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1.
BMC Cancer ; 21(1): 1085, 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620126

RESUMO

BACKGROUND: Circular RNAs (circRNAs) are implicated in the development of oral squamous cell carcinoma (OSCC). The aim of current research is to elucidate the role and mechanism of circ_0011946 in the functional behaviors of OSCC cells. METHODS: Circ_0011946, microRNA (miR)-216a-5p, B cell lymphoma-2-like 2 protein (BCL2L2) abundances were exposed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) or western blot. Cell proliferation, migration, invasion and apoptosis were detected by MTT, colony formation assay, transwell, wound-healing and flow cytometry assays, respectively. Target correlation was tested by dual-luciferase reporter and RNA pull-down assays. An in vivo xenograft experiment was employed to investigate the function of circ_0011946 on tumor growth in vivo. RESULTS: Circ_0011946 and BCL2L2 levels were increased, while miR-216a-5p level was decreased in OSCC tissues and cells. Circ_0011946 knockdown impeded proliferation, migration, and invasion, but promoted apoptosis in OSCC cells. Circ_0011946 functioned as a sponge for miR-216a-5p, and BCL2L2 was targeted by miR-216a-5p. Besides, miR-216a-5p or BCL2L2 knockdown partly attenuated the inhibitory influences of circ_0011946 silence or miR-216a-5p overexpression on OSCC cell progression. Furthermore, circ_0011946 post-transcriptionally regulated BCL2L2 through sponging miR-216a-5p. Moreover, circ_0011946 knockdown constrained OSCC tumor growth in vivo. CONCLUSION: Circ_0011946 silence repressed OSCC cell proliferation, migration, and invasion, but promoted apoptosis through the regulation of the miR-216a-5p/BCL2L2 axis.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma de Células Escamosas/metabolismo , MicroRNAs/metabolismo , Neoplasias Bucais/metabolismo , RNA Circular/metabolismo , Animais , Apoptose/genética , Proteínas Reguladoras de Apoptose/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Inativação Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Invasividade Neoplásica/genética , Transplante de Neoplasias , Interferência de RNA
2.
Anticancer Res ; 41(10): 4771-4779, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593426

RESUMO

BACKGROUND/AIM: P53-binding protein 1 (53BP1) is one of the DNA damage response (DDR) molecules. This study aimed to assess 53BP1 expression by immunofluorescence (IF) as a biomarker to differentiate between oral squamous epithelial lesions (OSELs). MATERIALS AND METHODS: We analyzed 129 archival oral biopsy samples, including 18 benign squamous lesions (BSLs), 37 low-grade dysplasias (LGDs), 22 high-grade dysplasias (HGDs), and 52 oral squamous cell carcinomas (OSCCs). 53BP1 and Ki-67 expressions were examined by double IF to assess the type of 53BP1 expression. RESULTS: We found that OSCC exhibited several 53BP1 nuclear foci, particularly high-DNA damage response (HDDR) and large focus (LF)-type, suggesting the presence of endogenous DNA double-strand breaks in the cancer genome, which could disrupt DDR and induce genomic injury. We also found a difference in 53BP1 expression between LGD and HGD, but not between BSL and LGD. Among the Ki-67-positive cells, HDDR- and LF-type expressions were higher in OSELs of higher grades. CONCLUSION: 53BP1 expression can be a valuable biomarker for OSELs to help estimate the grade of oral epithelial dysplasia.


Assuntos
Quebras de DNA de Cadeia Dupla , Doenças da Boca/metabolismo , Lesões Intraepiteliais Escamosas/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Núcleo Celular/metabolismo , Progressão da Doença , Feminino , Instabilidade Genômica , Humanos , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Doenças da Boca/patologia , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Lesões Intraepiteliais Escamosas/patologia
3.
PLoS One ; 16(10): e0254966, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34679081

RESUMO

OBJECTIVE: The oxygen concentration within cancer tissue is known to be low, but is expected to increase rapidly when oxygen is supplied by angiogenesis and hematogenous metastasis, suggesting that rapid increases in oxygen levels might influence cancer cell physiology. Therefore, we investigated the effects of oxygen concentration fluctuations on the glucose metabolism of cancer cells. METHODS: The glucose metabolism of oral squamous cell carcinoma (HSC-2 and HSC-3) and normal epithelial (HaCaT) cells cultured under normoxic (21% oxygen) or hypoxic (1% oxygen) conditions was measured using a pH-stat system under normoxic or hypoxic conditions. The acidic end-products and reactive oxygen species (ROS) generated by glucose metabolism were also measured. RESULTS: Under normoxic conditions, the metabolic activity of hypoxically cultured cancer cells was significantly increased, and the production of acids other than lactate was upregulated, while the normal cells did not respond to rapid increases in oxygen levels. ROS production was higher in normoxic conditions in all cells, especially the hypoxically cultured HSC-3 cells. CONCLUSIONS: Rapid increases in oxygen levels might enhance the glucose metabolism of hypoxically cultured cancer cells by mainly activating the TCA cycle and electron transport system, which might activate cancer cells through the ATP and ROS generation.


Assuntos
Hipóxia Celular/fisiologia , Glucose/metabolismo , Neoplasias Bucais/metabolismo , Oxigênio/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Trifosfato de Adenosina/metabolismo , Linhagem Celular Tumoral , Humanos , Ácido Láctico/metabolismo , Espécies Reativas de Oxigênio/metabolismo
4.
J Appl Oral Sci ; 29: e20210209, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34644781

RESUMO

OBJECTIVE: Oral squamous cell carcinoma (OSCC) is one of the common type of cancer that leads to death; and is becoming a global concern. Due to the lack of efficient chemotherapeutic agents for patients with oral cancer, the prognosis remains poor. 6-shogaol, a bioactive compound of ginger, has a broad spectrum of bioactivities and has been widely used to relieve many diseases. However, its effects on human oral cancer have not yet been fully evaluated. In our study, we investigated the anticancer effects of 6-shogaol on the proliferation, migration, invasion, apoptosis, and underlying mechanisms within human OSCC cell lines. METHODOLOGY: We investigated the effect of 6-shogaol on the growth of OSCC cells by cell viability and soft agar colony formation assay. Migration and invasion assays were conducted to confirm the effect 6-shogaol on OSCC cell metastasis. Apoptosis was detected by flow cytometry and the underlying mechanism on the antigrowth effect of 6-shogaol in OSCC cells was assessed using western blotting. RESULTS: In our results, 6-shogaol not only suppressed proliferation and anchorage-independent cell growth in OSCC cells, but also induced apoptosis by regulating the apoptosis-associated factors such as p53, Bax, Bcl-2, and cleaved caspase-3. Migration and invasion of OSCC cells were inhibited following the regulation of E-cadherin and N-cadherin by 6-shogaol. Additionally, 6-shogaol treatment significantly inhibited the PI3K/AKT signaling pathway. CONCLUSION: Therefore, our results may provide critical evidence that 6-shogaol can be a potential new therapeutic candidate for oral cancer.


Assuntos
Catecóis/farmacologia , Neoplasias Bucais/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
5.
BMC Cancer ; 21(1): 979, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34465286

RESUMO

BACKGROUND: Ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) has been identified as a histone 3 lysine 27 (H3K27) demethylase and acted as a tumor suppressor gene or oncogenic function. The current study was to explore the significance of UTX in oral tongue squamous cell carcinoma (OTSCC) patients who received surgical resection. METHODS: A total of 148 OTSCC patients who underwent surgical resection were identified, including 64 patients (43%) with overexpression of UTX and 84 patients (57%) harboring low expression of UTX. We also used two OTSCC cell lines, SAS and Cal 27, to determine the modulation of cancer. Chi-square test was used to investigate the difference of categorical variables between the groups; survival outcome was analyzed using the Kaplan-Meier method in univariate analysis, and a Cox regression model was performed for multivariate analyses. RESULTS: Univariate and multivariate analyses showed overexpression of UTX were significantly related to worse disease-free survival (P = 0.028) and overall survival (P = 0.029). The two OTSCC cell lines were treated with GSK-J4, a potent inhibitor of UTX, and transwell migration and invasion assays showed an inhibitory effect with a dose-dependent manner. In addition, western blot analyses also revealed the inhibition of cell cycle and epithelial-mesenchymal transition. CONCLUSION: Our study suggests that UTX plays an important role in the process of OTSCC and overexpression of UTX may predict poor prognosis in OTSCC patients who received surgical resection.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Histona Desmetilases/metabolismo , Neoplasias Bucais/patologia , Neoplasias da Língua/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/cirurgia , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , Neoplasias Bucais/cirurgia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias da Língua/metabolismo , Neoplasias da Língua/cirurgia
6.
Anticancer Res ; 41(9): 4563-4570, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475084

RESUMO

BACKGROUND/AIM: Maspin has tumor-suppressor functions; however, its prognostic value in patients with oral squamous cell carcinoma (OSCC) remains unknown. We aimed to assess the prognostic importance of the subcellular localization of maspin in patients with OSCC. PATIENTS AND METHODS: Eighty resected specimens were analyzed by immunohistochemistry. Cytoplasmic-only expression observed in >10% of the tumor was defined as maspin-positive. RESULTS: The maspin-positive status (25%) was significantly associated with a higher recurrence rate and shorter disease-free survival (DFS). Cox's multivariate analysis showed that maspin-positive status was an independent factor for shorter DFS. All OSCC cell lines (HSC2, HSC3, HSC4, Ca9-22 and SAS) showed maspin protein localization to both the cytoplasm and nucleus using western blot analysis. In HSC4 cells, cell invasion was significantly increased in response to maspin knockdown. CONCLUSION: Cytoplasmic-only expression of maspin could be an independent poor prognostic factor for patients with OSCC.


Assuntos
Carcinoma de Células Escamosas/cirurgia , Citoplasma/metabolismo , Neoplasias Bucais/cirurgia , Serpinas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , Análise Multivariada , Prognóstico , Análise de Sobrevida
7.
PLoS One ; 16(9): e0256979, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34478472

RESUMO

PURPOSES: Although clinical and radiological examinations can be used to diagnose oral cancer, and surgical pathology remains the gold standard, these conventional methods have limitations. We evaluated the feasibility of longitudinal next-generation sequencing-based liquid biopsy for oral squamous cell carcinoma surveillance. MATERIALS AND METHODS: Eleven patients were enrolled, and plasma and saliva were collected before, and 1, 3, and 6 months after surgery. Tumor-specific mutations were selected using paired, whole-exome analyses of tumor tissues and whole blood. Genes frequently mutated in head and neck cancer were identified using the Cancer Genome Atlas (TCGA) and Catalogue of Somatic Mutations in Cancer (COSMIC) databases to design targeted deep sequencing panels. RESULTS: In five of the six patients with recurrent cancer, circulating tumor DNA (ctDNA) was detected earlier with liquid biopsy than with conventional monitoring techniques. Moreover, patients without recurrence exhibited decreased ctDNA allele frequency post-treatment. CONCLUSIONS: Longitudinal liquid biopsy of plasma and saliva may be feasible for detecting somatic mutations associated with oral squamous cell carcinomas. It might be attributable to determine early tumor recurrence through genetic analysis of ctDNA.


Assuntos
Carcinoma de Células Escamosas , DNA Tumoral Circulante/metabolismo , Biópsia Líquida/métodos , Neoplasias Bucais , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/metabolismo , Recidiva Local de Neoplasia , Saliva/metabolismo
8.
Molecules ; 26(17)2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34500779

RESUMO

Up-regulated expression of programmed death-ligand 1 (PD-L1) by interferon-gamma (IFN-γ) has been associated with promotion of cancer cell survival and tumor cell escape from anti-tumor immunity. Therefore, a blockade of PD-L1 expression can potentially be used as a molecular target for cancer therapy. The aim of this study was to investigate whether suppression of IFN-γ induced PD-L1 expression in two oral cancer cell lines, HN6 and HN15, by hesperidin effectively decreased cell proliferation and migration. Further, our objective was to elucidate the involvement of the signal transducer and activator of transcription 1 (STAT1) and STAT3 in the inhibition of induced PD-L1 expression by hesperidin. Our findings indicate that IFN-γ induced expression of PD-L1 protein in HN6 and HN15 via phosphorylation of STAT1 and STAT3 and that hesperidin significantly reduced that induction through suppression of phosphorylated STAT1 and STAT3 in both cell lines. Moreover, hesperidin also significantly decreased the viability, proliferation, migration, and invasion of both cell lines. In conclusion, hesperidin exerted anticancer effects against oral cancer cells through the suppression of PD-L1 expression via inactivation of the STAT1 and STAT3 signaling molecules. The findings of this study support the use of hesperidin as a potential adjunctive treatment for oral cancer.


Assuntos
Antineoplásicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Hesperidina/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Bucais/tratamento farmacológico , Antineoplásicos/química , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Hesperidina/química , Humanos , Inibidores de Checkpoint Imunológico/química , Estrutura Molecular , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Relação Estrutura-Atividade , Regulação para Cima/efeitos dos fármacos
9.
Cells ; 10(9)2021 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-34572115

RESUMO

OBJECTIVES: Tissue architecture and cell morphology suffer profound alterations during oral cancer and are important markers for its progression and outcome. For precise visualization of tissue architecture in oral cancer, we used confocal microscopy to examine the staining pattern of wheat germ agglutinin, a lectin that binds membrane glycoproteins, and the staining patterns of structural proteins. MATERIALS AND METHODS: Paraffin sections of oral squamous cell carcinoma were stained with fluorescently labeled wheat germ agglutinin and with antibodies against structural proteins, which were revealed by immunohistochemistry with tyramide signal amplification. RESULTS: Membrane localization of wheat germ agglutinin was markedly decreased in the basal layers and in regions of tumor invasion, accompanied by cytoplasmic redistribution of E-cadherin, ß-actin and syndecan-1. Wheat germ agglutinin staining clearly identified tumor clusters within the surrounding stroma, and tumor cells with elongated morphology. CONCLUSIONS: Our results suggest that the wheat germ agglutinin staining pattern is indicative of the degree of cell cohesion in oral squamous cell carcinoma, which decreases in basal layers and invasive tumor clusters with more migratory morphologies. Wheat germ agglutinin staining in combination with confocal microscopy could constitute, therefore, a valuable tool for the study of tissue architecture in oral cancer.


Assuntos
Carcinoma de Células Escamosas/patologia , Glicoproteínas de Membrana/metabolismo , Neoplasias Bucais/patologia , Aglutininas do Germe de Trigo/metabolismo , Carcinoma de Células Escamosas/metabolismo , Humanos , Imuno-Histoquímica , Microscopia Confocal , Neoplasias Bucais/metabolismo , Inclusão em Parafina , Coloração e Rotulagem
10.
Cells ; 10(9)2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34571828

RESUMO

Lymph node metastasis is the most reliable indicator of a poor prognosis for patients with oral tongue cancers. Currently, there are no biomarkers to predict whether a cancer will spread in the future if it has not already spread at the time of diagnosis. The aim of this study was to quantitatively profile the proteomes of extracellular vesicles (EVs) isolated from blood samples taken from patients with oral tongue squamous cell carcinoma with and without lymph node involvement and non-cancer controls. EVs were enriched using size exclusion chromatography (SEC) from pooled plasma samples of patients with non-nodal and nodal oral tongue squamous cell carcinoma (OTSCC) and non-cancer controls. Protein cargo was quantitatively profiled using isobaric labelling (iTRAQ) and two-dimensional high-performance liquid chromatography followed by tandem mass spectrometry. We identified 208 EV associated proteins and, after filtering, generated a short list of 136 proteins. Over 85% of the EV-associated proteins were associated with the GO cellular compartment term "extracellular exosome". Comparisons between non-cancer controls and oral tongue squamous cell carcinoma with and without lymph node involvement revealed 43 unique candidate EV-associated proteins with deregulated expression patterns. The shortlisted EV associated proteins described here may be useful discriminatory biomarkers for differentiating OTSCC with and without nodal disease or non-cancer controls.


Assuntos
Biomarcadores Tumorais/metabolismo , Vesículas Extracelulares/metabolismo , Metástase Linfática/patologia , Neoplasias Bucais/metabolismo , Proteoma/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Neoplasias da Língua/metabolismo , Idoso , Feminino , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Proteômica/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Neoplasias da Língua/patologia
11.
BMC Cancer ; 21(1): 922, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34391381

RESUMO

OBJECTIVE: Tongue and mouth floor squamous cell carcinoma (T/MF SCC) exhibits a high rate of local recurrence and cervical lymph node metastasis. The effect of the tumor microenvironment on T/MF SCC remains unclear. MATERIALS AND METHODS: Transcriptome and somatic mutation data of patients with T/MF SCC were obtained from HNSC projects of the Cancer Genome Atlas. Immune infiltration quantification in early- (clinical stage I-II) and advanced-stage (clinical stage III-IV) T/MF SCC was performed using single sample Gene Set Enrichment Analysis and MCPcounter. Differentially expressed gene data were filtered, and their function was assessed through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Kaplan-Meier survival curve analysis and Cox regression model were conducted to evaluate the survival of patients with the CCL22 signature. Maftools was used to present the overview of somatic mutations. RESULTS: In T/MF SCC, T helper (Th)2 cell counts were significantly increased in patients with early-stage disease compared to those with advanced-stage disease. Expression of the Th2 cell-related chemokine, CCL22, was downregulated in patients with advanced-stage T/MF SCC. Univariate and multivariate Cox analyses revealed that CCL22 was a good prognostic factor in T/MF SCC. A nomogram based on the expression of CCL22 was constructed to serve as a prognostic indicator for T/MF SCC. NOTCH1 mutations were found at a higher rate in patients with advanced-stage T/MF SCC than in those with early-stage T/MF SCC, resulting in the inhibition of the activation of the NOTCH1-Th2 cell differentiation pathway. The expression levels of CCL22, GATA-3, and IL4 were higher in patients with early-stage T/MF SCC than in those with advanced-stage T/MF SCC. CONCLUSION: In T/MF SCC, high expression of CCL22 may promote the recruitment of Th2 cells and help predict a better survival. Mutations in NOTCH1 inhibit the differentiation of Th2 cells, facilitating tumor progression through a decrease in Th2 cell recruitment and differentiation.


Assuntos
Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/metabolismo , Quimiocina CCL22/genética , Neoplasias Bucais/etiologia , Neoplasias Bucais/metabolismo , Receptor Notch1/genética , Células Th2/imunologia , Células Th2/metabolismo , Adulto , Idoso , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Quimiotaxia de Leucócito/genética , Quimiotaxia de Leucócito/imunologia , Biologia Computacional/métodos , Feminino , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Contagem de Linfócitos , Linfócitos do Interstício Tumoral , Masculino , Pessoa de Meia-Idade , Soalho Bucal/metabolismo , Soalho Bucal/patologia , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Mutação , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais
12.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445346

RESUMO

Corosolic acid (CA; 2α-hydroxyursolic acid) is a natural pentacyclic triterpenoid with antioxidant, antitumour and antimetastatic activities against various tumour cells during tumourigenesis. However, CA's antitumour effect and functional roles on human oral squamous cell carcinoma (OSCC) cells are utterly unknown. In this study, our results demonstrated that CA significantly exerted an inhibitory effect on matrix metalloproteinase (MMP)1 expression, cell migration and invasion without influencing cell growth or the cell cycle of human OSCC cells. The critical role of MMP1 was confirmed using the GEPIA database and showed that patients have a high expression of MMP1 and have a shorter overall survival rate, confirmed on the Kaplan-Meier curve assay. In the synergistic inhibitory analysis, CA and siMMP1 co-treatment showed a synergically inhibitory influence on MMP1 expression and invasion of human OSCC cells. The ERK1/2 pathway plays an essential role in mediating tumour progression. We found that CA significantly inhibits the phosphorylation of ERK1/2 dose-dependently. The ERK1/2 pathway played an essential role in the CA-mediated downregulation of MMP1 expression and in invasive motility in human OSCC cells. These findings first demonstrated the inhibitory effects of CA on OSCC cells' progression through inhibition of the ERK1/2-MMP1 axis. Therefore, CA might represent a novel strategy for treating OSCC.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/patologia , Triterpenos/farmacologia , Carcinoma de Células Escamosas/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinase 1 da Matriz/metabolismo , Neoplasias Bucais/metabolismo , Metástase Neoplásica , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Células Tumorais Cultivadas
13.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445392

RESUMO

Oral cancer is a major global health problem with high incidence and low survival rates. The oral cavity contains biofilms as dental plaques that harbour both Gram-negative and Gram-positive bacterial antigens, lipopolysaccharide (LPS) and lipoteichoic acid (LTA), respectively. LPS and LTA are known to stimulate cancer cell growth, and the bioactive phytochemical capsaicin has been reported to reverse this effect. Here, we tested the efficacy of oral cancer chemotherapy treatment with capsaicin in the presence of LPS, LTA or the combination of both antigens. LPS and LTA were administered to Cal 27 oral cancer cells prior to and/or concurrently with capsaicin, and the treatment efficacy was evaluated by measuring cell proliferation and apoptotic cell death. We found that while capsaicin inhibits oral cancer cell proliferation and metabolism (MT Glo assay) and increases cell death (Trypan blue exclusion assay and Caspase 3/7 expression), its anti-cancer effect was significantly reduced on cells that are either primed or exposed to the bacterial antigens. Capsaicin treatment significantly increased oral cancer cells' suppressor of cytokine signalling 3 gene expression. This increase was reversed in the presence of bacterial antigens during treatment. Our data establish a rationale for clinical consideration of bacterial antigens that may interfere with the treatment efficacy of oral cancer.


Assuntos
Antígenos de Bactérias/efeitos adversos , Capsaicina/farmacologia , Neoplasias Bucais/metabolismo , Transdução de Sinais/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lipopolissacarídeos/efeitos adversos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/microbiologia , Ácidos Teicoicos/efeitos adversos
14.
Biomolecules ; 11(8)2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34439735

RESUMO

Oral squamous cell carcinoma (OSCC) is a prevalent malignancy associated with a poor prognosis. The Warburg effect can be observed in OSCCs, with tumours requiring a robust glucose supply. Glucose transporters (GLUTs) and sodium-glucose co-transporters (SGLTs) are overexpressed in multiple malignancies, and are correlated with treatment resistance, clinical factors, and poor overall survival (OS). We conducted a systematic review to evaluate the differences in GLUT/SGLT expression between OSCC and normal oral keratinocytes (NOK), as well as their role in the pathophysiology and prognosis of OSCC. A total of 85 studies were included after screening 781 papers. GLUT-1 is regularly expressed in OSCC and was found to be overexpressed in comparison to NOK, with high expression correlated to tumour stage, treatment resistance, and poor prognosis. No clear association was found between GLUT-1 and tumour grade, metastasis, and fluorodeoxyglucose (FDG) uptake. GLUT-3 was less thoroughly studied but could be detected in most samples and is generally overexpressed compared to NOK. GLUT-3 negatively correlated with overall survival (OS), but there was insufficient data for correlations with other clinical factors. Expression of GLUT-2/GLUT-4/GLUT-8/GLUT-13/SGLT-1/SGLT-2 was only evaluated in a small number of studies with no significant differences detected. GLUTs 7 and 14 have never been evaluated in OSCC. In conclusion, the data demonstrates that GLUT-1 and GLUT-3 have a role in the pathophysiology of OSCC and represent valuable biomarkers to aid OSCC diagnosis and prognostication. Other GLUTs are comparatively understudied and should be further analysed because they may hold promise to improve patient care.


Assuntos
Proteínas Facilitadoras de Transporte de Glucose/fisiologia , Neoplasias Bucais/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular , Humanos , Camundongos , Prognóstico
15.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361027

RESUMO

The experimental animal model is still essential in the development of new anticancer drugs. We characterized mouse tumors derived from two-dimensional (2D) monolayer cells or three-dimensional (3D) spheroids to establish an in vivo model with highly standardized conditions. Primary cancer-associated fibroblasts (CAFs) were cultured from head and neck squamous cell carcinoma (HNSCC) tumor tissues and co-injected with monolayer cancer cells or spheroids into the oral mucosa of mice. Mice tumor blood vessels were stained, followed by tissue clearing and 3D Lightsheet fluorescent imaging. We compared the effect of exosomes secreted from 2D or 3D culture conditions on the angiogenesis-related genes in HNSCC cells. Our results showed that both the cells and spheroids co-injected with primary CAFs formed tumors. Interestingly, vasculature was abundantly distributed inside the spheroid-derived but not the monolayer-derived mice tumors. In addition, cisplatin injection more significantly decreased spheroid-derived but not monolayer-derived tumor size in mice. Additionally, exosomes isolated from co-culture media of FaDu spheroid and CAF upregulated angiogenesis-related genes in HNSCC cells as compared to exosomes from FaDu cell and CAF co-culture media under in vitro conditions. The mouse tumor xenograft model derived from 3D spheroids of HNSCC cells with primary CAFs is expected to produce reliable chemotherapy drug screening results given the robust angiogenesis and lack of necrosis inside tumor tissues.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias Bucais/patologia , Neovascularização Patológica/patologia , Esferoides Celulares/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Carcinoma de Células Escamosas/metabolismo , Exossomos/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Bucais/metabolismo , Neovascularização Patológica/metabolismo , Cultura Primária de Células/métodos , Esferoides Celulares/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto/normas
16.
Exp Cell Res ; 406(2): 112767, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34364882

RESUMO

Oral squamous cell carcinoma (OSCC) is one of the most common malignancies in the world, with a high mortality rate. RAN is a member of the Ras GTPase family and is overexpressed in a range of cancers, however, the relationship between RAN and OSCC is rarely reported. In this study, we found that RAN is overexpressed in OSCC tissues. RAN inhibition retarded OSCC cell proliferation and led to apoptosis and cell cycle arrest. Knockdown of RAN inhibited tumor growth in vivo. Strikingly, we found that RAN and oncogene Y-box binding protein-1 (YBX1) are positively associated with the immune infiltrates of CD4+ Th2 cells in multiple types of cancer, and can promote IL-4 expression. IL-4 treatment can partially rescue RAN knockdown-induced cell apoptosis in OSCC cells. Moreover, overexpression of RAN could rescue cell growth inhibition caused by knockdown of YBX1. Furthermore, patients with low expression of both RAN and YBX1 had better overall survival than others. Collectively, these findings indicate that RAN is a target of YBX1. RAN and YBX1 are required for cell proliferation and IL-4 expression. RAN and YBX1 are co-expressed and can serve as potential co-biomarkers for poor prognosis in OSCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Regulação Neoplásica da Expressão Gênica , Interleucina-4/metabolismo , Neoplasias Bucais/patologia , Proteína 1 de Ligação a Y-Box/metabolismo , Proteína ran de Ligação ao GTP/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Ciclo Celular , Movimento Celular , Proliferação de Células , Feminino , Humanos , Interleucina-4/genética , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína 1 de Ligação a Y-Box/genética , Proteína ran de Ligação ao GTP/genética
17.
Biomed Res Int ; 2021: 6661520, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34195277

RESUMO

Objective: Oral squamous cell carcinoma (OSCC) is the most common malignant tumor of the head and neck, with strong local invasiveness and cervical lymph node metastasis. The purpose of this study was to investigate the role of LINC01296 in oral squamous cell carcinoma and its possible mechanism. Materials and Methods: GEPAI database analysis and clinical samples were used to detect the expression of LINC01296 in head and neck cancer. In vivo experiment, MTT, clone formation assay, and transwell were used to detect the proliferation, migration, and invasion of oral squamous cell carcinoma. The effect of LINC01296 on EMT was detected by western blot and qRT-PCR to measure the expression of epithelial and mesenchymal phenotypic markers. BALB/c nude mice were used to carry out in vitro treatment experiment. In terms of mechanism, the binding relationship between LINC01296 and SRSF1 was predicted and verified by the RBPDB database and RNA pull-down assay. Results: LINC01296 was highly expressed in clinical samples and cell lines of oral squamous cell carcinoma. Overexpression of LINC01296 promoted the proliferation, invasion, and migration of oral squamous cell carcinoma cells and accelerated the formation of xenografts, while silencing LINC01296 inhibited tumor progression. In mechanism, LINC01296 plays a tumor-promoting role by binding to SRSF1 protein. Conclusion: LINC01296 promotes malignant lesions in oral squamous cell carcinoma by binding to SRSF1 protein, which provides important experimental data and theoretical basis for the prevention, diagnosis, and treatment of oral squamous cell carcinoma.


Assuntos
Neoplasias Bucais/metabolismo , RNA Longo não Codificante/metabolismo , Fatores de Processamento de Serina-Arginina/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Idoso , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Invasividade Neoplásica , Ligação Proteica , RNA Longo não Codificante/genética , Fatores de Processamento de Serina-Arginina/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética
18.
Biomed Res Int ; 2021: 6616547, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34212035

RESUMO

Objective: To observe the therapeutic effect of Carvacrol on oral squamous cell carcinoma (OSCC) and dissect underlying molecular mechanisms. Methods: Keap1/Nrf2, NALP3, Vimentin, and E-cadherin expression was detected in OSCC and normal oral mucosa (NOM) tissues using immunofluorescence or western blot. When treated with Carvacrol or tert-butylhydroquinone (TBHQ) that activates Nrf2, the expression of Keap1/Nrf2/HO-1, epithelial-mesenchymal transition- (EMT-) related proteins, and NALP3 was examined in OSCC cells. Nrf2 was silenced by treatment with sh-Nrf2 or ML385. After silencing Nrf2 or Carvacrol treatment, cell proliferation and migration were assessed by clone formation and scratch and transwell tests in OSCC cells. Moreover, the expression of Keap1/Nrf2/HO-1, EMT-related proteins, and NALP3 was detected. Results: Keap1/Nrf2, NALP3, Vimentin, and E-cadherin proteins were all significantly upregulated in OSCC than NOM tissues. Carvacrol significantly suppressed Keap1/Nrf2/HO-1 activation. Carvacrol or silencing Nrf2 markedly inhibited the expression of Keap1/Nrf2/HO-1, EMT-related proteins, and NALP3 inflammasome in OSCC cells. Furthermore, clone formation and migration capacities were suppressed following treatment with Carvacrol or Nrf2 depletion. The opposite results were found when there is overexpression of Nrf2. However, Carvacrol distinctly improved the cancer-promoting effect induced by Nrf2 overexpression. Conclusion: Our findings suggested that Carvacrol ameliorated inflammation, proliferation, and migration for OSCC, which was related to inhibition of the Nrf2/Keap1 pathway.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Cimenos/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Inativação Gênica , Humanos , Inflamação , Metástase Linfática , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Regulação para Cima , Cicatrização
19.
Cancer Sci ; 112(10): 4037-4049, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34309966

RESUMO

Immunotherapy with immune-checkpoint therapy has recently been used to treat oral squamous cell carcinomas (OSCCs). However, improvements in current immunotherapy are expected because response rates are limited. Transforming growth factor-ß (TGF-ß) creates an immunosuppressive tumor microenvironment (TME) by inducing the production of regulatory T-cells (Tregs) and cancer-associated fibroblasts and inhibiting the function of cytotoxic T-lymphocytes (CTLs) and natural killer cells. TGF-ß may be an important target in the development of novel cancer immunotherapies. In this study, we investigated the suppressive effect of TGF-ß on CTL function in vitro using OSCC cell lines and their specific CTLs. Moreover, TGFB1 mRNA expression and T-cell infiltration in 25 OSCC tissues were examined by in situ hybridization and multifluorescence immunohistochemistry. We found that TGF-ß suppressed the function of antigen-specific CTLs in the priming and effector phases in vitro. Additionally, TGF-ß inhibitor effectively restored the CTL function, and TGFB1 mRNA was primarily expressed in the tumor invasive front. Interestingly, we found a significant negative correlation between TGFB1 mRNA expression and the CD8+ T-cell/Treg ratio and between TGFB1 mRNA expression and the Ki-67 expression in CD8+ T-cells, indicating that TGF-ß also suppressed the function of CTLs in situ. Our findings suggest that the regulation of TGF-ß function restores the immunosuppressive TME to active status and is important for developing new immunotherapeutic strategies, such as a combination of immune-checkpoint inhibitors and TGF-ß inhibitors, for OSCCs.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia Adotiva/métodos , Neoplasias Bucais/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Linfócitos T Citotóxicos/efeitos dos fármacos , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Microambiente Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Fibroblastos Associados a Câncer/citologia , Fibroblastos Associados a Câncer/imunologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Interferon gama/análise , Interferon gama/metabolismo , Antígeno Ki-67/metabolismo , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , RNA Mensageiro/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Sais de Tetrazólio/farmacologia , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta1/análise , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
20.
Biochem Cell Biol ; 99(4): 424-434, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34283652

RESUMO

Genetic studies have revealed a critical role of the distal-less homeobox gene 5 (Dlx5) in the pathogenesis of ovarian cancer, lung cancer, and T-cell lymphoma; however, the role and underlying mechanisms of Dlx5 in oral squamous cell carcinoma (OSCC) are largely unknown. In this study, we demonstrated that Dlx5 is up-regulated in OSCC tissues and cell lines, compared with their control groups. The results from our immunohistochemistry (IHC) analyses show that high expression levels of Dlx5 correlated with advanced TNM stages (P = 0.0001), lymph node metastasis (P = 0.0049), poor cellular differentiation (P = 0.0491), location of the tumors (P = 0.0132), and poor prognosis for the patient. We also demonstrated that knockdown of Dlx5 inhibited the viability, proliferation, and colony formation of OSCC cell lines CAL-27 and WSU-HN6 cells, probably by blocking cell cycle in the G1 phase. Furthermore, we revealed that Dlx5 exerts its biological functions via direct regulation of CCND1 in CAL-27 and WSU-HN6 cells. Ultimately, we have demonstrated that silencing of Dlx5 inhibits the growth of xenograft tumors in vivo, and that Dlx5 affects the progression of OSCC both in vitro and in vivo via directly regulating CCND1, providing a potential diagnostic biomarker and therapeutic target for OSCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Ciclina D1/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Neoplasias Bucais/patologia , Fatores de Transcrição/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Proliferação de Células , Ciclina D1/genética , Progressão da Doença , Feminino , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Prognóstico , Taxa de Sobrevida , Fatores de Transcrição/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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