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Oral squamous cell carcinoma (OSCC) is the most prevalent malignancy among the Head and Neck cancer. OSCCs are highly inflammatory, immune-suppressive, and aggressive tumors. Recent sequencing based studies demonstrated the involvement of different oral microbiota in oral cavity diseases leading OSCC carcinogenesis, initiation and progression. Researches showed that oral microbiota can activate different inflammatory pathways and cancer stem cells (CSCs) associated stemness pathways for tumor progression. We speculate that CSCs and their niche cells may interact with the microbiotas to promote tumor progression and stemness. Certain oral microbiotas are reported to be involved in dysbiosis, pre-cancerous lesions, and OSCC development. Identification of these specific microbiota including Human papillomavirus (HPV), Porphyromonas gingivalis (PG), and Fusobacterium nucleatum (FN) provides us with a new opportunity to study the bacteria/stem cell, as well as bacteria/OSCC cells interaction that promote OSCC initiation, progression and stemness. Importantly, these evidences enabled us to develop in-vitro and in-vivo models to study microbiota interaction with stem cell niche defense as well as CSC niche defense. Thus in this review, the role of oral microbiota in OSCC has been explored with a special focus on how oral microbiota induces OSCC initiation and stemness by modulating the oral mucosal stem cell and CSC niche defense.

The CD169+ macrophages in lymph nodes are implicated in cytotoxic T lymphocyte (CTL) activation and are associated with improved prognosis in several malignancies. Here, we investigated the significance of CD169+ macrophages in oral squamous cell carcinoma (OSCC). Further, we tested the anti-tumor effects of naringenin, which has been previously shown to activate CD169+ macrophages, in a murine OSCC model. Immunohistochemical analysis for CD169 and CD8 was performed on lymph node and primary tumor specimens from 89 patients with OSCC. We also evaluated the effects of naringenin on two murine OSCC models. Increased CD169+ macrophage counts in the regional lymph nodes correlated with favorable prognosis and CD8+ cell counts within tumor sites. Additionally, naringenin suppressed tumor growth in two murine OSCC models. The mRNA levels of CD169, interleukin (IL)-12, and C-X-C motif chemokine ligand 10 (CXCL10) in lymph nodes and CTL infiltration in tumors significantly increased following naringenin administration in tumor-bearing mice. These results suggest that CD169+ macrophages in lymph nodes are involved in T cell-mediated anti-tumor immunity and could be a prognostic marker for patients with OSCC. Moreover, naringenin is a new potential agent for CD169+ macrophage activation in OSCC treatment.

Background: Microbial dysbiosis and microbiome-induced inflammation have emerged as important factors in oral squamous cell carcinoma (OSCC) tumorigenesis during the last two decades. However, the “rare biosphere” of the oral microbiome, including fungi, has been sparsely investigated. This study aimed to characterize the salivary mycobiome in a prospective Sudanese cohort of OSCC patients and to explore patterns of diversities associated with overall survival (OS).Materials and Methods: Unstimulated saliva samples (n = 72) were collected from patients diagnosed with OSCC (n = 59) and from non-OSCC control volunteers (n = 13). DNA was extracted using a combined enzymatic–mechanical extraction protocol. The salivary mycobiome was assessed using a next-generation sequencing (NGS)-based methodology by amplifying the ITS2 region. The impact of the abundance of different fungal genera on the survival of OSCC patients was analyzed using Kaplan–Meier and Cox regression survival analyses (SPPS).Results: Sixteen genera were identified exclusively in the saliva of OSCC patients. Candida, Malassezia, Saccharomyces, Aspergillus, and Cyberlindnera were the most relatively abundant fungal genera in both groups and showed higher abundance in OSCC patients. Kaplan–Meier survival analysis showed higher salivary carriage of the Candida genus significantly associated with poor OS of OSCC patients (Breslow test: p = 0.043). In contrast, the higher salivary carriage of Malassezia showed a significant association with favorable OS in OSCC patients (Breslow test: p = 0.039). The Cox proportional hazards multiple regression model was applied to adjust the salivary carriage of both Candida and Malassezia according to age (p = 0.029) and identified the genus Malassezia as an independent predictor of OS (hazard ratio = 0.383, 95% CI = 0.16–0.93, p = 0.03).Conclusion: The fungal compositional patterns in saliva from OSCC patients were different from those of individuals without OSCC. The fungal genus Malassezia was identified as a putative prognostic biomarker and therapeutic target for OSCC.

The tumour-associated microbiota is an intrinsic component of the tumour microenvironment across human cancer types 1 , 2 . Intratumoral host–microbiota studies have so far largely relied on bulk tissue analysis 1 – 3 , which obscures the spatial distribution and localized effect of the microbiota within tumours. Here, by applying in situ spatial-profiling technologies 4 and single-cell RNA sequencing 5 to oral squamous cell carcinoma and colorectal cancer, we reveal spatial, cellular and molecular host–microbe interactions. We adapted 10x Visium spatial transcriptomics to determine the identity and in situ location of intratumoral microbial communities within patient tissues. Using GeoMx digital spatial profiling 6 , we show that bacterial communities populate microniches that are less vascularized, highly immuno‑suppressive and associated with malignant cells with lower levels of Ki-67 as compared to bacteria-negative tumour regions. We developed a single-cell RNA-sequencing method that we name INVADEseq (invasion–adhesion-directed expression sequencing) and, by applying this to patient tumours, identify cell-associated bacteria and the host cells with which they interact, as well as uncovering alterations in transcriptional pathways that are involved in inflammation, metastasis, cell dormancy and DNA repair. Through functional studies, we show that cancer cells that are infected with bacteria invade their surrounding environment as single cells and recruit myeloid cells to bacterial regions. Collectively, our data reveal that the distribution of the microbiota within a tumour is not random; instead, it is highly organized in microniches with immune and epithelial cell functions that promote cancer progression. Spatial profiling and single-cell RNA sequencing are used to map the spatial distribution of the microbiota within human tumours, revealing how intratumoral microbial communities contribute to tumour heterogeneity and cancer progression.

Oral potentially malignant disorders (OPMDs) are oral mucosal conditions associated with an increased risk of oral squamous cell carcinoma (OSCC), and their clinical manifestations may be subtle and insidious. The primary aim of this study was to identify metabolite-based biomarkers for early, non-invasive detection of tumor-related metabolic signals in this at-risk population. We enrolled 21 OPMD and 46 OSCC patients, collecting saliva and plasma from all participants and tissue samples from a subset of the same cohort (12 OPMD and 5 OSCC). Untargeted metabolomics identified 491 and 303 differential metabolites in saliva and plasma, respectively. Five metabolites—dodecanoic acid, tetradecanedioic acid, porphobilinogen, uridine, and isocitrate—were significantly altered in both biofluids. Tissue validation showed significant alterations in dodecanoic acid, tetradecanedioic acid, and isocitrate. Using all biologically annotated differential metabolites, AUCs were 0.888 (saliva) and 0.994 (plasma), while the tissue-anchored three-metabolite classifier yielded 0.694 (saliva) and 0.852 (plasma). Full-length 16S rDNA sequencing and integrative microbiome–metabolome analysis indicated potential correlations between microbial shifts and metabolite profiles. Our findings highlight metabolic alterations and cross-compartment associations across saliva, plasma, and tissue in OPMDs and OSCC. Notably, despite the higher internal discrimination of all-differential models, the tumor-informed three-metabolite model captures tissue-aligned metabolic changes detectable in saliva and plasma, providing a specific, non-invasive readout for early detection.

Malignant transformation of oral precancerous lesions is a multistep process intricately linked to the disruption of epithelial cell polarity and activation of the epithelial–mesenchymal transition (EMT) program. This study provides an integrated analysis of the polarity regulators PAR3, SCRIBBLE, and DLG7, elucidating their differential expression across normal oral mucosa (NOM), oral epithelial dysplasia (OED), and oral squamous cell carcinoma (OSCC). By combining histopathological evaluation, immunohistochemical profiling, and whole-transcriptome sequencing, this work offers novel insights into polarity disruption as a driving mechanism in oral tumorigenesis. Formalin-fixed, paraffin-embedded (FFPE) tissue specimens were obtained from 50 habitual tobacco users from West Bengal, India. Sections were stained with hematoxylin and eosin (H&E) for histopathological assessment and classification into normal oral mucosa (NOM), oral epithelial dysplasia (OED), and oral squamous cell carcinoma (OSCC) (well- and moderately-differentiated grades). Immunohistochemical (IHC) analysis was conducted to evaluate the expression and localization patterns of the polarity-associated proteins PAR3, SCRIBBLE, and DLG7. Complementing this, whole-transcriptome RNA sequencing was performed on biopsy specimens from an independent cohort of 25 oral cancer patients exhibiting both OED and OSCC lesions, enabling comparative gene expression profiling of the same polarity regulators. Statistical analysis using IBM SPSS (version 20.0) and Chi-square testing revealed a significant reduction or complete loss of PAR3, SCRIBBLE, and DLG7 expression in both oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC), compared to their moderate to strong expression in normal oral mucosa (NOM). This study reveals a striking decline in epithelial polarity protein expression from normal oral mucosa (NOM) to oral epithelial dysplasia (OED), followed by a modest resurgence in oral squamous cell carcinoma (OSCC). The strong concordance between immunohistochemical and transcriptomic profiles—with the exception of DLG7—highlights the disruption of cell polarity as an early and central molecular event in oral carcinogenesis. Collectively, the polarity regulators PAR3, SCRIBBLE, and DLG7 emerge as promising biomarkers for early malignant transformation in oral potentially malignant disorders (OPMDs) and as potential modulators of tumor initiation, progression, and invasive behavior.

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

Oral squamous cell carcinoma (OSCC) develops on the mucosal epithelium of the oral cavity. It accounts for approximately 90% of oral malignancies and impairs appearance, pronunciation, swallowing, and flavor perception. In 2020, 377,713 OSCC cases were reported globally. According to the Global Cancer Observatory (GCO), the incidence of OSCC will rise by approximately 40% by 2040, accompanied by a growth in mortality. Persistent exposure to various risk factors, including tobacco, alcohol, betel quid (BQ), and human papillomavirus (HPV), will lead to the development of oral potentially malignant disorders (OPMDs), which are oral mucosal lesions with an increased risk of developing into OSCC. Complex and multifactorial, the oncogenesis process involves genetic alteration, epigenetic modification, and a dysregulated tumor microenvironment. Although various therapeutic interventions, such as chemotherapy, radiation, immunotherapy, and nanomedicine, have been proposed to prevent or treat OSCC and OPMDs, understanding the mechanism of malignancies will facilitate the identification of therapeutic and prognostic factors, thereby improving the efficacy of treatment for OSCC patients. This review summarizes the mechanisms involved in OSCC. Moreover, the current therapeutic interventions and prognostic methods for OSCC and OPMDs are discussed to facilitate comprehension and provide several prospective outlooks for the fields.

This study aimed to elucidate the role of glutathione peroxidase 4 (GPX4) on the sterol regulatory element binding proteins (SREBPs)-proliferation pathway in oral cancer cells, and determine its protein expression in oral cancer tissues. Quantitative RT-PCR and immunoblot analysis were carried out. Cell viability assay, apoptosis detection assay, immunohistochemistry and GPX4 knockdown were performed. The levels of both GPX4 mRNA and protein were highest in SAS cells. GPX4 knockdown in SAS cells, a human oral squamous cell carcinoma cell line, using GPX4 siRNA resulted in a reduction in cell number, which appeared to be due to non-apoptotic cell death such as ferroptosis. Furthermore, SREBP was clearly down-regulated by GPX4 knockdown in SAS cells. Immunopositivity for GPX4 was revealed on the membrane of human oral squamous cell carcinoma cells, and this was correlated with p53 immunoreactivity. GPX4 appears to play an important role in oral cancer proliferation.

ObjectivesSurvival for patients with recurrent oral squamous cell carcinoma is usually poor, and the most effective treatment has not yet been clearly defined. The present study evaluates the outcome in radiotherapy-naïve patients after recurrence of oral squamous cell carcinoma with respect to different treatment modalities including surgery, radiation, chemoradiation, and palliative treatment.Patients and methodsIn this retrospective study, we included all patients with primary oral squamous cell carcinoma who received exclusively surgical therapy between 2010 and 2020 and who suffered from locoregional recurrence in their follow-up. Patients with previous adjuvant therapy were excluded from this protocol. Clinical and pathological parameters were collected and statistically evaluated. Survival analysis was performed according to Kaplan–Meier. The primary endpoints were overall and progression-free survival in dependance of treatment strategy for recurrent tumors.ResultsOut of a total of 538 patients with surgically treated primary oral squamous cell carcinoma, 76 patients met the inclusion criteria. The mean follow-up was 38 ± 32 months. Patients who received surgically based therapy had a significantly better outcome in terms of disease-free survival (DFS) and overall survival (OS) (DFS p < 0.001; OS p < 0.001). The presence of regional metastases and a short disease-free interval (DFI) between primary and recurrent cancer were significant predictors for adverse outcomes (DFI p < 0.001).ConclusionWe recommend primary surgical therapy for radiotherapy-naïve patients with recurrent oral squamous cell carcinoma, supplemented by risk-adapted adjuvant therapy.Clinical relevanceSurgical therapy continues to play a central role in the treatment of radiotherapy-naïve patients with recurrent oral squamous cell carcinoma.