proliferation biomarkers in SGTs can contribute as an important tool in the differentiation of benign and malignant tumors or detection of initial areas with malignant transformation. [ABSTRACT FROM AUTHOR]

Objectives: The splicing factor transformer‐2 homolog beta (Tra2β) plays a pivotal role in various cancers. Nonetheless, its role in oral squamous cell carcinoma (OSCC) has not been comprehensively explored. This study sought to discern the influence of Tra2β on OSCC and its underlying mechanisms. Materials and Methods: We assessed Tra2β expression in OSCC utilizing immunohistochemistry, qRT‐PCR, and western blotting techniques. siRNA transfection was used to silence Tra2β. Whole transcriptome RNA sequencing (RNA‐seq) analysis was carried out to reveal the alternative splicing (AS) events. KEGG pathway analysis enriched the related pathways. Colony formation, transwell, wound healing, and Annexin V‐FITC/PI were employed to appraise the consequences of Tra2β silencing on OSCC. Results: Tra2β was highly expressed in both OSCC tissues and cell lines. Knockdown of Tra2β‐regulated AS events with skipped exon (SE) accounts for the highest proportion. Meanwhile, downregulation of Tra2β reduced cell proliferation, migration, and invasion, however increasing cell apoptosis. Moreover, Wnt signaling pathway involved in the function of Tra2β knockdown which was demonstrated directly by a discernible reduction in the expression of GSK3/β‐catenin signaling axis. Conclusions: These findings suggest that knockdown of Tra2β may exert anti‐tumor effects through the GSK3/β‐catenin signaling pathway in OSCC. [ABSTRACT FROM AUTHOR]

Objective: Fibroblast growth factor receptor‐2 (FGFR2) and miR‐889‐3p expression in oral squamous cell carcinoma (OSCC) tumours were compared to normal controls. We then examined the relationship between miR‐889‐3p, FGFR2 expression and patient clinicopathological features. Materials and Methods: The interaction of FGFR2 and miR‐889‐3p was investigated using bioinformatics. Then, OSCC tumour biopsies and normal gingiva were collected and processed for expression analysis of FGFR2‐specific mRNA and miR‐889‐3p using real‐time PCR. Immunohistochemistry evaluated the expression of the FGFR2 protein. Results: The protein and mRNA expression levels of FGFR2 were significantly greater in tumours when contrasted with controls. Expression of miR‐889‐3p was significantly lower in OSCC compared to normal tissues. The FGFR2 and miR‐889‐3p expressions were inversely related (−0.86 and −0.73, respectively) in both cases and controls. Changes in miR‐889‐3p and FGFR2 expression in tumour tissues were associated with lymph node metastasis (LNM), with ~0.57 and ~3.0 folds of change in positive‐LNM patients, respectively. Conclusion: Decreased expression of miR‐889‐3p in OSCC tumours suggests that miR‐889‐3p functions as a tumour suppressor gene. Overexpression of FGFR2 further proves the role of miR‐889‐3p in the regulation of the FGFR2 pathway. This was further confirmed by showing differences in miR‐889‐3p expression in positive and negative LNM cases. [ABSTRACT FROM AUTHOR]

Objective: Diagnosing lesions with unusual clinical presentation can be challenging, mostly for cases in which the inclusion of oral metastasis in the differential diagnosis is necessary. Materials and Methods: A 55‐year‐old man complaining of a large mass in the oral cavity was referred to the Hospital Dentistry Service. The patient reported bleeding episodes and pain, with a 5‐month evolution. Intraoral examination revealed a 5 cm tumour with purplish‐red and ulcerated focal areas at the right buccal mucosa. Differential diagnosis included malignant mesenchymal tumours, lymphoproliferative lesions, and metastasis of an occult primary lesion. Two biopsies were conducted, with the first one presenting an intense haemorrhage, and the second performed under general anaesthesia and difficult bleeding control. Results: Histologic and immunohistochemical analysis diagnosed a clear cell carcinoma infiltration. A whole‐body CT scan reveals a renal tumour with multiple metastasis sites in the abdomen and bones. Metastatic clear cell renal cell carcinoma was finally confirmed, and the patient was followed with palliative care for 4 months. Conclusion: A challenging diagnosis of a rare metastatic lesion in the oral cavity was conducted after two procedures under difficult bleeding conditions. [ABSTRACT FROM AUTHOR]

Objective: Downregulation of N‐myc downstream‐regulated gene 2 (NDRG2), a tumor suppressor gene, has been associated with poor clinical outcomes in various cancers. However, the prognostic significance of NDRG2 in oral squamous cell carcinoma (OSCC) remains unknown. This study aimed to evaluate the prognostic value of NDRG2 downregulation in OSCC and to elucidate the mechanism by which NDRG2 is downregulated and the biological role of NDRG2 in tumor progression. Methods: Immunohistochemical and in silico analyses of NDRG2 expression were performed, and the correlation between NDRG2 expression and clinicopathological data was analyzed. The effect of NDRG2 knockdown on the biological behavior of OSCC cells was investigated and the effect of 5‐aza‐2′‐deoxycytidine (5‐aza‐dC) on NDRG2 expression was determined. Results: NDRG2 expression was significantly downregulated and DNA hypermethylation of NDRG2 was frequently found in head and neck SCC, including OSCC. Low NDRG2 expression was significantly correlated with adverse clinicopathological features and worse survival in OSCC. NDRG2 knockdown could enhance the oncogenic properties of OSCC cells. NDRG2 mRNA levels in OSCC cells could be restored by 5‐aza‐dC. Conclusion: Downregulation of NDRG2 promotes tumor progression and predicts poor prognosis in OSCC. Therefore, restoration of NDRG2 expression may be a potential therapeutic strategy in OSCC. [ABSTRACT FROM AUTHOR]

Objectives: Uncertainties remain regarding the effect of elevated glucose levels on lymphatic metastasis of cancer cells. Our study elucidated the mechanisms linking high glucose to lymphangiogenesis and lymphatic barrier‐related factors and investigated the protective role of linagliptin against lymphatic barrier dysfunction. Materials and Methods: A CAL‐27‐LEC co‐culture system was established. Sodium fluorescein permeability assay observed lymphatic endothelial cell permeability. Western blotting and RT‐qPCR detected protein and mRNA expression under different conditions, respectively. CCK‐8, scratch wound healing, and transwell assays revealed cell migration and proliferation. Tube formation experiment tested capacity for endothelial tube formation. Immunohistochemical staining analyzed tissue sections from 43 oral cancer individuals with/without diabetes. Results: In high‐glucose co‐culture system, we observed increased lymphatic barrier permeability and decreased expression of ZO‐1 and occludin, two tight‐junction proteins; conversely, the expression of PAR2, a high permeability‐related protein, was increased. Following linagliptin treatment, the expression levels of VEGF‐C, VEGFR‐3, and PAR2 decreased, while those of ZO‐1 and occludin increased. Considerably higher levels of LYVE‐1 expression in individuals with diabetes than in those without diabetes. Conclusions: By ameliorating the high glucose‐induced disruption of the lymphatic endothelial barrier, linagliptin may reduce lymphangiogenesis and exhibit an inhibitory effect on lymphatic metastasis in oral cancer patients with diabetes. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to determine the role of c‐Fos in growth and invasion of oral squamous cell carcinoma (OSCC). Methods: Immunohistochemistry was used to assess c‐Fos expression in 94 OSCC tissues and 30 adjacent normal tissues, the correlation between c‐Fos expression and clinicopathological characteristics was examined, and Kaplan–Meier and Cox analysis were used to investigate the role of c‐Fos in predicting the prognosis of OSCC patients. The effects of c‐Fos on the growth and invasion of OSCC were disclosed by overexpression and knockdown of c‐Fos. Furthermore, based on bioinformatics prediction, the effect of miR‐155‐5p on c‐Fos expression was examined, and dual‐luciferase reporter assay system was used to determine whether miR‐155‐5p regulated the transcriptional activity of c‐Fos in OSCC. Results: c‐Fos was markedly increased in OSCC tissues and cells. c‐Fos upregulation indicates a poor prognosis in OSCC patients, and c‐Fos promotes cell proliferation, migration, and invasion in OSCC. miR‐155‐5p could regulate the expression and the transcriptional activity of c‐Fos by directly targeting the c‐Fos 3′‐UTR. Conclusion: This study demonstrated that c‐Fos contributed to the progression of OSCC and may act as a potential target for OSCC therapy, and a potential prognostic biomarker of OSCC. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the inhibitory effects of STM2457, which is a novel METTL3 (m6A writer) inhibitor, both as a monotherapy and in combination with anlotinib, in the treatment of oral squamous cell carcinoma (OSCC) both in vitro and in vivo. Materials and Methods: The efficacy of STM2457 or STM2457 plus anlotinib was evaluated using two OSCC cell lines by CCK8, transwell, colony formation, would‐healing, sphere formation, cell cycle, apoptosis assays, and nude mice tumor xenograft techniques. The molecular mechanism study was carried out by western blotting, qRT‐PCR, MeRIP‐qPCR, immunofluorescence, and immunohistochemistry. Results: STM2457 combined with anlotinib enhanced inhibition of cellular survival/proliferation and promotion of apoptosis in vitro. Moreover, this combinatorial approach exerted a notable reduction in stemness properties and EMT (epithelial‐mesenchymal transition) features of OSCC cells. Remarkably, in vivo studies validated the efficacy of the combination treatment. Mechanistically, our investigations revealed that the combined action of STM2457 and anlotinib exerted downregulatory effects on EGFR (epidermal growth factor receptor) expression in OSCC cells. Conclusions: The combination of STM2457 and anlotinib targeting EGFR exerted a multiple anti‐tumor effect. In near future, anlotinib combined with STM2457 may provide a novel insight for the treatment of OSCC. [ABSTRACT FROM AUTHOR]

Objectives: Tumor‐associated neutrophils (TANs) are among the most abundant inflammatory cells in tumor microenvironment (TME). Aldehyde dehydrogenase 3A1 (ALDH3A1) is significantly reduced in oral squamous cell carcinoma (OSCC), ALDH3A1 overexpression suppresses tumorigenesis by inhibiting inflammation. This study investigated the relationship and mechanisms underlying the crosstalk between ALDH3A1 and TANs in OSCC. Materials and Methods: Immunohistochemistry and immunofluorescence were performed to investigate the abundance of TANs and the expression of ALDH3A1. dHL‐60 were induced with tumor‐conditioned media and recombinant IL‐6/IL‐8. The expression of key proteins in PI3K/AKT/NF‐κB pathway were detected by RT‐PCR and western blot. A xenograft model was utilized to examine the effect of ALDH3A1 on tumorigenicity and polarization of TANs. Results: In patients with OSCC, TANs significantly increased and were associated with a worse prognosis. Additionally, ALDH3A1 negatively correlated with TANs infiltration and especially the N2 phenotype which was the prominent part in OSCC. Furthermore, our study demonstrated that tumor‐derived IL‐8 drives ALDH3A1‐mediated TANs N2 polarization in the TME through PI3K/AKT/NF‐κB pathway in vitro and in vivo. Conclusion: Our results indicate that TANs can serve as a prognostic biomarker and ALDH3A1 could be a promising therapeutic target for regulating TANs N2 polarization in antitumor therapy. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the expression of programmed death‐ligand 1 (PD‐L1) and of T cell immunoglobulin and mucin domain‐containing protein (TIM3) in oral epithelial dysplasia and head and neck squamous cell carcinoma (HNSCC). Mouse HNSCC was induced with 4‐nitroquinoline‐1 oxide (4NQO). Oral epithelial dysplastic lesions, carcinoma in situ and HNSCC lesions were stained with anti‐PD‐L1 and TIM3 antibodies. The expression of PD‐L1 and TIM3 in tumor cells and immune cells was semiquantitatively measured and compared. In parallel, human dysplasia and HNSCC were stained with anti‐PD‐L1 and anti‐TIM3. The expression pattern of PD‐L1+ and TIM3+ cells was further compared. In human and mouse samples both PD‐L1 and TIM3 were found to be expressed in neoplastic and immune cells in HNSCC, but not in dysplasia. There was no significant difference in PD‐L1 and TIM3 expression between metastatic and nonmetastatic HNSCC. We conclude that the 4NQO‐induced mouse HNSCC model may be an excellent preclinical model for immune checkpoint therapy. [ABSTRACT FROM AUTHOR]

Background. Fascin is a protein that is increased in many epithelial cancers, and this increased expression is related to the more aggressive behavior and metastasis of many of these cancers. Considering the relatively high prevalence of oral lichen planus (OLP) and the inconsistencies regarding its malignant transformation potential, this study aimed to investigate the expression level of fascin in OLP and oral squamous cell carcinoma (OSCC). Methods. In this experimental study, 27 samples of erosive OLP and 30 samples of OSCC were immunohistochemically stained with fascin. The extent of fascin expression (epithelial cells with cytoplasmic immunoreactivity) in OLP was categorized into 4 scores based on the extent of epithelial staining. SCC specimens were scored according to the intensity and percentage of staining, and the sum of these two numbers was finally considered the total score, which ranged from 0 to 7. Fascin expression in two groups was compared using the Kruskal-Wallis test. Results. About half of the lichen planus samples (48.15%) received a score of 3. Most of the SCC samples received a score of 5 or 6. The comparison of the expression of fascin between the two groups demonstrated a statistically significant difference (P<0.001). Conclusion. The increased expression of fascin in lichen planus and SCC may indicate the role of fascin in carcinogenesis. Practical Implications. Overexpression of fascin in lichen planus and SCC may be a diagnostic marker for malignant transformation and a prognostic marker, respectively. [ABSTRACT FROM AUTHOR]

Background: Herbal medicine combined with nanotechnology offers an alternative to the increasing burden of surgery and/or chemotherapy, the main therapeutics of oral carcinoma. Phytosomes are nano-vesicular systems formed by the interaction between phospholipids and phyto-active components via hydrogen bonding, exhibiting superior efficacy over pure phytocomponents in drug delivery. Methods: Tetrahydrocurcumin (THC)-phytosomes were prepared by thin film hydration method. After characterization, in vitro cytotoxicity, antiproliferative capacity, antioxidant potential and full apoptotic workup were paneled on oral squamous cell carcinoma (SCC4) in comparison with native THC-solution and cisplatin (3.58 µg/mL intravenous injection), as positive controls. In addition, we tested the three medications on normal oral keratinocytes and gingival fibroblasts to attest to their tissue-selectivity. Results: Successful preparation of THC-phytosomes using 1:1 molar ratio of THC to phospholipid exhibited significantly increased aqueous solubility, good colloidal properties, and complete drug release after one hour. On SCC4 cells, THC-phytosomes, at their dose-/time-dependency at ~ 60.06 µg/mL escalated cell percentages in the S-phase with 32.5 ± 6.22% increase, as well as a startling 29.69 ± 2.3% increase in apoptotic population. Depletion of the cell colonies survival to 0.29 ± 0.1% together with restraining the migratory rate by -6.4 ± 6.8% validated THC-phytosomes' antiproliferative capacity. Comparatively, the corresponding results of THC-solution and cisplatin revealed 12.9 ± 0.9% and 25.8 ± 1.1% for apoptosis and 0.9 ± 0.1% and 0.7 ± 0.08% for colony survival fraction, respectively. Furthermore, the nanoformulation exhibited the strongest immuno-positivity to caspase-3, which positively correlated with intense mitochondrial fluorescence by Mitotracker Red, suggesting its implication in the mitochondrial pathway of apoptosis, a finding further explained by the enormously high Bax and caspase-8 expression by RT-qPCR. Finally, the THC groups showed the lowest oxidative stress index, marking their highest free radical-scavenging potential among the test groups. Conclusions: THC-phytosomes are depicted to be an efficient nanoformulation that enhanced the anticancer efficacy over the free drug counterpart and the conventional chemotherapeutic. Additionally, being selective to cancer cells and less cytotoxic to normal cells makes THC-phytosomes a potential candidate for tissue-targeted therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Oral cancer is a challenging disease to treat, and new therapies are needed to improve patient outcomes. Okanin, a natural compound derived from Bidens pilosa L., has been known for its anti-inflammatory properties, but its effects on cancer, particularly oral cancer, are less understood. In this study, we investigated the anticancer potential of okanin in human oral cancer cells. Our results showed that okanin effectively reduced the growth of oral cancer cells by inducing cell death through mechanisms involving both apoptosis and pyroptosis. Additionally, okanin inhibited tumor growth in a mouse model of oral cancer. These findings suggest that okanin may be a promising natural compound for developing new treatments for oral cancer. Background: Okanin, a flavonoid compound derived from Bidens pilosa L., has garnered attention for its anti-inflammatory properties. Although Bidens pilosa is commonly used in healthcare products and functional foods, the anticancer potential of okanin, particularly in oral cancer, remains underexplored. This study aims to investigate the effects of okanin on oral cancer cell lines and its potential as a therapeutic agent. Methods: The study involved assessing the cytotoxic effects of okanin on oral cancer cell lines SAS, SCC25, HSC3, and OEC-M1. The IC50 values were determined using methylene blue assays, and the clonogenic capacity was evaluated through colony formation assays. Flow cytometry was used to analyze cell cycle progression and apoptosis. Caspase-3/7 activity assays and annexin V/7-AAD staining confirmed the induction of apoptosis and pyroptosis. In vivo efficacy was assessed using a SAS xenograft model, and immunohistochemical analysis of xenograft tissue was performed to examine pyroptosis-related markers. Results: Okanin exhibited potent cytotoxic effects with IC50 values of 12.0 ± 0.8, 58.9 ± 18.7, 18.1 ± 5.3, and 43.2 ± 6.2 μM in SAS, SCC25, HSC3, and OEC-M1 cells, respectively. It caused dose- and time-dependent reductions in cell viability and significantly impaired clonogenic capacity. Flow cytometry revealed G2/M cell cycle arrest and increased sub-G1 population, indicating cell cycle disruption and death. Okanin induced both apoptosis and pyroptosis, as confirmed by caspase-3/7 activity and annexin V/7-AAD staining. In vivo, okanin reduced tumor growth and involved pyroptosis-related markers such as CASP1, GSDMC, GSDMD, and GSDME. Conclusions: Okanin demonstrates significant anticancer potential, particularly in oral cancer, by inducing both apoptosis and pyroptosis. Its efficacy in reducing tumor growth in vivo further supports its potential as a novel therapeutic option. Further mechanistic studies are needed to elucidate the pathways involved in okanin-mediated cell death and to explore its clinical applications. [ABSTRACT FROM AUTHOR]

Objective: Lidocaine, a common local anesthetic in medical practice, exhibits anticancer properties across various tumor types. In this study, we aimed to investigate the effects and mechanisms of lidocaine on oral squamous cell carcinoma. Methods: Cell viability and proliferation were assessed through CCK‐8 and EdU assays. Transwell assays were used to analyze cell migration and invasion. Immunofluorescence assays were conducted to determine MMP9 levels. In vivo tumor growth was evaluated using a tumor xenograft model, and Ki67 and MMP9 levels were determined using immunohistochemistry. N6‐methyladenosine levels were assessed using dot plots and ELISA. mRNA and protein levels were examined through reverse transcription‐quantitative PCR or western blot analysis. The association between IGF2BP2 and caveolin‐1 was validated through RIP and luciferase reporter assays. Results: Lidocaine exhibited suppressive effects on the viability, migration, invasion, and tumor formation of oral squamous cell carcinoma. IGF2BP2 expression correlated with poor survival and was downregulated by lidocaine. Lidocaine reduced caveolin‐1 stability by decreasing IGF2BP2 levels. Caveolin‐1 overexpression partially reversed the suppressive effects of lidocaine on the progression of oral squamous cell carcinoma cells. Conclusion: Lidocaine exerts an anticancer role in oral squamous cell carcinoma via IGF2BP2‐mediated regulation of caveolin‐1 stability. [ABSTRACT FROM AUTHOR]

Background: Human epidermal growth factor receptor 2 (HER2) plays an important role in the progression of multiple solid tumors and induces resistance to epidermal growth factor receptor (EGFR) target treatment. However, the expression status and the clinical significance of HER2 in oral squamous cell carcinoma (OSCC) is still controversial. Pyrotinib (PYR) is a promising novel EGFR/HER2 dual inhibitor, whose efficacy in OSCC has not been determined. Methods: 57 locally advanced de novo OSCC patients were included in this study to investigate the relationship between the HER2 expression levels and the prognosis by the tissue microarray analysis (TMA). In vitro and in vivo experiments were performed to retrieve the efficacy of PYR in OSCC. The main downstream of HER2 was evaluated by western blotting in OSCC cell lines and xenograft tumors to explore the potential mechanism of PYR. Results: This study revealed the primary tumor of OSCC had higher HER2 expression levels. Patients with HER2 overexpression had poor overall survival (P < 0.014) and poor disease free survival (P < 0.042). In vitro, PYR suppressed the proliferation, colony formation and migration of OSCC cells. It also promoted apoptosis of OSCC cells and induced cell cycle arrest. Furthermore, PYR was able to inhibit the occurrence and development of OSCC effectively in vivo. Western blotting revealed that PYR suppressed OSCC by inhibiting the phosphorylation of HER2, AKT and ERK. Conclusions: This study exhibited the anti-OSCC effects of PYR in vitro and in vivo, and demonstrated PYR inhibited OSCC cells by inducing apoptosis via the HER2/ AKT and ERK pathway. The result of this study also indicated locally advanced OSCC patients might benefit from HER2 assay and EGFR/HER2 dual inhibit treatment. [ABSTRACT FROM AUTHOR]

Objective: To report the clinicopathologic features of 19 oral solitary fibrous tumors (SFTs). Methods: Clinical data were collected from the records of seven pathology services. All cases were re‐evaluated by HE staining and confirmed by immunohistochemistry. Results: The series comprised 11 females (57.9%) and 8 males (42.1%), with a mean age of 47.3 ± 14.7 years (range: 22–71 years) and a 1.3:1 female‐to‐male ratio. Most tumors affected the buccal mucosa (n = 7; 36.8%) and presented clinically as an asymptomatic solitary submucosal well‐circumscribed nodule with coloration similar to the oral mucosa. Morphologically, most SFTs (n = 10; 52.6%) exhibited a classic hybrid pattern characterized by a well‐circumscribed proliferation of densely cellular areas alternating with hypocellular areas in a variably collagenous vascular stroma. Remnants of accessory salivary glands were observed in two cases (n = 2; 10.5%). All tumors were positive for STAT6 and CD34 (n = 19; 100%). Outcome information was available from 6 patients (31.6%), with clinical follow‐up ranging from 6 to 24 months (mean ± SD, 9.5 ± 6.8 months), and none developed local recurrence. Conclusions: Oral SFTs are rare and often clinically misdiagnosed. Pathologists should consider SFT in the differential diagnosis of oral spindle cell tumors. Accurate diagnosis requires careful morphological evaluation supported by immunohistochemical analysis. [ABSTRACT FROM AUTHOR]

Objective: Oral lichen planus carries a risk for malignancy. The pathogenesis of the disease is mediated by various inflammatory mediators. Several mediators could be responsible for the oncogenic behavior in certain cases. Hypoxia-inducible factor-1a (HIF-1), and its possible correlation to Galactin-3 (Gal-3) and matrix metalloproteinase-9 (MMP-9) over expression represents an important indicator for malignant transformation. The investigation of these factors may present evidence-based information on malignant transformation of the disease. Subjects and methods: The study investigated the expression of HIF-1, Gla-3 and MMP-9 in tissue samples of OLP compared to control subjects of un-inflamed gingival overgrowth. 20 biospecimen were allocated in each group. Results: Immunohistochemical findings of OLP showed immunoreactivity for Galectin 3, HIF1a and MMP-9 by most of the epithelial cells. There was a positive correlation between HIF1α and MMP-9, r = 0.9301 (P-value < 0.00001). A positive correlation was detected between Galectin 3 and MMP-9, r = 0.7292 (P-value = 0.000264) between Galectin 3 and HIF1α, r = 0.5893 (P-value = 0.006252). Conclusion: These findings confirm the hypothesis that the adaptive pathways to hypoxia as Gal 3 and MMP-9 expressions and their HIF-1 may play a crucial role in carcinogenesis of OLP. [ABSTRACT FROM AUTHOR]

Background: Oral lichen planus (OLP) is a chronic inflammatory mucosal disease that is classified as a premalignant condition. Epithelial growth factor receptor (EGFR) is associated with tumorigenesis and tumor progression and is overexpressed in several oral malignant disorders. Despite the association of EGFR overexpression with oral potentially malignant lesions, few studies have analyzed its expression in OLP, showing controversial results. This study aimed to compare the expression of EGFR as a protein marker in Reticular and Erosive OLP. Methods: This descriptive-analytical cross-sectional was conducted on 15 paraffin blocks of reticular lichen planus lesions, 16 paraffin blocks of erosive OLP lesions, and 8 paraffin blocks of inflammatory fibrous hyperplasia lesions as the control group (39 in total). After immunohistochemical staining for EGFR, samples were simultaneously observed by two maxillofacial pathologist, and the percentage of stained cells, intensity of staining, pattern of staining, and the location of stained cells were obtained. Results: The Mann-Whitney-U test showed that there was no significant difference in the mean percentage of stained cells between erosive OLP and reticular OLP (P-value = 0.213) and between reticular OLP and control group (P-value = 0.137), but there was a significant difference between erosive OLP and control group (P-value = 0.035). Fisher's exact test showed that there was no significant difference between the frequency distribution of staining patterns in three types of lesions (P-value = 0.90). Kruskal-Wallis test showed that there was no significant difference between the intensity of staining in the three groups (P-value = 0.19) and also there was no significant difference between the location of stained cells in different layers of the epithelium in the three groups (P-value = 0.90). Conclusions: The results of this study showed that in comparison of reticular OLP, erosive OLP, and the control group there was a significant difference just between erosive OLP and control group in the percentage of stained cells. [ABSTRACT FROM AUTHOR]

Background: Neurofibroma is a common benign tumor of neuronal origin that can occur as a solitary tumor or as a component of the generalized syndrome of neurofibromatosis. Neurofibromas are primarily located in the subcutaneous soft tissues and commonly involve extra-oral sites. Solitary intraosseous neurofibromas of the oral cavity are infrequent, with occurrences in the maxilla being exceedingly rare. Case presentation: A 22-year-old male patient presented with an asymptomatic mass in the maxilla. Cone-beam computed tomography revealed a round, well-outlined, radiolucent lesion with expansive growth. The neoplasm with the complete capsule was completely removed and confirmed as a neurofibroma based on histopathological and immunohistochemical findings. The reported cases of solitary intraosseous neurofibromas located in the maxilla published in the English literature were compiled to assist in the diagnosis of solitary intraosseous neurofibromas of the maxilla. Nine months after the surgery, there were no signs of tumor recurrence or malignant transformation. Conclusions: This report emphasizes that rare locations of neurofibromas, such as solitary intraosseous neurofibromas in the maxilla, typically demonstrate nonspecific clinical and radiological features. Clinicians should consider solitary intraosseous neurofibromas as possible differential diagnoses and recognize the histopathological and immunohistochemical features to confirm the correct diagnosis. A longer follow-up period is required because of the potential for local recurrence and malignant transformation of these tumors. [ABSTRACT FROM AUTHOR]

Background: Odontogenic carcinoma with dentinoid (OCD) is a rare and controversial entity, which has not yet been included in the current World Health Organization classification of odontogenic lesions. Owing to the small number of reported cases, the clinicopathological characteristics, biological behavior, prognosis, and appropriate treatment strategies for OCD remain to be defined. Herein, we present an additional case of OCD with a focus on the differential diagnosis and review of the pertinent literature, in order to enable better recognition by oral clinicians and pathologists and further characterization of this entity. Case presentation: This paper reports a case of OCD in the posterior mandible of a 22-year-old female. Radiography showed a well-defined unilocular radiolucency with radiopaque materials. The intraoperative frozen section pathology gave a non-committed diagnosis of odontogenic neoplasm with uncertain malignant potential. Then a partial mandibulectomy with free iliac crest bone graft and titanium implants was performed. Microscopically, the tumor consisted of sheets, islands, and cords of round to polygonal epithelial cells associated with an abundant dentinoid matrix. Immunohistochemically, the tumor cells were diffusely positive for CK19, p63, and β-catenin (cytoplasmic and nuclear). No rearrangement of the EWSR1 gene was detected. The final diagnosis was OCD. There has been no evidence of recurrence or metastasis for 58 months after surgery. We also provide a literature review of OCD cases, including one case previously reported as ghost cell odontogenic carcinoma from our hospital. Conclusions: OCD is a locally aggressive low grade malignancy without apparent metastatic potential. Wide surgical excision with clear margins and long-term period follow-up to identify any possible recurrence or metastases are recommended. Histopathological examination is essential to conclude the diagnosis. Special care must be taken to distinguish OCD from ghost cell odontogenic carcinoma and clear cell odontogenic carcinoma, as misdiagnosis might lead to unnecessary overtreatment. Study of additional cases is required to further characterize the clinicopathological features and clarify the nosologic status and biological behavior of this tumor. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Journal of Dental Hygiene is the property of Canadian Dental Hygienists Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objectives: Previously, we demonstrated that IL17RB plays an essential role in lung cancer progression. This study aimed to determine whether IL17RB correlates with oral cancer and promotes oral cancer progression. Subjects and Methods: IL17RB expression in oral cancer tissues and normal tissues was determined by immunohistochemistry staining, while the association of IL17RB expression with the clinicopathological characteristics of oral squamous cell carcinoma (OSCC) patients was analyzed and its correlation with progression‐free survival and response to radiotherapy and chemotherapy in OSCC patients was also explored. Western blotting was performed to investigate the expression of IL17RB in various OSCC cell lines; moreover, transwell assay was performed to evaluate the effect of IL17RB expression on cell migration ability. Results: In this study, we found that IL17RB was expressed higher in OSCC tissues compared to normal oral mucosa tissues and its expression was positively correlated with tumor size, lymph node metastasis, advanced cancer stage, and poor prognosis. In vitro study showed that IL17RB expression in OSCC cell lines as determined by Western blotting, was positively correlated with their migration ability. Conclusion: Clinical and in vitro studies suggest that IL17RB might serve as an independent risk factor and a therapeutic target for oral cancer. [ABSTRACT FROM AUTHOR]

Hamartomas, a focal excess of normal tissue usually presenting as isolated masses, are rarely found in the head and neck region. The purpose of this report is to discuss a rare case of an intra-oral angioleiomyomatous hamartoma in a 14-year-old male who presented with a congenital nodule over the anterior palatal mucosa. The confirmatory diagnosis was done based on histopathology and immunohistochemistry using various markers. A brief review of the literature and clinical differential diagnoses are discussed, along with the clinical significance of hamartomas associated with syndromes. Hence, the identification of such hamartomas may lead to early diagnosis of associated syndromes in pediatric patients. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to investigate bone metastasis induced by Notch signalling pathway dysregulation and to demonstrate that SPARC is a potential therapeutic target in adenoid cystic carcinoma (AdCC) with Notch dysregulation. Materials and Methods: This retrospective study enrolled 144 AdCC patients. RNA‐sequencing and enrichment analyses were performed using 32 AdCC samples. Osteonectin/SPARC and the Notch activation indicator Notch intracellular domain (NICD) were detected using immunohistochemistry. Cell proliferation and migration assays were conducted using stably NICD over‐expressing cells. The effect of SPARC on osteoclast differentiation in NICD cells was investigated using western blotting, quantitative reverse transcription PCR, tartrate‐resistant acid phosphatase staining and resorption assays. Results: RNA‐sequencing analysis showed that genes down‐regulated in Notch‐mutant AdCCs, such as SPARC, were enriched in ossification and osteoblast differentiation. Most (75/110, 68.2%) Notch1‐wild‐type AdCCs showed SPARC over‐expression, whereas 30 out of 34 (88.2%) Notch1‐mutant tumours showed low SPARC expression. SPARC over‐expression was then found negatively to be correlated with NICD expression in 144 AdCCs. NICD over‐expression promoted cell growth, migration and osteoclast differentiation, which could be partly reversed by exogenous SPARC. Conclusions: Notch activation in AdCC contributes to bone metastasis through SPARC inhibition. The study results suggest that SPARC may represent a prognostic biomarker and potential therapeutic target. [ABSTRACT FROM AUTHOR]

Objectives: The fibroblast growth factor receptor (FGFR) members including FGFR1–4 have been identified as promising novel therapeutic targets and prognostic markers in multiple solid tumors. However, the predictive role of the expression of FGFR proteins in oral squamous cell carcinoma (OSCC) requires further exploration. Materials and Methods: Immunohistochemical evaluation of FGFR1–4 was performed on 161 paired OSCC samples. The associations of FGFRs with clinicopathologic and prognostic parameters were analyzed. To further assess the contribution of FGFRs to OSCC proliferation, cell lines, and one PDX model was utilized to examine the anti‐tumor effect of the pan‐FGFR inhibitor AZD4547. Results: All FGFR members were found to be overexpressed in OSCC tumors when compared to normal tissues, and their expression was significantly associated with poor overall survival and disease‐free survival. Multivariate Cox regression analysis revealed high expression of FGFR1 (p = 0.014) and FGFR4 (p = 0.009) were independent prognostic factors and co‐overexpression of FGFR1 and FGFR4 with lymph node metastasis increased HR for death (p = 0.02). The pan‐FGFR inhibitor AZD4547 showed anti‐tumor activity in cell lines and in a patient‐derived xenograft of OSCC. Conclusions: This study highlights the co‐overexpression of FGFR1 and FGFR4 as a significantly poor prognosis indicator in OSCC when combined with lymph node metastasis. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the molecular mechanism by which the transcription factor ETS1 regulates N‐myc downstream regulatory gene 1 (NDRG1) to provide a new theoretical basis for the study of oral squamous cell carcinoma (OSCC). Methods: In this study, eight human OSCC and paraneoplastic samples were collected. The expressions of NDRG1, ETS1, and Ki67 were detected by immunohistochemistry; apoptosis was detected by tdt‐mediated dUTP notched end labeling; cell migration and invasion were detected by Transwell; quantitative real‐time PCR was performed to detect the expression of NDRG1; RNA‐binding protein immunoprecipitation (RIP) assays detected NDRG1 expression; immunofluorescence assays detected ETS1 expression. Results: NDRG1 and ETS1 expression was significantly upregulated in cancer tissues and CAL‐27 and SCC‐6 cells. Knockdown of NDRG1 and ETS1 inhibited cell proliferation, migration, invasion, cloning, and EMT while promoting apoptosis and inhibited tumor development; ETS1 positively regulated NDRG1 expression; Finally, overexpression of NDRG1 in vivo and in vitro reversed the effect of ETS1 knockdown on CAL‐27 and SCC‐6 cells. Conclusions: ETS1 positively regulates the expression of NDRG1 and promotes OSCC. Therefore, ETS1 may serve as a new target for the clinical diagnosis and treatment of OSCC. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to investigate the combined effect of X‐ray radiation (IR) and hyperbaric oxygen (HBO) on oral squamous cell carcinoma (OSCC) cells and to explore the possible molecular mechanism. Methods: The OSCC cells were treated with or without IR, together with or without HBO co‐exposure. Cells were transfected with specific plasmids using Lipofectamine 2000. The cell varieties, apoptosis markers, and ferroptosis markers were determined by using appropriate method. OSCC xenograft mice model was categorized into several subgroups according to the specific treatement. GPX4 expressions were determined by immunohistochemistry (IHC) in OSCC tissues and were tested by ELISA in serums from OSCC patients. Results: The co‐exposure of IR and HBO significantly strengthened the cytotoxicity of IR on SCC15‐S cells in ferroptosis‐dependent manner. The regulated GPX4/ferroptosis mediated the HBO function on re‐sensitizing the radio‐resistant OSCC cells to IR. In xenograft mice, co‐exposure of IR and HBO can significantly reduce the tumor under IR activation compared with IR alone. Clinical data indicated that high GPX4 levels were associated with poor chemo‐radiotherapy outcome. Conclusions: HBO could re‐sensitize radio‐resistant OSCC cells through GPX4/ferroptosis regulation. These results provide a potential therapeutic strategy for clinical radio‐resistance. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study is to identify and analyze the existing literature on the utility of podoplanin to predict the risk of malignancy development (MD) in patients previously diagnosed with oral leukoplakia (OL). Methods: A systematic review and meta‐analysis (SRMA) was performed though a search strategy using several electronic databases and a combination of keywords related to podoplanin and MD of OL, until 15 May, 2022 (PROSPERO CRD42022329326). Evaluation of the risk of bias (ROB) was performed using the Quality in Prognosis Studies Tool. The meta‐analyses were estimated using fixed‐effect models. Results: From 421 articles, 6 studies were finally included, that enrolled 546 patients with OL, of whom 125 presented with an oral cancer during follow‐up (32 to 90 months). Some limitations regarding the ROB were identified mostly related to small sample sizes, short follow‐up times, lack of information on covariables in the included studies and lack of accuracy (including sensitivity and specificity). Meta‐analysis of 6 studies reveal that high expression of podoplanin carries a pooled hazard ratio (HR) of 3.72 (95% CI, 2.40–5.76; p < 0.00001) for MD without statistical heterogeneity (I2 = 0%, p = 0.53). Conclusion: The results of this SRMA support the role of podoplanin immunohistochemical expression as a potential predictive biomarker to assess the risk of malignancy development in oral leukoplakia. [ABSTRACT FROM AUTHOR]

Objectives: To identify the engagement of CD8+ T cells in the lymph node metastasis (LNM) of oral squamous cell carcinoma (OSCC) and significant CD8+ T cell‐related genes regulating the LNM. Subjects and methods: Tumor samples of primary OSCC patients were obtained (n = 71). CD8 expression in LNM− and LNM+ tumors were identified using tissue microarray (TMA)‐based immunohistochemistry (IHC) and compared using the Mann–Whitney U test. The LNM status, as well as the metagene expression of CD8+ T cells of OSCC patients, were obtained from The Cancer Genome Atlas (TCGA) database. Metagenes related to LNM were screened using logistic regression analyses and further identified using TMA‐based IHC. Results: CD8 was significantly positively associated with LNM (p < 0.05). Furthermore, tumors with higher expression of FKBP4 had significantly higher LNM rate (HR: 1.63; 95% CI: 1.08 ~ 2.53; p < 0.05), which was also proven using TMA‐based IHC analysis. Conclusion: CD8+ T cells might engage in the lymphatic metastases of OSCC. Among CD8+ T cell‐related genes, FKBP4 could be a promising biomarker to predict the risk of LNM of OSCC. [ABSTRACT FROM AUTHOR]

Objectives: Our study elucidates the prognostic role of cluster of differentiation (CD) 24 expression in oral squamous cell carcinoma (OSCC) and determines whether targeting CD24 enhances the anti‐tumor immune response by inhibiting tumor‐associated macrophages (TAMs). Materials and Methods: The expression of CD24 and CD68 was analyzed immunohistochemically via tissue microarrays constructed using 56 cohorts of patients with OSCC and 20 control specimens. Further, CD24 was inhibited in an allograft squamous cell carcinoma (SCC) related mouse model with CD24mAb to determine the tumor volume and weight. Changes in immune cells such as TAMs and T cells in the tumor microenvironment (TME) were analyzed by Flow cytometry. The expression of CD4, CD8, and Ki67 was analyzed via immunohistochemistry. The inhibition of CD24 was confirmed by Western blot and immunohistochemistry. Results: CD24 was overexpressed in OSCC. High expression of CD24 indicated poor survival in patients with OSCC (p = 0.0334). CD24 expression was significantly correlated with CD68 (p = 0.0424). The inhibition of CD24 delayed tumor growth in vivo. A decrease in TAMs number and an increase in T cell number were confirmed, while the ability of tumor proliferation was impaired. Conclusion: Targeting CD24 could enhance anti‐tumor immune response by inhibiting TAMs. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to investigate the clinical and prognostic relevance of the Hippo‐YAP transactivators YAP1 and TAZ in oral squamous cell carcinoma, and their possible relationship with PI3K/mTOR pathway activation. Materials and Methods: Immunohistochemical analysis of YAP1, TAZ, PIK3CA (p110α), p‐AKT (Ser473), and p‐S6 (Ser235) was performed in paraffin‐embedded tissue specimens from 165 OSCC patients. Correlations between protein expression and clinical data were further assessed. Results: YAP1 expression was detected in both cytoplasm and nucleus of tumor cells, whereas TAZ expression was only found in the nucleus. Nuclear YAP1 was significantly associated with tumor size (p = 0.03), neck lymph node metastasis (p = 0.02), TNM stage (p = 0.02), and poor differentiation (p = 0.04). Nuclear TAZ was associated with tobacco (p = 0.03) and alcohol consumption (p = 0.04), and poor tumor differentiation (p = 0.04). There was a positive significant correlation between nuclear and cytoplasmic YAP1, nuclear TAZ, p110α expression, and mTORC1 activation p‐S6 (S235). Combined expression of nuclear and cytoplasmic YAP1 was prognostic in both univariate and multivariate analyses. Active nuclear YAP1 was significantly and independently associated with poor disease‐specific (p = 0.005, HR = 2.520; 95% CI = 1.319–4.816) and overall survival (p = 0.015, HR = 2.126; 95% CI = 1.155–3.916). Conclusion: Nuclear YAP1 is an independent predictor of poor survival in oral squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Background: High-risk Human Papillomavirus (HPV) genotypes are found in malignant oral epithelial lesions, and HPV infection is proposed as a risk factor for initiating Squamous cell carcinoma (SCC) in the head and neck region. This study suggests a practical approach to detect HPV in HPVassociated oral epithelial dysplasia (HAOED). Methods: Fifty-four oral epithelial dysplasia specimens were examined, comprising twenty-seven cases diagnosed with highgrade dysplasia and twenty-seven cases diagnosed with lowgrade dysplasia using a binary grading system. To assess the cases for HPV, the specimens were examined for p16 protein using an immunohistochemical (IHC) study, and then, the Chromatin In Situ Hybridization (CISH) test was performed for all positive cases. Chromatin Immunoprecipitation-Polymerase Chain Reaction (ChIP-PCR) was performed on CISH-positive specimens to assess the outcome. This cross-sectional study was conducted in 2020 at Tehran University of Medical Science. SPSS software version 22.0 was used to perform the Chi square or Fisher's exact test to examine the relationship between variables (statistically significant level P<0.05). Results: The expression of p16 protein was not associated with the severity of epithelial dysplasia (81.5% in low-grade and 59.2% in high-grade cases) (P=0.16). Moreover, according to the CISH test result, 9.25% of all specimens were positive (P>0.99), and in the nine cases, undergone the ChIP-PCR study, two cases (22.2%) showed positivity for HPV-16, while one case (11.1%) demonstrated positivity for HPV-51. Conclusion: Regarding HAOED, here, we proposed a step-bystep combination approach using different diagnostic methods, including IHC for p16 protein, CISH, and ChIP-PCR based on a complementary algorithm. [ABSTRACT FROM AUTHOR]

A granular cell tumor (GCT) is an unusual benign mesenchymal neoplasm with Schwann cells origin. The most common site is the dorsum of the tongue. It has a striking tendency to occur in females and is more frequent in adult patients. GCT typically shows an asymptomatic, slow-growing, single nodule. Histopathologically, it reveals a proliferation of polygonal cells with granular cytoplasm penetrating the adjacent muscles. In some cases, the overlying epithelium demonstrates pseudoepitheliomatous hyperplasia (PEH), which can complicate its precise diagnosis and may mimic squamous cell carcinoma (SCC). This paper presents a 58-year-old woman with a chief complaint of painless mass on the dorsal of the tongue for two years. The lesion was pink and circumscribed with firm consistency measuring 1×1cm. The surface of the lesion was intact. Microscopic examination demonstrated unencapsulated sheets of large, polygonal cells with abundant eosinophilic, granular cytoplasm, and vesicular nuclei. The overlying epithelium showed florid PEH and keratin pearl formation. S100 protein was positive diffusely. The diagnosis of oral GCT was made. Though GCT is a non-aggressive lesion, it may be confused with SCC due to florid PEH and keratin pearl formation. Although PEH is a neglected topic among oral pathologists, it is of great importance in the field of research. Diagnosis can sometimes be problematic because they mimic other lesions. The pathogenesis of PEH is still uncertain. Therefore, familiarity with these characteristics and determining the cause of the PEH leads to correct treatment. This article intends to raise the insight of oral pathologists about PEH in oral lesions. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Cancer Biotherapy is the property of Editorial Office of Chinese Journal of Cancer Biotherapy and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Extramedullary plasmacytomas are rare solitary tumors consisting of neoplastic plasma cell proliferations other than bone. In contrast to the medullary plasmacytoma, which are localized to the bone, these tumors are localized to submucosal areas, with 80% of them occurring in the head and neck. These tumors do not usually disseminate, but may be locally aggressive and destroy adjacent structures. Here, we present a case report of extramedullary plasmacytoma of the buccal mucosa who has been treated surgically in our institution. [ABSTRACT FROM AUTHOR]

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]

Objective: We previously reported that dickkopf WNT signaling inhibitor 3 (DKK3) would modulate malignant potential of oral squamous cell carcinoma (OSCC) via activating Akt. Recently, cytoskeleton associated protein 4 (CKAP4) functions as receptor of DKK3, which activates Akt in esophageal squamous cell carcinoma, but its expression and function in OSCC were unclear. Methods: We studied DKK3 and CKAP4 protein expression in OSCC tissue and investigated the correlation between protein expression and clinical data. We also investigated whether antibodies (Ab) for DKK3 or CKAP4 could suppress malignant potential of the cancer cells. Results: DKK3/CKAP4 protein expression was observed in majority of OSCC cases and was associated with significantly higher T‐stage and TNM stage. Multivariate analysis revealed that DKK3 and CKAP4 were independent prognostic biomarkers for overall survival (OS) and disease‐free survival (DFS), respectively. Survival analyses revealed that DKK3‐positive cases and CKAP4‐positive cases showed significantly shorter OS and DFS, respectively, and that DKK3/CKAP4 double‐negative cases showed significantly favorable prognosis. Both anti‐DKK3Ab and anti‐CKAP4Ab could suppress cancer cell proliferation, migration, and invasion. Conclusion: DKK3/CKAP4 axis is thought to be important in OSCC, and it would be a promising therapeutic target. [ABSTRACT FROM AUTHOR]

The oncoprotein survivin plays a pivotal role in controlling cell division and preventing apoptosis by inhibiting caspase activation. Its significant contribution to tumorigenesis and therapeutic resistance has been well established. Isoliquiritigenin (ISL), a natural compound, has been recognized for its powerful inhibitory effects against various tumors. However, whether ISL exerts regulatory effects on survivin and its underlying mechanism in oral squamous cell carcinoma (OSCC) remains unclear. Here, we found that ISL inhibited the viability and colony formation of OSCC, and promoted their apoptosis. The immunoblotting data showed that ISL treatment significantly decreased survivin expression. Mechanistically, ISL suppressed survivin phosphorylation on Thr34 by deregulating Akt-Wee1-CDK1 signaling, which facilitated survivin for ubiquitination degradation. ISL inhibited CAL27 tumor growth and decreased p-Akt and survivin expression in vivo. Meanwhile, survivin overexpression caused cisplatin resistance of OSCC cells. ISL alone or combined with cisplatin overcame chemoresistance in OSCC cells. Overall, our results revealed that ISL exerted potent inhibitory effects via inducing Akt-dependent survivin ubiquitination in OSCC cells. [ABSTRACT FROM AUTHOR]

Background: Oral squamous cell carcinoma (OSCC) is the most common malignant tumor among oral cancers. Cyclin D1 and Ki-67 have associated with cell division. The aim of this study was to compare the expression of these markers in OSCC with and without cervical lymph node (LN) metastasis. Materials and Methods: This cross-sectional study was performed on 40 OSCCs with and without cervical LN metastasis (20 in each group) that was recorded in the pathology archive of Ayatollah Kashani Hospital in Isfahan. Clinical information including age, gender, and location was collected. Some histopathological parameters including depth of invasion, lymphovascular invasion (LVI), perineural invasion (PNI), number of LN metastases, histopathological grade, and stage of disease were evaluated. Immunohistochemical staining was performed for cyclin D1 and Ki-67. All data were entered into SPSS24 software and were analyzed by Mann--Whitney, Kruskal--Wallis, Chi-square, Fisher's exact, and t-tests. P < 0.05 was considered statistically significant. Results: Based on LVI and stage of disease, a significant correlation was found between the two groups (P < 0.001). There was a significant difference between the two groups based on cyclin D1 expression (P = 0.05). The expression of the Ki-67 showed a significant difference based on tumor location (P = 0.026) and PNI (P = 0.033). Conclusion: The use of markers should be considered in determining the prognosis of OSCC, and the cyclin D1 marker is one of the useful markers for predictors of cervical LN metastasis. [ABSTRACT FROM AUTHOR]

Background: The molecular makeup of a head and neck squamous cell carcinoma (HNSCC) could vary as per the geography and corresponding variability in prevalent etiopathological factors. The objective of this study was to analyze the expression pattern of E-cadherin (E-cad), a transmembrane glycoprotein with tumour suppressor function, in a cohort of HNSCC treated at a tertiary care medical centre in the southern part of India. Material and methods: After obtaining the institutional ethics committee's permission, the expression of E-cad in HNSCC was assessed by using immunohistochemistry on retrospectively collected tumour specimens, obtained by a surgical cohort of cases operated between September 2018 and July 2019. The E-cad expression was then correlated with various clinical and pathological characteristics of HNSCC, retrieved via the medical records of corresponding patients. Results: A total of 60 patients of HNSCC were included, most of whom had lesion in the oral cavity, in an advanced stage. The majority had a strong or moderate expression of E-cad on the surface. On analyzing further, oral cavity tumours had significantly less expression of E-cad compared to laryngeal and hypopharyngeal tumours taken together, and primary tumours had less E-cad expression than recurrent cases. Multivariate analysis with proportional odds regression showed the significant associations of low expression of E-cad expression with the moderate/poor differentiation of tumours and with the extranodal extension. Conclusions: Among the HNSCC, the loss of E-cad expression was mostly associated with primary tumours of the oral cavity, moderate/poorly differentiated tumours, and in those HNSCCs that had an extranodal extension. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer-associated fibroblasts (CAFs) are a major component of the stroma in oral squamous cell carcinoma (OSCC) and are considered important therapeutic targets. In this study, we demonstrated that aortic carboxypeptidase-like protein (ACLP) is highly expressed in CAFs of OSCC, thereby activating them. Cancer cells induce ACLP expression in CAFs through the TGF-β1 signaling pathway, and CAF-derived ACLP enhances the migration and infiltration of cancer cells. Furthermore, ACLP co-expresses with collagen and shows an inverse correlation with tumor infiltration of CD8+ T lymphocytes. Our data suggest that targeting ACLP could be a potential approach for stromal-targeted therapy and a novel target for cancer immunotherapy. We previously showed that upregulation of adipocyte enhancer-binding protein 1 (AEBP1) in vascular endothelial cells promotes tumor angiogenesis. In the present study, we aimed to clarify the role of stromal AEBP1/ACLP expression in oral squamous cell carcinoma (OSCC). Immunohistochemical analysis showed that ACLP is abundantly expressed in cancer-associated fibroblasts (CAFs) in primary OSCC tissues and that upregulated expression of ACLP is associated with disease progression. Analysis using CAFs obtained from surgically resected OSCCs showed that the expression of AEBP1/ACLP in CAFs is upregulated by co-culture with OSCC cells or treatment with TGF-β1, suggesting cancer-cell-derived TGF-β1 induces AEBP1/ACLP in CAFs. Collagen gel contraction assays showed that ACLP contributes to the activation of CAFs. In addition, CAF-derived ACLP promotes migration, invasion, and in vivo tumor formation by OSCC cells. Notably, tumor stromal ACLP expression correlated positively with collagen expression and correlated inversely with CD8+ T cell infiltration into primary OSCC tumors. Boyden chamber assays suggested that ACLP in CAFs may attenuate CD8+ T cell migration. Our results suggest that stromal ACLP contributes to the development of OSCCs, and that ACLP is a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Background: HSP60 is a heat shock proteins (HSPs) family member and help mitochondrial protein to fold correctly. Survivin is one of the inhibitors of apoptosis protein family member, which plays a significant part in cancer progression. They were capable of forming HSP60-survivin complexes and involved in the development of various tumors. Methods: The Cancer Genome Atlas (TCGA) database demonstrated that HSP60 and survivin and their correlation on mRNA expression level with OSCC patients. Besides, expression of HSP60 and survivin proteins was studied utilizing immunohistochemistry in tissue microarrays (TMA) in OSCC and in adjacent non-cancerous squamous epithelium (Non-CCSE) tissues. Results: Significantly increased levels of HSP60 and survivin in most cancers compared to normal tissue by pan-cancer analysis. HSP60 and survivin proved a significantly increased expression in OSCC samples compared to Non-CCSE both on mRNA and protein (both P < 0.05). Additionally, elevated HSP60 displayed a positive correlation with survivin in terms of mRNA and protein expression levels (all P < 0.001). Patients with OSCC who had advanced clinical stage or lymph node metastasis (LNM) showed higher HSP60 expression (P = 0.004, P = 0.006, respectively). Higher levels of the proteins HSP60 and survivin were significantly inversely correlated relationship with OSCC patients' overall survival rates in multivariate survival analysis (P = 0.018, P = 0.040). From the above results, overexpression of HSP60 and survivin protein may serve as independent biomarkers predicting poor prognosis in OSCC. Conclusions: Elevated HSP60 and survivin might be served as novel poor prognosis biomarkers for surgically resected OSCC patients. [ABSTRACT FROM AUTHOR]

Hexokinase 2 (HK2), the first glycolytic rate-limiting enzyme, is closely correlated with the occurrence and progression of tumors. Effective therapeutic agents targeting HK2 are urgently needed. Bergenin has exhibited various pharmacological activities, such as antitumor properties. However, the effects of bergenin on the abnormal glucose metabolism of cancer cells are yet unclear. In this study, HK2 was overexpressed in OSCC tissues, and the depletion of HK2 inhibited the growth of OSCC cells in vitro and in vivo. Moreover, these results showed that the natural compound, bergenin, exerted a robust antitumor effect on OSCC cells. Bergenin inhibited cancer cell proliferation, suppressed glycolysis, and induced intrinsic apoptosis in OSCC cells by downregulating HK2. Notably, bergenin restored the antitumor efficacy of irradiation in the radioresistant OSCC cells. A mechanistic study revealed that bergenin upregulated the protein level of phosphatase and the tensin homolog deleted on chromosome 10 (PTEN) by enhancing the interaction between PTEN and ubiquitin-specific protease 13 (USP13) and stabilizing PTEN; this eventually inhibited AKT phosphorylation and HK2 expression. Bergenin was identified as a novel therapeutic agent against glycolysis to inhibit OSCC and overcome radioresistance. Targeting PTEN/AKT/HK2 signaling could be a promising option for clinical OSCC treatment. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the role and related mechanism of chordin‐like 1 (CHRDL1) in oral squamous cell carcinoma (OSCC). Methods: The expressions of CHRDL1 were analyzed in both mRNA and protein levels by bioinformatics analysis, immunohistochemistry, and fluorescence in situ hybridization in OSCC. Survival analysis was used to determine the relationship between CHRDL1 and prognosis. In addition, enrichment analysis was used to suggest signal pathways involved in CHRDL1. Besides, the relationships between CHRDL1 and miRNAs, hypoxia, and immune infiltration were explored. Results: The mRNA level of CHRDL1 in OSCC was significantly lower than that in normal tissues, while the protein level was significantly higher than that in normal tissues. The high mRNA levels of CHRDL1 suggested a poor prognosis in patients with OSCC. The enrichment results showed that CHRDL1 might be involved in the Calcium signaling pathway, dilated cardiomyopathy, and focal adhesion. 7 immune cells were positively correlated with CHRDL1, while Tgd was negatively correlated with CHRDL1. In addition, we also found that hsa‐miR‐455‐3p directly targeted CHRDL1 and reduced the mRNA levels of CHRDL1. Conclusion: CHRDL1 plays a vital role in promoting cancer in OSCC and is down‐regulated at the mRNA levels by hsa‐miR‐455‐3p. [ABSTRACT FROM AUTHOR]

Objective: Tumor‐stroma ratio (TSR) is a promising parameter representing the abundance of the stroma which has been validated in many solid tumors. However, it is still not clear which part of stroma mainly contribute to the prognostic value of TSR. The aim of this study is to confirm the prognostic value of TSR in a large cohort of oral squamous cell carcinoma (OSCC) and further demonstrated that cancer‐associated fibroblasts (CAFs)‐stroma ratio (CSR) contributed to the prognostic value of TSR. Materials and methods: TSR was evaluated on hematoxylin and eosin stained tissue samples from 581 patients with OSCC, which divides patients into high (>50%) and low (<50%) stroma. Then, CSR was estimated on immunohistochemical staining slides of 100 patients selected from 581 patients. Results: In multivariate analysis, TSR was identified as an independent prognostic factor for disease‐free survival (DFS) (p < 0.001) and oral cancer‐specific survival (OCSS) (p < 0.001). The interaction term reached statistical significance for histological grade for DFS and OCSS separately. Furthermore, the high‐stroma group had a higher CSR than the low‐stroma group. Conclusion: The prognostic value of TSR is validated in OSCC particularly in moderate and high differentiation, and CSR plays its part in the prognosis of TSR. [ABSTRACT FROM AUTHOR]

Background and Aim: Head-and-neck cancers (HNCs) are significant causes of morbidity and mortality in both the developed and developing worlds. One of the most common types of HNC is oral squamous cell carcinoma (OSCC). The rationale behind the present study is to analyze the effectiveness of nuclear proliferative markers in comparison to the various grades of OSCC. This study utilizes Anneroth's histopathological multifactorial grading system for squamous cell carcinoma and further tends to compare this histological grading with nuclear proliferative indices of p53 and argyrophilic nucleolar organizer region (AgNOR). The aim of this study was to establish and develop a correlation between the proliferative markers, AgNOR and p53, and the histologic grade of the tumor (Anneroth's grading). Materials and Methods: A total of 60 cases of oral squamous cell carcinoma were taken from October 2020 to September 2022. The histological grading was done according to Anneroth's grading, and a score was given. P53 expression was graded according to the percentage of cells showing p53-positive immunostaining, and scoring was done from 0 to 3. The AgNOR score was calculated by examining 100 nuclei and calculating the mean AgNOR score per nucleus. Results: A significant linear correlation was obtained between the histological grading of OSCC and the proliferative markers (p53 and AgNOR). Conclusion: The analysis of the NOR count provides invaluable assistance in determining tumor aggressiveness and cellular proliferation rates. They can prove to be efficient tools to procure information on the malignant potential of different premalignant lesions. Elevated p53 expression implies greater clinical severity, a higher histological grade, and a poor prognosis for oral squamous cell carcinoma. Hence, the proliferative markers can be used as adjuncts to the histological grading system of OSCC. [ABSTRACT FROM AUTHOR]

Oncocytic carcinoma (OC) is a pretty rare malignant neoplasm. Oncocytic carcinomas mainly occur in major salivary glands but infrequently occur in minor salivary glands. We report a case of OC occurring in the retromolar glands involving the ipsilateral tonsil, which has not been reported in the English literature. This case may expand the database of OC, and provide diagnosis and treatment ideas for clinicians. [ABSTRACT FROM AUTHOR]