The Role of Interferon-γ-Induced Granzyme B in Enhancing Antitumour Immune Responses in Oral Squamous Cell Carcinoma.

Although mucins are generally linked to aggressive tumor behavior and poor clinical outcomes, the role of MUC21 in oral squamous cell carcinoma (OSCC) remains unexplored. Previous in vitro studies suggest that MUC21 may inhibit cancer cell adhesion, indicating its potential significance in OSCC pathogenesis. We analyzed microarray data from 10 OSCC tissues and paired adjacent normal tissues (para-OSCC), along with GEO and TCGA RNA-seq datasets, to identify differentially expressed genes, including MUC21. qRT-PCR was performed to validate MUC21 expression and its co-expressed epithelial differentiation-related genes. Additionally, immunohistochemistry (IHC) on 102 paired OSCC/para-OSCC samples assessed the correlation between MUC21 expression and clinical outcomes. In vitro functional assays (CCK-8, wound healing, Transwell) were conducted using OSCC cell lines (CAL27, HN6) with MUC21 overexpression or knockdown. MUC21 was significantly downregulated in OSCC compared to normal tissue, supported by high-throughput datasets, qRT-PCR, and IHC. We identified 11 co-expressed genes, including epithelial differentiation markers (KRT4, KRT13, CRNN), which were further validated. Low MUC21 expression correlated with pathological lymph node metastasis, poor tumor differentiation, and reduced survival. Furthermore, MUC21 Knockdown significantly increased cell proliferation, migration and invasion in OSCC cell lines and vice versa. MUC21 downregulation is associated with reduced epithelial differentiation, increased clinical aggressiveness, and worse prognosis in OSCC. MUC21 may serve as a novel prognostic biomarker and tumor suppressor gene in OSCC.

BackgroundTumor necrosis factor receptor superfamily member (10B TNFRSF10B), as a key apoptosis regulator of Oral Squamous Cell Carcinoma (OSCC), exerts a critical effect on its development.MethodsDifferentially expressed genes in OSCC (GSE25099) were screened first. Weighted gene co-expression network analysis identified gene modules, followed by Lasso regression and Cox modeling to pinpoint pivotal genes. Expression was validated in the Cancer Genome Atlas databases and in clinical samples. The Search Tool for the Retrieval of Interacting Genes/Proteins database was used to generate a protein-protein interaction (PPI) network, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses explored biological functions. Then, for in vitro assays, core gene-targeted siRNAs were introduced into SCC-4 and SCC-9 cell lines to mediate gene knockdown. Cell proliferation was quantified by the CCK-8 method, and apoptotic activity was assessed via flow cytometry, TUNEL staining, and Western blotting for apoptosis-associated proteins.ResultsAmong the 10 core genes that were further screened, TNFRSF10B was most notably linked to unfavorable OSCC prognosis and showed strong diagnostic power. Additionally, its overexpression was associated with clinical stage, nodal metastasis, and chemoresistance. PPI and enrichment analyses revealed its role in extrinsic and necroptotic apoptosis. Moreover, the knockdown of TNFRSF10B suppressed viability and induced apoptosis by upregulating Bax, downregulating Bcl-2, and activating Caspase-3/PARP.ConclusionsTNFRSF10B drives OSCC progression by impairing apoptosis. Its overexpression correlates with poor prognosis and represents a potential diagnostic and therapeutic target. Furthermore, targeting TNFRSF10B may restore apoptosis, thus making precision therapy achievable.

Background & aim:Oral squamous cell carcinoma (OSCC) is a devastating disease with poor prognosis and low survival rates, despite advancements in diagnosis and treatment. Early detection and identification of molecular targets are crucial for improving patient outcomes. This study aims to identify differentially expressed genes (DEGs) and key molecular pathways involved in the OSCC. This study’s findings will contribute to the development of effective targeted therapies, ultimately improving the prognosis and survival rates of OSCC patients.Materials & methods:Three gene expression profiles (GSE37991, GSE30784, and GSE107591) from the GEO database were analyzed for differentially expressed genes using EnrichR. Subsequent downstream analyses of the selected module genes were conducted using various bioinformatics tools including STRING, Cytoscape, GEPIA, cBioPortal, NetworkAnalyst, MirWalk, and a bipartite miRNA-mRNA correlation network.Result:The reanalysis indicated that the Toll-like receptor (TLR) signaling pathway plays a significant role in the development of oral SCC and CXCL8, CCL5, CXCL10, STAT1, IL1B, and TLR2 genes were up-regulated and enriched significantly in the signaling pathways’ interactions in oral SCC. Genetic mutation analysis of hub genes in OSCC revealed that STAT1 have 2.5% mutation rate and 0% for other genes. It was revealed that the development and prediction of OSCC may be affected by hsa-mir-146a-5 and hsa-mir-155-5p.Conclusion:Novel potential biomarkers and signaling pathways associated with OSCC have been identified, which may be important in the transformation of OSCC adenocarcinoma and may serve as therapeutic targets for OSCC.

Bisphenol A (BPA), an environmental pollutant, has been implicated in oral squamous cell carcinoma (OSCC) progression, yet its molecular mechanisms remain unclear. This study explores the role of GABBR1 in BPA-induced OSCC malignancy. Bioinformatics analysis identified GABBR1 as a key gene in OSCC. Expression patterns and clinical relevance were assessed using TCGA, GTEx, and HPA databases. Molecular docking and dynamics simulations further elucidated the binding interaction between BPA and GABBR1. Functional assays, including western blot, immunofluorescence, CCK-8, EdU, and transwell evaluated the effects of BPA exposure and GABBR1 knockdown on OSCC cell function. Transwell co-culture, RT-PCR and ELISA assays examined exosome-mediated interactions between OSCC cells and macrophages. BPA exposure enhanced OSCC proliferation, migration, and invasion while promoting stemness through the GABBR1/MEK/ERK signaling pathway. Additionally, it induced M2 macrophage polarization via exosomal communication, contributing to an immunosuppressive microenvironment. This study uncovers a novel mechanism by which BPA promotes OSCC progression via GABBR1-mediated signaling and exosome-driven immunomodulation, highlighting GABBR1 as a potential therapeutic target in BPA-associated OSCC.

Oral squamous cell carcinoma (OSCC), a subset of head and neck cancers, primarily originates in the epithelial tissues of the oral cavity. Despite advancements in treatment, the mortality rate for OSCC remains around 50%, underscoring the urgent need for improved prognostic markers. This review explores the role of the BRCA1 and BRCA2 genes-traditionally associated with breast and ovarian cancers-in the context of OSCC. We discuss the molecular pathways involving BRCA genes, their potential as diagnostics and prognostic biomarkers, and their implications for personalized treatment strategies, including addressing chemotherapy resistance. Furthermore, this review emphasizes the significance of genome stability in cancer progression and examines both current and emerging methodologies for detecting BRCA mutations in OSCC patients. Despite limited prevalence of BRCA mutations in OSCC compared to other cancers, their role in DNA repair and therapeutic response underscores their potential as clinical biomarkers. However, standardized, multicenter studies are still needed to validate their utility in OSCC management. A better understanding of the role of BRCA genes in OSCC could pave the way for more effective therapeutic approaches and improved patient outcomes.

Oral squamous cell carcinoma (OSCC) is the eighth leading cause of cancer-related death worldwide. JAK2 and STAT3 primarily influence intrinsic tumor cell behavior, and CTLA4 impacts the interplay between the tumor and the host immune system in the context of cancers. There is scarce information regarding the involvement and roles of JAK2, STAT3, and CTLA4 genes in OSCC; however, the molecular mechanisms are still unclear. This study examined the relationship between JAK2, STAT3, and CTLA4 gene expression levels and OSCC in a group of patients in the southeast of Iran. This cross-sectional study was conducted in which the relative gene expression levels of JAK2, STAT3, and CTLA4 were compared between 23 oral paraffin tissue blocks collected from OSCC patients and 20 fresh gingival tissues collected from healthy individuals. The Real-Time quantitative PCR (RT-qPCR) assay was employed to assess relative gene expression levels. SPSS 27 was employed to perform statistical analyses. Significant differences were found between OSCC patients and healthy individuals concerning gene expression levels of JAK2 (2.4-fold, p< 0.0001), STAT3 (2.32-fold, p< 0.0001), and CTLA4 (4.09-fold, p< 0.0001). Additionally, there were significant positive correlations among JAK2-STAT3 (ρ= 0.667, p< 0.001), JAK2-CTLA4 (ρ= 0.771, p< 0.001), and STAT3-CTLA4 (ρ= 0.635, p= 0.001) co-expressions. Moreover, gender, age groups, and tumor locations did not significantly correlate with the expression levels of these genes (p> 0.05). Nevertheless, significant differences occurred between histopathological grades and the gene expression levels of JAK2 (p< 0.001), STAT3 (p= 0.001), and CTLA4 (p< 0.001). The overexpression of JAK2, STAT3, and CTLA4 can be considered triggers for OSCC development. It may be beneficial to conduct future research on OSCC by considering downstream genes involved in the JAK2/STAT3/CTLA4 axis.

Background:Oral squamous cell carcinoma (OSCC) remains a significant global health burden, with early detection being critical for improving outcomes. Aberrant DNA methylation of tumour suppressor genes has emerged as a promising biomarker for early oral carcinogenesis. This study investigates the methylation status of p16, DAPK, and MGMT genes in OSCC, leukoplakia, and adjacent normal tissues.Methods:Tissue samples from 18 patients were collected from a single contiguous field, including clinically normal mucosa, leukoplakia, and OSCC lesions. DNA was extracted and subjected to bisulfite conversion followed by methylation-specific PCR (MS-PCR). Methylation patterns were analysed for frequency, statistical association (Chi-square), and diagnostic performance (sensitivity and specificity).Results:DAPK showed progressive and statistically significant promoter methylation from normal to OSCC (P = 0.0021), with 100% sensitivity and 50% specificity. MGMT exhibited consistently high methylation across all stages but low specificity (16.67%), while p16 displayed highest methylation in leukoplakia, suggesting early involvement but limited diagnostic power. Only DAPK demonstrated a significant association with disease progression.Conclusion:Among the three genes studied, DAPK emerged as a reliable biomarker for early OSCC detection. The findings support its integration into methylation-based screening panels, while MGMT and p16 may serve as complementary markers. Further large-scale studies are recommended to validate their clinical utility.

Homeobox A5 (HOXA5) has been identified as a tumor suppressor gene in breast cancers, but its role in oral squamous cell carcinoma (OSCC) has not been confirmed. The Illumina GoldenGate Assay for methylation identified that DNA methylation patterns differ between tumorous and normal tissues in the oral cavity and that HOXA5 is one of the genes that are hypermethylated in oral tumor tissues. The present study obtained more-complete information on the methylation status of HOXA5 by using the Illumina Infinium MethylationEPIC BeadChip and bisulfite sequencing assays. The results indicated that HOXA5 hypermethylation has great potential as a biomarker for detecting OSCC. Comparing HOXA5 RNA expression between normal oral tissue and OSCC tissue samples indicated that its median level was 2.06-fold higher in normal tissues that in OSCC tissues. Moreover, treatment using the demethylating agent 5-aza-2′-deoxycytidine can upregulate HOXA5 expression in OSCC cell lines, verifying that the silencing of HOXA5 is primarily regulated by its hypermethylation. It was also found that upregulation of HOXA5 expression can not only increase OSCC cell death but that it can also enhance the therapeutic effect of cisplatin both in vitro and in vivo, suggesting that HOXA5 is an epigenetically downregulated proapoptotic gene in OSCC.

TNO155 is a selective SHP2 inhibitor to target PTPN11-dependent oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is an aggressive disease whose incomplete biological comprehension contributes to the inappropriate clinical management and poor prognosis. Thus, the identification of new promising molecular targets to treat OSCC is of paramount importance. Ferroptosis is a regulated cell death caused by the iron-dependent accumulation of reactive oxygen species and the consequent oxidative damage of lipid membranes. Over the last five years, a growing number of studies has reported that OSCC is sensitive to ferroptosis induction and that ferroptosis inducers exert a remarkable antitumor effect in OSCC, even in those displaying low response to common approaches, such as chemotherapy and radiotherapy. In addition, as ferroptosis is considered an immunogenic cell death, it may modulate the immune response against OSCC. In this review, we summarize the so far identified ferroptosis regulatory mechanisms and prognostic models based on ferroptosis-related genes in OSCC. In addition, we discuss the perspective of inducing ferroptosis as a novel strategy to directly treat OSCC or, alternatively, to improve sensitivity to other approaches. Finally, we integrate data emerging from the research studies, reviewed here, through in silico analysis and we provide a novel personal perspective on the potential interconnection between ferroptosis and autophagy in OSCC.

Oral squamous cell carcinoma (OSCC) is a frequently occurring malignancy in the head and neck region. The most commonly mutated gene in OSCC is the tumor suppressor gene p53 (TP53), linked to lower survival and treatment resistance in OSCC patients. Astilbin is a flavonoid amongst several herbal treatments with a variety of pharmacological actions mainly including antioxidant, anti-inflammatory, and anti-cancer characteristics. This study evaluated the effects of astilbin on proliferation of OSCC cell lines SCC90 and SCC4 (bearing a p53 mutation) in relevance to p53 and Mdm-2 pathways. Astilbin inhibited the proliferation of SCC4 and SCC90 cells in a dose- and time-dependent manner. The IC50 values for both the cell lines were about 75 μM for astilbin. A p53 activator (RITA) was used to determine the effects of astilbin on p53 activity, and the results demonstrated synergistic reduction in cell growth. However, when combined with pifithrin-α (a p53 inhibitor), astilbin demonstrated a strong inhibition of its response. Astilbin reduced the mitochondrial membrane potential in SCC4 cells, which is a sign of apoptotic activity. Astilbin decreased the amounts of Mdm-2 (negative regulator of p53) and increased the expression of the p53 gene and protein. In a p53-dependent manner, astilbin suppressed the ability of SCC4 cells to form colonies and heal wounds. This was followed by the induction of mitochondrial intrinsic apoptosis via the activation of caspases 9 and 3, cleavage of PARP, and the suppression of pro-apoptotic Bid. Astilbin-induced p53-mediated apoptosis in OSCC cells as herbal medicinal ingredients.

Hsa_circRNA_101036 aggravates hypoxic-induced endoplasmic reticulum stress via the miR-21-3p/TMTC1 axis in oral squamous cell carcinoma

The association between Porphyromonas gingivalis infection and oral squamous cell carcinoma (OSCC) has been established by numerous epidemiological studies. However, the underlying mechanism specific to this connection remains unclear. By bioinformatical analysis, we identified ZFP36 as a potentially significant co‐expressed gene in both the OSCC gene database and the persistent infection model of P. gingivalis. To further investigate the role of ZFP36, we established a cell model that human immortalized oral epithelial cells (HIOECs) that were sustainedly infected by P. gingivalis (MOI = 1) for a duration of 30 weeks. Our findings indicated that sustained infection with P. gingivalis inhibited the expression of ZFP36 protein and induced changes in the biological behaviour of HIOECs. The mechanism investigation demonstrated the potential role of ZFP36 in regulating the cancer‐related biological behaviour of HIOECs. Subsequent studies revealed that highly expressed CCAT1 could serve as a molecular scaffold in the formation of the ZFP36/CCAT1/MK2 complex. This complex formation enhanced the binding abundance of MK2 and ZFP36, thereby promoting the inhibition of ZFP36 protein phosphorylation. To summarize, low expression of ZFP36 protein under persistent P. gingivalis infection enhances the cancer‐related biological behaviour of HIOECs.

DDX27 regulates oral squamous cell carcinoma development through targeting CSE1L

Abstract Background Oral squamous cell carcinoma (OSCC) represents a prevalent malignancy in the oral and maxillofacial area, having a considerable negative impact on both the quality of life and overall survival of affected individuals. Our research endeavors to leverage bioinformatic approaches to elucidate oncogenic signaling pathways, with the ultimate goal of gaining deeper insights into the molecular underpinnings of OSCC pathogenesis, and thus laying the groundwork for the development of more effective therapeutic and preventive strategies. Methods Differential expression analysis was performed on mRNA data from tumor and normal tissue groups to identify genes associated with OSCC, using The Cancer Genome Atlas database. Predictions of oncogenic signaling pathways linked to differentially expressed mRNAs were made, and these results were presented visually using R software, using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichments. Results GO and KEGG analyses of 2938 differentially expressed genes in OSCC highlighted their significant involvement in various biological processes. Notably, these processes were related to the extracellular matrix, structural organization, connective tissue development, and cell cycle regulation. Conclusions The comprehensive exploration of gene expression patterns provides valuable insights into potential oncogenic mechanisms in OSCC.

Oral squamous cell carcinoma (OSCC) is one of the most common squamous cell carcinomas of the head and neck. The morbidity and mortality rates of OSCC have increased in recent years. However, the pathogenesis of this disease remains unknown. The present study aimed to identify predictive biomarkers and therapeutic targets for OSCC. Bioinformatics screening of differentially expressed genes in OSCC was performed based on data from The Cancer Genome Atlas and Gene Expression Omnibus databases. Dickkopf Wnt signaling pathway inhibitor 1 (DKK1) was identified to be associated with survival, tumor immunity and DNA repair in OSCC. Furthermore, the effects of DKK1 were evaluated by the knockdown of DKK1 in two OSCC cell lines. The proliferation, clonogenicity, migration and invasion of the cells were assessed in vitro using Cell Counting Kit-8, colony formation, wound healing and Transwell assays, respectively, and were found to be inhibited by DKK1 knockdown. The present study suggests that DKK1 may be used in the prognosis of patients with OSCC and that targeting DKK1 is a potential strategy for OSCC therapy.

ObjectiveNowadays, many studies focus on the relationship between microRNAs (miRs) and the development of oral squamous cell carcinoma (OSCC). Here, we broaden the understanding of miR-30a-5p in OSCC. MethodsIn silico analysis was implemented to screen differentially expressed genes in OSCC and the related upstream regulatory miR. OSCC SCC9 cells were manipulated with lentivirus-mediated miR-30a-5p mimic, oe-ITGA6 or sh-ITGA6 and LY294002 (the PI3K/AKT pathway inhibitor) for studying their roles in cell biological processes. Tumors were xenografted in nude mouse for in vivo mechanism verification. ResultsIn silico analysis results depicted that ITGA6 was highly expressed in OSCC, and that miR-30a-5p was the upstream regulatory miR of ITGA6. miR-30a-5p was downregulated and ITGA6 was highly expressed in OSCC tissues and cells. miR-30a-5p targeted and downregulated ITGA6. ITGA6 promoted epithelial-mesenchymal transition, migration and invasion in OSCC cells by activating PI3K/AKT pathway. miR-30a-5p could suppress the in vivo growth and metastasis of OSCC by inhibiting the ITGA6/PI3K/AKT axis. ConclusionTaken together, miR-30a-5p prevents OSCC progression by inhibiting PI3K/AKT pathway through inhibition of ITGA6 expression.

ObjectiveThe sequencing panel composed of 61 target genes was used to explore the related mutation genes of oral squamous cell carcinoma (OSCC) and oral submucous fibrosis (OSF) cancerization, so as to provide a theoretical basis for the early diagnosis of oral submucous fibrosis cancerization, find the most important mutations in OSF cancerization, and more targeted prevention of OSF cancerization.MethodsA total of 74 clinically diagnosed samples were included, including 36 cases of OSCC and 38 cases of OSF cancer patients. DNA was extracted, and targeted gene panel sequencing technology was used to analyze the gene frequency of pathogenic mutation sites in clinical samples.ResultsGene panel sequencing analysis showed that there were 69 mutations in 18 genes in OSCC and OSF cancerous specimens. The results of gene panel sequencing were screened, and 18 mutant genes were finally screened out and their mutation frequencies in the samples were analyzed. According to the frequency of gene mutations from high to low, they were TP53, FLT4, PIK3CA, CDKN2A, FGFR4, HRAS, BRCA1, PTPN11, NF1, KMT2A, RB1, PTEN, MSH2, MLH1, KMT2D, FLCN, BRCA2, APC. The mutation frequency of FLT4 gene was significantly higher than that of OSCC group (P < 0.05).ConclusionFLT4 gene may be related to OSF cancerization and is expected to be an early diagnostic biomarker for OSF cancerization.

This study explores the effects of curcumin as a therapeutic agent against oral squamous cell carcinoma (OSCC). We acquired the targets of curcumin from three digital databases, including the Comparative Toxicogenomics Database, Search Tool for Interactions of Chemicals, and SwissTargetPrediction. Then, we identified the differentially expressed genes (DEGs) and the weighted gene coexpression network analysis-based key modules using the expression profiles of GSE23558 to acquire the OSCC-related genes. Additionally, the GeneCards and Online Mendelian Inheritance in Man databases were also used to identify the OSCC-related genes. Finally, curcumin-OSCC interaction genes were obtained by overlapping curcumin targets and OSCC-related genes. The enrichment analysis was performed by the ClusterProfiler algorithm and Metascape, respectively. Then, a protein-protein interaction network was created, and the maximal clique centrality algorithm was used to identify the top 10 hub genes. Besides, we examined the expression levels of hub genes in OSCC using The Cancer Genome Atlas database. 927 DEGs were identified, including 308 upregulated ones and 619 downregulated ones. The cluster one-step network construction function of the WGCNA algorithm recognized a soft-thresholding power of 6, and 9083 genes were acquired. 2591 OSCC-related genes were obtained by overlapping the GSE23558-identified genes and the OSCC-related genes from disease target bases. Finally, we identified 70 candidate drug-disease interaction genes by overlapping the disease-related genes with the curcumin target. The enrichment analysis suggested that response to oxidative stress, epithelial cell proliferation, and AGE/RAGE pathway might involve in the effect of curcumin on OSCC. The topologic study identified the ten hub genes, including VEGFA, AKT1, TNF, HIF1A, EGFR, JUN, STAT3, MMP9, EGF, and MAPK3. A significant difference was observed in VEGFA, AKT1, TNF, HIF1A, EGFR, MMP9, EGF, and MAPK3 expression levels between head and neck squamous cell carcinoma and the normal controls. However, no significant difference was observed in JUN (P = 0.14) and STAT3 (P = 0.054). This study provided an overview and basis for the potential mechanism of curcumin against OSCC. The following experiments should be performed to further understand the effectiveness and safety of curcumin in treating OSCC.