RESUMEN
It is still challenging to predict the efficacy of cisplatin-based therapy, particularly in relation to the activation of macroautophagy/autophagy in oral squamous cell carcinoma (OSCC). We studied the effect of selected chromatin remodeling genes on the cisplatin resistance and their interplay with autophagy in 3-dimensional tumor model and xenografts. We analyzed gene expression patterns in the cisplatin-sensitive UMSCC1, and a paired cisplatin-resistant UM-Cis cells. Many histone protein gene clusters involved in nucleosome assembly showed significant difference of expression. Gain- and loss-of-function analyses revealed an inverse correlation between cisplatin resistance and HIST1H3D expression, while a positive correlation was observed with HIST3H2A or HIST3H2B expression. In UM-Cis, HIST3H2A- and HIST3H2B-mediated chromatin remodeling upregulates autophagy status, which results in cisplatin resistance. Additionally, knockdown of HIST3H2A or HIST3H2B downregulated autophagy-activating genes via chromatin compaction of their promoter regions. MiTF, one of the key autophagy regulators upregulated in UM-Cis, negatively regulated transcription of HIST1H3D, suggesting an interplay between chromatin remodeling-dependent cisplatin resistance and autophagy. On comparing the staining intensity between cisplatin-sensitive and -insensitive tissues from OSCC patients, protein expression pattern of the selected histone protein genes were matched with the in vitro data. By examining the relationship between autophagy and chromatin remodeling genes, we identified a set of candidate genes with potential use as markers predicting chemoresistance in OSCC biopsy samples.
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Autofagia , Carcinoma de Células Escamosas , Ensamble y Desensamble de Cromatina , Cisplatino , Resistencia a Antineoplásicos , Neoplasias de la Boca , Cisplatino/farmacología , Cisplatino/uso terapéutico , Humanos , Autofagia/efectos de los fármacos , Autofagia/genética , Resistencia a Antineoplásicos/genética , Ensamble y Desensamble de Cromatina/efectos de los fármacos , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/tratamiento farmacológico , Animales , Línea Celular Tumoral , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ratones , Histonas/metabolismo , Ratones Desnudos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Oral cancer poses a significant health challenge due to limited treatment protocols and therapeutic targets. We aimed to investigate the invasive margins of gingivo-buccal oral squamous cell carcinoma (GB-OSCC) tumors in terms of the localization of genes and cell types within the margins at various distances that could lead to nodal metastasis. METHODS: We collected tumor tissues from 23 resected GB-OSCC samples for gene expression profiling using digital spatial transcriptomics. We monitored differential gene expression at varying distances between the tumor and its microenvironvent (TME), and performed a deconvulation study and immunohistochemistry to identify the cells and genes regulating the TME. RESULTS: We found that the tumor-stromal interface (a distance up to 200 µm between tumor and immune cells) is the most active region for disease progression in GB-OSCC. The most differentially expressed apex genes, such as FN1 and COL5A1, were located at the stromal ends of the margins, and together with enrichment of the extracellular matrix (ECM) and an immune-suppressed microenvironment, were associated with lymph node metastasis. Intermediate fibroblasts, myocytes, and neutrophils were enriched at the tumor ends, while cancer-associated fibroblasts (CAFs) were enriched at the stromal ends. The intermediate fibroblasts transformed into CAFs and relocated to the adjacent stromal ends where they participated in FN1-mediated ECM modulation. CONCLUSION: We have generated a functional organization of the tumor-stromal interface in GB-OSCC and identified spatially located genes that contribute to nodal metastasis and disease progression. Our dataset might now be mined to discover suitable molecular targets in oral cancer.
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Fibroblastos , Regulación Neoplásica de la Expresión Génica , Metástasis Linfática , Neoplasias de la Boca , Células Mieloides , Microambiente Tumoral , Humanos , Neoplasias de la Boca/patología , Neoplasias de la Boca/genética , Metástasis Linfática/patología , Fibroblastos/patología , Fibroblastos/metabolismo , Células Mieloides/patología , Células Mieloides/metabolismo , Fibroblastos Asociados al Cáncer/patología , Fibroblastos Asociados al Cáncer/metabolismo , Perfilación de la Expresión Génica , Femenino , Masculino , Persona de Mediana Edad , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/genéticaRESUMEN
BACKGROUND: Exportin 1 (XPO1) is a nuclear export protein that facilitates the transportation of various substances. XPO1 promotes tumor development as a poor prognostic factor in a variety of tumors and is a therapeutic target for screening inhibitors. However, the role of XPO1 in oral squamous cell carcinoma (OSCC) has yet to be determined. METHODS: The expression patterns of XPO1 mRNA in OSCC were investigated using bioinformatics tools, and the expression levels of XPO1 protein in OSCC specimens were confirmed by immunohistochemical assays. Survival analysis was conducted to evaluate the impact of XPO1 on prognosis. GO and KEGG enrichment analyses were utilized to uncover the signaling pathways mediated by XPO1. Additionally, we examined the association between XPO1 and AKT/MAPK/TGFBR1 and immune infiltration. RESULTS: XPO1 mRNA and protein expression levels were significantly enhanced in OSCC and associated with OSCC severity. Enhanced XPO1 expression was indicative of poor survival. Functional analysis showed that XPO1 mediated pathways associated with cell cycle and DNA replication and reduced immune infiltration in OSCC. Additionally, XPO1 mRNA and protein expression levels had significant positive relationships with AKT/MAPK/TGFBR1. CONCLUSIONS: XPO1, as a marker of poor prognosis in OSCC, can promote OSCC through AKT/MAPK/TGFBR1.
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Biomarcadores de Tumor , Proteína Exportina 1 , Carioferinas , Neoplasias de la Boca , Proteínas Proto-Oncogénicas c-akt , Receptores Citoplasmáticos y Nucleares , Humanos , Carioferinas/metabolismo , Carioferinas/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Pronóstico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Neoplasias de la Boca/patología , Neoplasias de la Boca/genética , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/mortalidad , Masculino , Femenino , Regulación Neoplásica de la Expresión Génica , Transducción de Señal , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/mortalidad , Persona de Mediana EdadRESUMEN
Oral squamous cell carcinoma (OSCC), the most prevalent form of oral cancer, poses significant challenges to the medical community due to its high recurrence rate and low survival rate. Mitochondrial Damage-Related Genes (MDGs) have been closely associated with the occurrence, metastasis, and progression of OSCC. Consequently, we constructed a prognostic model for OSCC based on MDGs and identified potential mitochondrial damage-related biomarkers. Gene expression profiles and relevant clinical information were obtained from The Cancer Genome Atlas (TCGA) database. Differential analysis was conducted to identify MDGs associated with OSCC. COX analysis was employed to screen seven prognosis-related MDGs and build a prognostic prediction model for OSCC. Cases were categorized into low-risk or high-risk groups based on the optimal risk score threshold. Kaplan-Meier (KM) analysis revealed significant survival differences (P < 0.05). Additionally, the area under the ROC curve (AUC) for patient survival at 1 year, 3 years, and 5 years were 0.687, 0.704, and 0.70, respectively, indicating a high long-term predictive accuracy of the prognostic model. To enhance predictive accuracy, age, gender, risk score, and TN staging were incorporated into a nomogram and verified using calibration curves. Risk scoring based on MDGs was identified as a potential independent prognostic biomarker. Furthermore, BID and SLC25A20 were identified as two potential independent mitochondrial damage-related prognostic biomarkers, offering new therapeutic targets for OSCC.
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Carcinoma de Células Escamosas , Neoplasias de la Boca , Humanos , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Pronóstico , Femenino , Masculino , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Mitocondrias/genética , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Estimación de Kaplan-Meier , NomogramasRESUMEN
Pituitary tumortransforming gene 1 (PTTG1), also known as securin, is a protooncogene involved in the development of various cancers by promoting cell proliferation and mobility. However, its underlying biological mechanisms in oral squamous cell carcinoma (OSCC) progression remain unclear. in the present study, it was sought to elucidate the role of PTTG1 as an oncogene in OSCC progression and was attempted to unravel the underlying mechanism and impact of PTTG1 expression on cell cycle, cell death, and cellular senescence. The effect of double strand break on PTTG1 expression was investigated in OSCC growth. To identify the role of PTTG1 in OSCC growth, the cell viability and senescence was analyzed by EdU and senescenceassociated betagalactosidase (SAßgal) assay, respectively. To verify the DNA damageinduced senescence of PTTG1, the chromosomal damage in OSCC was analyzed in vitro. Finally, the effect of PTTG1 on tumor growth and gene expression related to cell viability and DNA damagedinduced senescence was investigated in vivo. PTTG1 expression was compared between OSCC and healthy patient samples (n=32) using reverse transcriptionquantitative PCR and immunohistochemistry; and it was found that PTTG1 expression was upregulated in OSCC. Small interfering RNAmediated knockdown of PTTG1 in two OSCC cell lines revealed that PTTG1 downregulation significantly inhibited cell proliferation and arrested the cell cycle pathway as evidenced by changes in checkpoint genes (such as cyclin D1, E and B1). PTTG1 knockdown also increased apoptosis, as evidenced by the upregulation of apoptotic genes [such as cleaved (c) Caspase7 and cpoly (ADPribose) polymerase]. Moreover, PTTG1 downregulation promoted cellular senescence, as shown by western blotting and SAßgal staining. Finally, senescenceinduced DNA damage was observed in OSCC cells, which accelerates genomic instability, through chromosomal damage analysis. Taken together, the present findings suggested that PTTG1 acts as a protooncogene; regulates cell proliferation, cell cycle, cellular senescence and DNA damage in OSCC; and may serve as a novel diagnostic biomarker and potential therapeutic target for OSCC.
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Apoptosis , Carcinoma de Células Escamosas , Proliferación Celular , Senescencia Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Daño del ADN , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Boca , Proto-Oncogenes Mas , Securina , Humanos , Securina/genética , Securina/metabolismo , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Neoplasias de la Boca/metabolismo , Senescencia Celular/genética , Apoptosis/genética , Proliferación Celular/genética , Línea Celular Tumoral , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Masculino , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Femenino , Ratones , Animales , Persona de Mediana Edad , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismoRESUMEN
OBJECTIVES: Chemoprevention can be a treatment for potentially malignant lesions (PMLs). We aimed to evaluate whether artemisinin (ART) and cisplatin (CSP) are associated with apoptosis and immunogenic cell death (ICD) in vitro, using oral leukoplakia (OL) and oral squamous cell carcinoma (OSCC) cell lines, and whether these compounds prevent OL progression in vivo. METHODS: Normal keratinocytes (HaCat), Dysplastic oral cells (DOK), and oral squamous cell carcinoma (SCC-180) cell lines were treated with ART, CSP, and ART + CSP to analyze cytotoxicity, genotoxicity, cell migration, and increased expression of proteins related to apoptosis and ICD. Additionally, 41 mice were induced with OL using 4NQO, treated with ART and CSP, and their tongues were histologically analyzed. RESULTS: In vitro, CSP and CSP + ART showed dose-dependent cytotoxicity and reduced SCC-180 migration. No treatment was genotoxic, and none induced expression of proteins related to apoptosis and ICD; CSP considerably reduced High-mobility group box-1 (HMGB-1) protein expression in SCC-180. In vivo, there was a delay in OL progression with ART and CSP treatment; however, by the 16th week, only CSP prevented progression to OSCC. CONCLUSION: Expression of proteins related to ICD and apoptosis did not increase with treatments, and CSP was shown to reduce immunogenic pathways in SCC-180, while reducing cell migration. ART did not prevent the malignant progression of OL in vivo; CSP did despite significant adverse effects.
Asunto(s)
Apoptosis , Artemisininas , Movimiento Celular , Cisplatino , Progresión de la Enfermedad , Leucoplasia Bucal , Neoplasias de la Boca , Artemisininas/farmacología , Animales , Leucoplasia Bucal/patología , Leucoplasia Bucal/tratamiento farmacológico , Humanos , Cisplatino/farmacología , Ratones , Neoplasias de la Boca/patología , Neoplasias de la Boca/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Proteína HMGB1/metabolismo , Antineoplásicos/farmacologíaRESUMEN
Oral squamous cell carcinoma (OSCC) is a prevalent cancer worldwide, exhibiting unique regional prevalence. Despite advancements in diagnostics and therapy, the 5-year survival rate for patients has seen limited improvement. A deeper understanding of OSCC pathogenesis, especially its molecular underpinnings, is essential for improving detection, prevention, and treatment. In this context, noncoding RNAs, such as circular RNAs (circRNAs), have gained recognition as crucial regulators and potential biomarkers in OSCC progression. Our study highlights the discovery of previously uncharacterized circRNAs, including a SNX5 gene-derived circRNA, circSNX5, through deep sequencing of OSCC patient tissue transcriptomes. We established circSNX5's tumor-specific expression and its strong correlation with patient survival using structure-specific and quantitative PCR analyses. In vitro and in vivo experiments underscored circSNX5 RNA's regulatory role in cancer growth and metastasis. Further, our omics profiling and functional assays revealed that ADAM10 is a critical effector in circSNX5-mediated cancer progression, with circSNX5 maintaining ADAM10 expression by sponging miR-323. This novel circRNA-miRNA-mRNA regulatory axis significantly contributes to oral cancer progression and malignancy. Moreover, we discovered that circSNX5 RNA is produced via noncanonical sequential back-splicing of pre-mRNA, a process negatively regulated by the RNA-binding protein STAU1. This finding adds a new dimension to our understanding of exonic circRNA biogenesis in the eukaryotic transcriptome. Collectively, our findings offer a detailed mechanistic dissection and functional interpretation of a novel circRNA, shedding light on the role of the noncoding transcriptome in cancer biology and potentially paving the way for innovative therapeutic strategies.
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Neoplasias de la Boca , ARN Circular , Nexinas de Clasificación , Humanos , ARN Circular/genética , ARN Circular/metabolismo , Nexinas de Clasificación/metabolismo , Nexinas de Clasificación/genética , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Neoplasias de la Boca/metabolismo , Animales , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proliferación Celular/genética , Ratones , Ratones Desnudos , MicroARNs/metabolismo , MicroARNs/genética , Masculino , Femenino , Proteína ADAM10/metabolismo , Proteína ADAM10/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismoRESUMEN
Pyrocurzerenone is a natural compound found in Curcuma zedoaria and Chloranthus serratus. However, the anticancer effect of pyrocurzerenone in oral cancer remains unclear. Using the MTT assay, wound healing assay, transwell assay and western blot analysis, we investigated the impact of pyrocurzerenone on antimetastatic activity, as well as the critical signalling pathways that underlie the processes of oral cancer cell lines SCC-9, SCC-1 and SAS in this work. Our findings suggested that pyrocurzerenone inhibits cell migration and invasion ability in oral cancer cell lines. Furthermore, phosphorylation of ERK1/2 had significant inhibitory effects in SCC-9 and SCC-1 cell lines. Combining ERK1/2 inhibitors with pyrocurzerenone decreased the migration and invasion activity of SCC-9 and SCC-1 cell lines. We also found that the expressed level of cathepsin S decreased under pyrocurzerenone treatment. This study showed that pyrocurzerenone reduced ERK1/2 expression of the proteins and cathepsin S, suggesting that it could be a valuable treatment to inhibit human oral cancer cell metastasis.
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Catepsinas , Movimiento Celular , Neoplasias de la Boca , Humanos , Neoplasias de la Boca/patología , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Catepsinas/metabolismo , Catepsinas/antagonistas & inhibidores , Fosforilación/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Metástasis de la Neoplasia , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/genética , Invasividad Neoplásica , Proliferación Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Betel quid and its major ingredient, areca nut, are recognized by IARC as major risk factors in oral cancer development. Areca nut extract (ANE) exposure has been linked to OPMD progression and malignant transformation to OSCC. However, the detailed mechanism through which ANE acts on other cell types in the oral microenvironment to promote oral carcinogenesis remains elusive. METHODS: Immunoprofiling of macrophages associated with OPMD and OSCC was carried out by immunohistochemical and immunofluorescence staining. Phosphokinase and cytokine arrays and western blotting were performed to determine the underlying mechanisms. Transwell assays were used to evaluate the migration-promoting effect of ANE. Hamster model was finally applied to confirm the in vivo effect of ANE. RESULTS: We reported that M2 macrophages positively correlated with oral cancer progression. ANE induced M2 macrophage differentiation, CREB phosphorylation and VCAM-1 secretion and increased mitochondrial metabolism. Conditioned medium and VCAM-1 from ANE-treated macrophages promoted migration and mesenchymal phenotypes in oral precancer cells. In vivo studies showed that ANE enhanced M2 polarization and related signaling pathways in the oral buccal tissues of hamsters. CONCLUSION: Our study provides novel mechanisms for areca nut-induced oral carcinogenesis, demonstrating that areca nut promotes M2 macrophage differentiation and secretion of oncogenic cytokines that critically activate malignant transformation of oral premalignant cells.
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Areca , Diferenciación Celular , Transformación Celular Neoplásica , Macrófagos , Neoplasias de la Boca , Animales , Areca/efectos adversos , Areca/química , Transformación Celular Neoplásica/metabolismo , Neoplasias de la Boca/patología , Neoplasias de la Boca/metabolismo , Humanos , Macrófagos/metabolismo , Cricetinae , Modelos Animales de Enfermedad , Nueces , Masculino , Reprogramación MetabólicaRESUMEN
The role of mast cell (MC), a common myeloid-derived immune cell, in the development of oral squamous cell carcinoma (OSCC) is unclear. The aim of this study was to investigate MC infiltration in oral precancer and oral cancer. The evaluation of immune cell infiltration and its association with prognosis in OSCC used RNA sequencing and multiple public datasets. Multiplex immunofluorescence was used to explore the infiltration of MC in the microenvironment of OSCC and oral precancer and the interaction with CD8+ cells. The role of MC in OSCC progression was verified by in vivo experiments. The resting MC infiltration was mainly present in oral precancer, whereas activated MC infiltration was significantly higher in OSCC. Activated MC was associated with malignant transformation of oral precancer and poor prognosis of OSCC. In vivo studies showed that MC promoted the growth of OSCC. The infiltration of activated MC was negatively correlated with the infiltration of CD8+ T cells. The subtype of MC containing tryptase without chymase (MCT) was significantly higher in OSCC compared with oral precancer and was associated with poor survival. Furthermore, spatial distance analysis revealed a greater distance between MCT and CD8+ cells, which was also linked to poor prognosis in OSCC. Cox regression analysis showed that MCT could be a potential diagnostic and prognostic biomarker. This study provides new insights into the role of MC in the immune microenvironment of OSCC. It might enhance the immunotherapeutic efficacy of OSCC by developing targeted therapies against MC. SIGNIFICANCE: In this study, we investigated the role of mast cells (MC) in oral precancer and oral cancer and demonstrated that MCs are involved in oral cancer progression and may serve as a potential diagnostic and prognostic marker. It might improve the immunotherapeutic efficacy through developing targeted therapies against MCs.
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Transformación Celular Neoplásica , Progresión de la Enfermedad , Mastocitos , Neoplasias de la Boca , Lesiones Precancerosas , Microambiente Tumoral , Mastocitos/patología , Mastocitos/inmunología , Neoplasias de la Boca/patología , Neoplasias de la Boca/inmunología , Neoplasias de la Boca/mortalidad , Humanos , Microambiente Tumoral/inmunología , Transformación Celular Neoplásica/inmunología , Transformación Celular Neoplásica/patología , Lesiones Precancerosas/patología , Lesiones Precancerosas/inmunología , Pronóstico , Animales , Linfocitos T CD8-positivos/inmunología , Ratones , Masculino , Triptasas/metabolismo , Triptasas/genética , Femenino , Quimasas/metabolismo , Quimasas/genética , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patologíaRESUMEN
Over the last decade, accumulating evidence has suggested that tumor-associated macrophages (TAMs) play a significant role in the tumor development. This commentary wishes to highlight the findings by You, et al. that M1-like TAMs could cascade a mesenchymal/stem-like phenotype of oral squamous cell carcinoma (OSCC) via the IL6/Stat3/THBS1 feedback loop. These unprecedented findings identified M1-like TAMs-regulated processes as potentially tumor-promotion in the context of OSCC immunomicroenvironment.
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Macrófagos , Neoplasias de la Boca , Humanos , Neoplasias de la Boca/patología , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/inmunología , Macrófagos/metabolismo , Macrófagos/inmunología , Carcinogénesis/inmunología , Microambiente Tumoral , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/inmunología , AnimalesRESUMEN
BACKGROUND: Nucleotide-binding domain-like receptor protein 3 (NLRP3), an inflammasome, is reported to be dysregulated or aberrantly expressed in chronic inflammation, leading to a myriad of inflammatory disorders, autoimmune diseases, and cancer. This study aimed to explore the expression and role of NLRP3 protein and the secreted cytokine IL-ß1 in oral squamous cell carcinoma (OSCC) and potentially malignant oral disorders (PMOD). MATERIAL & METHODS: Tissue NLRP3 expression was quantified using sandwich ELISA in 30 cases each of OSCC, PMOD, and normal oral mucosa. Serum IL-ß1 level was also measured by ELISA to determine their correlation. In surgically treated OSCC cases, pathological parameters such as tumor size, depth of invasion (DOI), pTNM stage, and perineural & lymphovascular invasion were assessed and correlated with NLRP3 & IL-ß1 levels to investigate their roles in tumor progression, invasion, and metastasis. RESULTS: Tissue NLRP3 expression was markedly elevated in OSCC, with significant IL-ß1 levels observed in the serum of both OSCC and PMOD cases. Both markers showed a pronounced increase with the severity of dysplasia, indicating a strong association (p = 0.003%). The expression levels of tissue NLRP3 and serum IL-ß1 were positively correlated with DOI and tumor size. Furthermore, their elevated levels, alongside higher histological grades, indicate roles in the dedifferentiation and progression of tumor cells. CONCLUSION: The findings indicated that increased expression of NLRP3 and IL-ß1 in PMOD correlates with higher transformation rates, along with tumor progression and dedifferentiation in OSCC. Consequently, these markers hold promise as valuable targets for prognostic assessment, diagnostics, and therapeutic strategies in OSCC.
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Biomarcadores de Tumor , Interleucina-1beta , Neoplasias de la Boca , Proteína con Dominio Pirina 3 de la Familia NLR , Humanos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Neoplasias de la Boca/patología , Neoplasias de la Boca/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Biomarcadores de Tumor/análisis , Pronóstico , Adulto , Anciano , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologíaRESUMEN
Oral squamous cell carcinoma (OSCC) is considered the most common type of head and neck squamous cell carcinoma (HNSCC) as it holds 90â¯% of HNSCC cases that arise from multiple locations in the oral cavity. The last three decades witnessed little progress in the diagnosis and treatment of OSCC the aggressive tumor. However, in-depth knowledge about OSCC's pathogenesis, staging & grading, hallmarks, and causative factors is a prime requirement in advanced diagnosis and treatment for OSCC patients. Therefore present review was intended to comprehend the OSCCs' prevalence, staging & grading, molecular pathogenesis including premalignant stages, various hallmarks, etiology, diagnostic methods, treatment (including FDA-approved drugs with the mechanism of action and side effects), and theranostic agents. The current review updates that for a better understanding of OSCC progress tumor-promoting inflammation, sustained proliferative signaling, and growth-suppressive signals/apoptosis capacity evasion are the three most important hallmarks to be considered. This review suggests that among all the etiology factors the consumption of tobacco is the major contributor to the high incidence rate of OSCC. In OSCC diagnosis biopsy is considered the gold standard, however, toluidine blue staining is the easiest and non-invasive method with high accuracy. Although there are various therapeutic agents available for cancer treatment, however, a few only are approved by the FDA specifically for OSCC treatment. The present review recommends that among all available OSCC treatments, the antibody-based CAR-NK is a promising therapeutic approach for future cancer treatment. Presently review also suggests that theranostics have boosted the advancement of cancer diagnosis and treatment, however, additional work is required to refine the role of theranostics in combination with different modalities in cancer treatment.
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Neoplasias de la Boca , Humanos , Neoplasias de la Boca/patología , Neoplasias de la Boca/diagnóstico , Neoplasias de la Boca/terapia , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/patologíaRESUMEN
OBJECTIVE: Given the implications of concurrent human papilloma viral infection (HPV) in the prognostic course and implications on therapeutic approached of patients with oral squamous cell carcinoma (OSCC), we seek to investigate the implications that P16 expression has on the clinical course and pathological appearance of patients with OSCC and concurrent infection. METHODS: Using S-P immunohistochemistry, we examined the expression of P16 and Ki67 in 460 patients with OSCC. We compared the expression of the protein between the tumor cells and normal epithelial mucosa within the same patient. The clinical and pathological characteristics (including gender, age, histological grade, lymph node metastasis, clinical stage, clinical recurrence, tumor diameter, Ki67 proliferation index) were analyzed by stratification statistically. RESULTS: In total 460 cases of OSCC were identified and expression of P16 was significantly higher in the OSCC group compared to the normal mucosal epithelial group (X2 = 60.545, p = .000). There also appear to be a gender predilection as the expression was higher in females compared to males (0.218 vs. 0.144, X2 = 3.921, p = .048). Younger age also appears to be a predictive factor as those under 35 years old had higher expression of the protein compared to those over 35 years old (0.294 vs. 0.157, X2 = 4.230, p = .040). P16 positivity showed a significant positive correlation with histologic grade (X2 = 4.114, p = .043). In addition, the positive rate of P16 was higher in patients with ki67 over 85% (0.455 vs. 0.160, X2 = 6.667, p = .023). CONCLUSION: OSCC with HPV infection tends to occur more frequently in female patients and those under 35 years of age. HPV infection with expression of the P16 and ki67 protein may promote the proliferation and growth of OSCC at a higher frequency.
Asunto(s)
Carcinoma de Células Escamosas , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Antígeno Ki-67 , Neoplasias de la Boca , Infecciones por Papillomavirus , Humanos , Femenino , Masculino , Neoplasias de la Boca/patología , Neoplasias de la Boca/virología , Neoplasias de la Boca/metabolismo , Persona de Mediana Edad , Adulto , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Antígeno Ki-67/metabolismo , Carcinoma de Células Escamosas/virología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/metabolismo , Infecciones por Papillomavirus/virología , Anciano , Papillomaviridae/aislamiento & purificación , Inmunohistoquímica , Factores Sexuales , Metástasis Linfática , Anciano de 80 o más Años , Virus del Papiloma HumanoRESUMEN
Fructose-6-phosphate 2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is a crucial enzyme in the glycolysis pathway, possessing both kinase and phosphatase capabilities. Although it has emerged as an important oncogene in various cancer types, its function in oral squamous cell carcinoma (OSCC) is still not well understood. In our research, PFKFB4 expression was assessed via immunohistochemical (IHC) staining of tissue microarrays and OSCC patient specimens. The transcriptional expression of PFKFB4 in OSCC was analyzed by utilizing The Cancer Genome Atlas (TCGA) dataset. Correlation between PFKFB4 expression and clinicopathological features was examined using the χ2 test. Prognostic investigation of PFKFB4 was conducted via Kaplan-Meier and Cox analyses. PFKFB4 levels were notably elevated in OSCC samples in comparison to adjacent normal tissues (P < 0.001). Elevated PFKFB4 expression was associated with higher histologic grade (P = 0.0438), higher T stage (P = 0.031), and more advanced clinical stage (P = 0.0063). The ROC curve demonstrated the diagnostic potential of PFKFB4 (AUC = 0.827). Increased levels of PFKFB4 were linked to decreased overall survival (OS) (P = 0.04), poorer disease-specific survival (DSS) (P = 0.04), and shorter progression-free interval (PFI) (P < 0.001). PFKFB4 expression was identified as an independent risk factor for OS based on Cox regression analysis [hazard ratio (HR) = 1.517, P = 0.044)]. An OS nomogram was constructed with a concordance index of 0.690. Our findings reveal that upregulated PFKFB4 expression in OSCC tissues could serve as a potential prognostic biomarker.
Asunto(s)
Biomarcadores de Tumor , Carcinoma de Células Escamosas , Estimación de Kaplan-Meier , Neoplasias de la Boca , Fosfofructoquinasa-2 , Humanos , Fosfofructoquinasa-2/genética , Fosfofructoquinasa-2/metabolismo , Femenino , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Neoplasias de la Boca/mortalidad , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/diagnóstico , Masculino , Pronóstico , Persona de Mediana Edad , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/mortalidad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Curva ROC , Modelos de Riesgos Proporcionales , Regulación Neoplásica de la Expresión Génica , Anciano , InmunohistoquímicaRESUMEN
BACKGROUND: While surgery remains the primary treatment for oral squamous cell carcinoma (OCSCC), induction chemotherapy (IC) can be used as a bridging or neoadjuvant therapy. This nationwide study in Taiwan examines the survival outcomes of OCSCC patients who received IC before surgery. METHODS: We analyzed data from 29,891 patients with OCSCC. Of these, 29,058 initially underwent surgery (OP group), whereas 833 received IC before surgery (IC + OP group). A propensity score (PS)-matched analysis (4, 1 ratio, 3260 vs. 815 patients) was performed considering tumor subsite, sex, age, Charlson comorbidity index, clinical T1-T4b tumors, clinical N0-3 disease, and clinical stage I-IV. RESULTS: In the PS-matched cohort, the 5-year disease-specific survival (DSS) and overall survival (OS) rates were 65% and 57%, respectively. When comparing the OP and IC + OP groups, the 5-year DSS rates were 66% and 62%, respectively (p = 0.1162). Additionally, the 5-year OS rates were 57% and 56%, respectively (p = 0.9917). No significant intergroup differences in survival were observed for specific subgroups with cT4a tumors, cT4b tumors, cN3 disease, pT4b tumors, and pN3 disease. However, for patients with pT4a tumors, the OP group demonstrated superior 5-year outcomes compared to the IC + OP group, with a DSS of 62% versus 52% (p = 0.0006) and an OS of 53% versus 44% (p = 0.0060). Notably, patients with cT2-3, cN1, and c-Stage II disease in the IC + OP group were significantly more likely to achieve pT0-1 status (p < 0.05). CONCLUSIONS: Following PS matching, the IC + OP group generally exhibited similar prognosis to the OP group. However, for pT4a tumors, the OP group showed superior 5-year outcomes. While IC may not universally improve survival, it could be advantageous for patients who respond positively to the treatment.
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Quimioterapia de Inducción , Neoplasias de la Boca , Terapia Neoadyuvante , Humanos , Masculino , Femenino , Neoplasias de la Boca/mortalidad , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/cirugía , Neoplasias de la Boca/patología , Neoplasias de la Boca/terapia , Terapia Neoadyuvante/métodos , Persona de Mediana Edad , Pronóstico , Anciano , Taiwán/epidemiología , Adulto , Estadificación de Neoplasias , Estudios de Cohortes , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Free flap reconstruction for postoperative tissue defects in oral and maxillofacial tumors is a critical component of reconstructive surgery. Identifying risk factors for flap necrosis is essential for improving surgical outcomes and patient quality of life. A retrospective study was conducted on patients who underwent free flap reconstruction between January 2020 and December 2023. Patients were included if they had comprehensive medical records and at least a six-month follow-up. We excluded those with a history of flap necrosis, uncontrolled systemic diseases, non-adherence to postoperative care, or concurrent malignancy treatments. Data on demographics, comorbidities, flap characteristics, and operative details were collected and analyzed using univariate analysis and logistic regression tests. Univariate analysis did not find a significant correlation between flap necrosis and factors such as hyperlipidemia, lymph node metastasis, or flap type. However, diabetes mellitus, oral infections, and albumin levels below 35 g/L were significantly associated with flap necrosis. Multivariate logistic regression showed diabetes mellitus increased the odds of flap necrosis by approximately ninefold, and oral infection increased it by over tenfold. Diabetes mellitus, oral infection, and low albumin levels are significant risk factors for flap necrosis in free flap reconstruction after oral and maxillofacial surgery. Prompt identification and management of these factors are crucial to mitigate the risk of flap necrosis.
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Colgajos Tisulares Libres , Necrosis , Procedimientos de Cirugía Plástica , Humanos , Masculino , Femenino , Persona de Mediana Edad , Factores de Riesgo , Procedimientos de Cirugía Plástica/métodos , Procedimientos de Cirugía Plástica/efectos adversos , Estudios Retrospectivos , Anciano , Complicaciones Posoperatorias/etiología , Adulto , Neoplasias de la Boca/cirugía , Neoplasias de la Boca/patologíaRESUMEN
High levels of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-2 and angiopoietin (ANG)-2 are found in tissues from oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs). As might be expected, VEGF, FGF-2, and ANG-2 overexpression parallels the development of new blood and lymphatic vessels that nourish the growing OPMDs or OSCCs and provide the latter with metastatic routes. Notably, VEGF, FGF-2, and ANG-2 are also linked to the epithelial-to-mesenchymal transition (EMT), a trans-differentiation process that respectively promotes or exasperates the invasiveness of normal and neoplastic oral epithelial cells. Here, we have summarized published work regarding the impact that the interplay among VEGF, FGF-2, ANG-2, vessel generation, and EMT has on oral carcinogenesis. Results from the reviewed studies indicate that VEGF, FGF-2, and ANG-2 spark either protein kinase B (AKT) or mitogen-activated protein kinases (MAPK), two signaling pathways that can promote both EMT and new vessels' formation in OPMDs and OSCCs. Since EMT and vessel generation are key to the onset and progression of OSCC, as well as to its radio- and chemo-resistance, these data encourage including AKT or MAPK inhibitors and/or antiangiogenic drugs in the treatment of this malignancy.
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Carcinoma de Células Escamosas , Transición Epitelial-Mesenquimal , Neoplasias de la Boca , Humanos , Neoplasias de la Boca/patología , Neoplasias de la Boca/metabolismo , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Progresión de la Enfermedad , Factor A de Crecimiento Endotelial Vascular/metabolismo , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Animales , Inductores de la Angiogénesis/metabolismo , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Transducción de SeñalRESUMEN
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.