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1.
J Oral Sci ; 63(2): 174-178, 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33731508

RESUMO

PURPOSE: The present study aimed to identify dysregulated exosomal miRNAs associated with diagnostic and therapeutic biomarkers in oral squamous cell carcinoma (OSCC). METHODS: Microarray analysis was used to compare expression profiles of exosomal miRNAs in the OSCC-derived cell lines HSC-2, HSC-3, Ca9-22, and HO-1-N1 with those in human normal keratinocytes (HNOKs). The identified OSCC-related miRNAs and their potential target genes were analyzed with bioinformatic analyses, and the data were subjected to Ingenuity Pathway Analysis (IPA) to clarify functional networks and gene ontologies of the identified exosomal miRNAs secreted by OSCC cells. RESULTS: Comparison with HNOKs detected 8 upregulated and 12 downregulated miRNAs in OSCC-secreted exosomes. The potential target mRNAs of these dysregulated miRNAs were suggested by IPA, and 6 significant genetic networks were indicated by genetic network analysis. Furthermore, 4 crucial upstream miRNAs-miR-125b-5p, miR-17-5p, miR-200b-3p, and miR-23a-3p-were identified. miR-125b-5p was a central node in the most significant network. Gene ontology analysis showed significant enrichment of genes with cancer-related functions, such as molecular mechanisms of cancer, cell cycle, and regulation of the epithelial-mesenchymal transition. CONCLUSION: These results provide a comprehensive view of the functions of dysregulated exosomal miRNAs in OSCC, thus illuminating OSCC tumorigenesis and development.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , MicroRNAs , Neoplasias Bucais , Carcinoma de Células Escamosas/genética , Biologia Computacional , Redes Reguladoras de Genes , Humanos , MicroRNAs/genética , Neoplasias Bucais/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço
2.
Gene ; 781: 145524, 2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-33631241

RESUMO

BACKGROUND: Oral Cancer (OC) is one of the leading causes of death and the disease mainly occurs over 50 years of age. Herein, a meta-analysis aimed to assess the association between X-ray repair cross complementing (XRCC) polymorphisms and OC risk. METHODS: Four databases were searched extensively until June 5, 2020. Subgroup analysis, meta-regression, and funnel plots, as well as the quality assessment were estimated. RESULTS: Fifteen studies were entered to the analysis. With regards to allele, homozygote, heterozygote, recessive, and dominant models, the pooled ORs for XRCC1 rs1799782 polymorphism were 1.51 (P = 0.01), 1.45 (P = 0.11), 1.45 (P = 0.0003), 1.44 (P = 0.0002), and 1.29 (P = 0.26); for XRCC1 rs1799782 polymorphism were 1.65 (P = 0.11), 1.50 (P = 0.33), 1.06 (P = 0.83), 1.57 (P = 0.12), and 1.32 (P = 0.45); for XRCC1 rs25489 polymorphism were 0.01 (P = 0.19), 1.44 (P = 0.48), 1.21 (P = 0.72), 1.17 (P = 0.19), and 1.38 (P = 0.54); for XRCC2 rs2040639 polymorphism were 0.68 (P = 0.0002), 0.63 (P = 0.02), 0.95 (P = 0.92), 0.79 (P = 0.49), and 0.61 (P = 0.005); and for XRCC3 rs861539 polymorphism were 1.24 (P = 0.20), 1.28 (P = 0.48), 0.99 (P = 0.95), 1.15 (P = 0.46), and 1.52 (P = 0.15), respectively. CONCLUSIONS: The T allele and CT genotype of XRCC1 rs1799782 polymorphism had an elevated risk, whereas the G allele and GG genotype of XRCC2 rs2040639 polymorphism had a protective role in OC.


Assuntos
Reparo do DNA , Proteínas de Ligação a DNA/genética , Neoplasias Bucais/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Predisposição Genética para Doença , Humanos , Polimorfismo Genético
3.
Head Face Med ; 17(1): 7, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637098

RESUMO

BACKGROUND: As a tumor-accelerating transcriptional factor, E2F transcription factor 7 (E2F7) was up-regulated in many forms of cancers. Nevertheless, little has been reported about the impacts of E2F7 on oral squamous cell carcinoma (OSCC). Here, we aimed to probe whether E2F7 had influences on OSCC and its potential mechanism. METHODS: The expression of E2F7 in OSCC tissues was analyzed using the data acquired from TCGA and ONCOMINE databases. E2F7 prognostic value in OSCC patients was analyzed utilizing TCGA database. The expression of E2F7 in OSCC cell lines was detected by qRT-PCR. Gain-and loss-function of E2F7 assays in TCA-83 and CAL27 cells were performed respectively to inquire the function of E2F7. Western blotting was applied to test the alternations of EMT-related markers. RESULTS: In OSCC tissues, E2F7 was highly expressed. Besides, high expression of E2F7 predicted worse prognosis in OSCC patients. Moreover, E2F7 was over-expressed in TCA-83, HSC-4 and CAL27 (all OSCC cell lines) cells relative to that in HNOK (a normal cell line) cells. Gain-and loss-function assays displayed that deficiency of E2F7 suppresses CAL27 cell growth, migration, invasion and E2F7 high-expression resulted in inverse outcomes in TCA-83 cells. Finally, we found that silencing of E2F7 facilitated E-cadherin protein expression level and reduced N-cadherin, Vimentin and Snail protein levels in CAL27 cells, whilst E2F7 high-expression exhibited the opposite effects in TCA-83 cells. CONCLUSIONS: These outcomes indicated that E2F7 performs a carcinogenic role in OSCC, which provides a theoretical basis for the therapeutic strategies of OSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Proliferação de Células , Fatores de Transcrição E2F , Humanos , Neoplasias Bucais/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética
4.
Anticancer Res ; 41(2): 765-772, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517281

RESUMO

BACKGROUND/AIM: This study aimed to identify novel biomarkers for oral squamous cell carcinoma (OSCC) screening to improve the survival rate of patients with oral cancer. MATERIALS AND METHODS: We investigated differential salivary gene expression in patients with OSCC, those with oral potentially malignant disorders (OPMDs), and healthy volunteers (HVs). CPLANE1 was selected for further investigation by microarray analysis. We used quantitative reverse transcription PCR (qRT-PCR) to determine CPLANE1 expression levels in the saliva. The expression of CPLANE1 in normal and oral cancer tissues was analyzed using the Gene Expression database of Normal and Tumor tissues. RESULTS: qRT-PCR analysis of saliva samples showed that CPLANE1 expression levels were significantly higher in OSCC patients than in HVs and OPMDs patients. Furthermore, we developed a screening test for OSCC using CPLANE1 and showed that it had good accuracy. CONCLUSION: Salivary CPLANE1 could be a useful biomarker for OSCC screening and early detection.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/diagnóstico , Proteínas de Membrana/genética , Neoplasias Bucais/diagnóstico , Saliva/química , Regulação para Cima , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Detecção Precoce de Câncer , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Leucoplasia Oral/genética , Líquen Plano Bucal/genética , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Estadiamento de Neoplasias , Sensibilidade e Especificidade
5.
Anticancer Res ; 41(2): 1035-1040, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517312

RESUMO

BACKGROUND/AIM: The definition of multiple oral cancers is based on the distances between the tumors. However, it is not possible to accurately predict tumor origins based only on clinical criteria. PATIENTS AND METHODS: We performed whole-exome sequencing (WES) to analyze the genetic alterations in five tumors of two patients who underwent surgery in our hospital. RESULTS: In case 1, the distances between tumors on the right mandibular gingiva and buccal mucosa were more than 15 mm, leading to a clinical diagnosis of multiple primary tumors. WES revealed common mutations between tumors, suggesting that the tumors were derived from the same clone. In contrast, in case 2, the distance between tumors on the right side of the tongue was only 10 mm, but the tumors were diagnosed as double primary tumors because their mutations were completely different. CONCLUSION: WES, rather than the available clinical criteria, can clarify the clonal origins of multiple oral cancers.


Assuntos
Células Clonais/patologia , Neoplasias Bucais/diagnóstico , Mutação , Neoplasias Primárias Múltiplas/diagnóstico , Sequenciamento Completo do Exoma/métodos , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Neoplasias Bucais/cirurgia , Metástase Neoplásica , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/cirurgia , Especificidade da Espécie
6.
Anticancer Res ; 41(2): 687-697, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517273

RESUMO

BACKGROUND/AIM: We investigated drugs that could sensitize P-glycoprotein (P-gp)-overexpressing drug-resistant cancer cells to vincristine (VIC) or eribulin treatment and assessed their associated mechanisms of action. MATERIALS AND METHODS: We investigated 15 bipolar drugs (quetiapine, risperidone, clozapine, asenapine, iloperidone, paliperidone, ziprasidone, trifluoperazine, loxapine succinate, pilocarpine, valproic acid, carbamazepine, levetiracetam, topiramate, and felbamate) to identify drugs with a sensitizing effect on VIC-resistant KBV20C cells at relatively low doses. Fluorescence-activated cell sorting (FACS), annexin V analyses, and rhodamine uptake tests were performed to further investigate the mechanism of action. RESULTS: We found that co-treatment with half the tested drugs (quetiapine, iloperidone, trifluoperazine, loxapine, risperidone, ziprasidone, or felbamate) at low doses could highly sensitize VIC-resistant KBV20C cells. With lower amounts of the bipolar drugs or VIC, we found that among the 15 bipolar drugs tested, 2 combinations (VIC-quetiapine and VIC-trifluoperazine) had much higher sensitization effects, suggesting that lower effective doses were sufficient for sensitizing P-gp-overexpressing resistant cells compared to those required with the other drugs. Furthermore, when we compared quetiapine and trifluoperazine to previously known bipolar drugs (fluphenazine, thioridazine, pimozide, or aripiprazole), we found that aripiprazole, administered at lower doses, had a much higher sensitization effect. We also demonstrated that co-treatment with another anti-mitotic drug (eribulin) increased the sensitization of KBV20C cells similar to VIC. We also found that aripiprazole had higher P-gp-inhibitory activity than the other bipolar drugs, indicating that this activity was involved in the higher level of VIC-aripiprazole sensitization. CONCLUSION: Co-treatment of anti-mitotic drug-resistant cancer cells with a low dose of aripiprazole had the strongest sensitization effect and is highly dependent on P-gp-inhibitory activity.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antipsicóticos/farmacologia , Aripiprazol/farmacologia , Reposicionamento de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Cetonas/farmacologia , Neoplasias Bucais/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Vincristina/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
7.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498448

RESUMO

BACKGROUND: Pituitary tumor-transforming gene 1 (PTTG1) was recently shown to be involved in the progression as well as the metastasis of cancers. However, their expression and function in the invasion of oral squamous cell carcinoma (SCC) remain unclear. METHODS: The expressions of PTTG1 and PTTG1-targeted miRNA in oral SCC cell lines and their invasion capability depended on PTTG1 expression were analyzed by quantitative RT-PCR, Western blots, the transwell insert system and Zymography. RESULTS: Invasion abilities were decreased in oral SCC cells treated with siRNA-PTTG1. When PTTG1 were downregulated in oral SCC cells treated with microRNA-186 and -655 inhibited their invasion abilities via MMP-9 activity. CONCLUSIONS: These results indicate that alteration of expression of PTTG1 in oral SCC cells by newly identified microRNA-186 and -655 can regulate invasion activity. Therefore, these data offer new insights into further understanding PTTG1 function in oral SCC and should provide new strategies for diagnostic markers for oral SCC.


Assuntos
Carcinoma de Células Escamosas/metabolismo , MicroRNAs/metabolismo , Neoplasias Bucais/metabolismo , Securina/genética , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Movimento Celular , Humanos , Metaloproteinase 9 da Matriz/metabolismo , MicroRNAs/genética , Neoplasias Bucais/genética , Securina/metabolismo
8.
Phytomedicine ; 80: 153386, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33113500

RESUMO

BACKGROUND: Overexpression of polycomb protein contributes to epigenetic repression in oral squamous cell carcinoma (OSCC) ensuing in poor prognosis and aggressive phenotype. Several plant-based compounds could help prevent epigenome alteration and cancer progression, but their low bioavailability limits their therapeutic activity. HYPOTHESIS: In this study, we have synthesized genistein nanoformulation (GLNPs) and evaluated its epigenetic regulation mechanism for selective apoptosis induction in OSCC. METHODS: Lactalbumin was used to prepare nanoformulation of Genistein. The mechanism of epigenetic regulation and selective apoptosis by Genistein loaded nanoparticles was studied in OSCC cell line JHU011 and fibroblast cell line L929 using immunofluorescence, Western blotting and ChIP-qPCR assay. RESULTS: We have found that GLNPs treatment selectively induced apoptosis in OSCC compared to the normal fibroblast cells. This selective effect in OSCC is achieved through enhanced reactive oxygen species (ROS) generation followed by Bax mitochondrial translocation and caspase 3 activation. Further, GLNPs induced withdrawal of epigenetic transcription repression through concurrent downregulation of the polycomb group proteins (PcG) Bmi 1 and EZH2 along with their successive targets, UbH2AK119 and H3K27me3, which have immense therapeutic implications in the treatment of OSCC. Last, we have established that GLNPs regulate EZH2expression through proteasomal mediated degradation and 3PK inhibition; 3PK protein was found physically linked with EZH2 protein and its promoter region (-1107 to -1002). This event indicates that 3PK might play some crucial role in EZH2 expression and epigenetic control of OSCC. Moreover, the formulation showed improved biodistribution, aqueous dispersibility and enhanced biocompatibility In-vivo. CONCLUSIONS: These results provide evidence that GLNPs may withdraw epigenetic transcriptional repression and selectively induce apoptosis in human oral squamous cell carcinoma.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Genisteína/farmacologia , Neoplasias Bucais/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/farmacocinética , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Epigênese Genética/efeitos dos fármacos , Genisteína/administração & dosagem , Genisteína/farmacocinética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Nanopartículas/administração & dosagem , Nanopartículas/química , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 38(6): 622-627, 2020 Dec 01.
Artigo em Chinês | MEDLINE | ID: mdl-33377337

RESUMO

OBJECTIVE: The microRNA (miRNA) prognostic model can predict the prognosis of patients with oral squamous cell carcinoma (OSCC) on the basis of bioinformatics. Moreover, it can accurately group OSCC patients to improve targeted treatment. METHODS: We downloaded the miRNA and mRNA expression profile and clinical data of OSCC from The Cancer Genome Atlas (TCGA). The risk score model of miRNA was screened and established by univariate and multivariate Cox regression models. The performance of this prognostic model was tested by receiver operating characteristic (ROC) curves and area under the curve (AUC). The target genes of six miRNAs were predicted and intersected with differential mRNA for enrichment analysis by Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway and gene ontology (GO) enrichment analysis. A protein protein interaction network (PPI) was constructed to screen hub genes. RESULTS: By using univariate and multivariate Cox regression analyses, the prognostic risk model was obtained. The AUC of the ROC curve for predicting 5-year survival in the training group, test group, and whole cohort were 0.757, 0.673, and 0.724, respectively. Furthermore, univariate Cox regression and multivariate Cox regression considering other clinical factors showed that the six-miRNAs signature could serve as an independent prognostic factor (P<0.001). The top 10 hub genes in the PPI network screened by intersecting target genes include CCNB1, EGF, KIF23, MCM10, ITGAV, MELK, PLK4, ADCY2, CENPF, and TRIP13. EGF and ADCY2 were associated with survival prognosis (P<0.05). CONCLUSIONS: The six-miRNAs signature could efficiently function as a novel and independent prognostic model for OSCC patients, which may be a new method to guide the accurate targeting treatment of OSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , MicroRNAs , Neoplasias Bucais , ATPases Associadas a Diversas Atividades Celulares , Biomarcadores Tumorais , Carcinoma de Células Escamosas/genética , Proteínas de Ciclo Celular , Biologia Computacional , Humanos , Neoplasias Bucais/genética , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço
10.
PLoS One ; 15(12): e0242465, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33332365

RESUMO

Peroxiredoxin 2 (PRDX2) is upregulated in various cancers including oral squamous cell carcinoma (OSCC). It is a known tumor promoter in some cancers, but its role in OSCC is unclear. This study aimed to investigate the effect of arecoline, an alkaloid of the betel nut, and human papillomavirus type 16 (HPV16) E6/E7 oncoproteins on induction of PRDX2 expression, and also the effects of PRDX2 overexpression in oral cell lines. Levels of PRDX2 protein were determined using western blot analysis of samples of exfoliated normal oral cells (n = 75) and oral lesion cells from OSCC cases (n = 75). Some OSCC cases were positive for HPV infection and some patients had a history of betel quid chewing. To explore the level of PRDX2 by western blot, the proteins were extracted from oral cell lines that were treated with arecoline or retroviruses containing HPV16 E6 gene and HPV16 E6/E7 expressing vector. For analysis of PRDX2 functions, cell proliferation, cell-cycle progression, apoptosis and migration was compared between oral cells overexpressing PRDX2 and cells with PRDX2-knockdown. PRDX2 expression levels tended to be higher in OSCC samples that were positive for HPV infection and had history of betel quid chewing. Arecoline treatment in vitro at low concentrations and overexpression of HPV16 E6 or E6/E7 in oral cells induced PRDX2 overexpression. Interestingly, in oral cells, PRDX2 promoted cell proliferation, cell-cycle progression (G2/M phase), cell migration and inhibited apoptosis. Upregulation of PRDX2 in oral cells was induced by arecoline and HPV16 oncoproteins and promoted growth of OSCC cells.


Assuntos
Arecolina/farmacologia , Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Bucais/genética , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus/genética , Peroxirredoxinas/genética , Proteínas Repressoras/genética , Idoso , Apoptose/genética , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Papillomavirus Humano 16/química , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/enzimologia , Neoplasias Bucais/patologia , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Peroxirredoxinas/antagonistas & inibidores , Peroxirredoxinas/metabolismo , Plasmídeos/química , Plasmídeos/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais , Transfecção
11.
Cell Death Dis ; 11(12): 1055, 2020 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-33311454

RESUMO

Oral squamous cell carcinoma (OSCC) is the most common oral cancer. The molecular mechanisms of this disease are not fully understood. Our previous studies confirmed that dysregulated function of long non-coding RNA (lncRNA) AC007271.3 was associated with a poor prognosis and overexpression of AC007271.3 promoted cell proliferation, migration, invasion, and inhibited cell apoptosis in vitro, and promoted tumor growth in vivo. However, the underlying mechanisms of AC007271.3 dysregulation remained obscure. In this study, our investigation showed that AC007271.3 functioned as competing endogenous RNA by binding to miR-125b-2-3p and by destabilizing primary miR-125b-2, resulted in the upregulating expression of Slug, which is a direct target of miR-125b-2-3p. Slug also inhibited the expression of E-cadherin but N-cadherin, vimentin, and ß-catenin had no obvious change. The expression of AC007271.3 was promoted by the canonical nuclear factor-κB (NF-κB) pathway. Taken together, these results suggested that the classical NF-κB pathway-activated AC007271.3 regulates EMT by miR-125b-2-3p/Slug/E-cadherin axis to promote the development of OSCC, implicating it as a novel potential target for therapeutic intervention in this disease.


Assuntos
Carcinogênese/genética , Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Bucais/genética , NF-kappa B/metabolismo , RNA Longo não Codificante/metabolismo , Fatores de Transcrição da Família Snail/genética , Animais , Sequência de Bases , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Inativação Gênica , Células HEK293 , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/metabolismo , Invasividade Neoplásica , Metástase Neoplásica , Estabilidade de RNA/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Regulação para Cima/genética
12.
Braz Dent J ; 31(6): 634-639, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33237235

RESUMO

Micro-RNA-221(miR-221) is one of oncogenic miRNAs that plays a vital role in the development and progression of oral cancers. The aim of this study is to introduce a new gene therapy for oral squamous cell carcinoma by blocking the expression of oncogenic miR-221 by its inhibitor. The present work was performed on squamous cell carcinoma cell line SCC-25 and anti-miR-221 was delivered to the cells using an ultrasound micro bubbles. Assessment of the effect of miR-221 inhibitor on SCC-25 cells was done using MTT assay, cell cycle analysis and apoptosis detection. In addition, reverse transcription-polymerase chain reaction was also used to detect the expression -miR-221 and its target genes. Using ANOVA, statistical analysis of the results showed significant inhibition of cell viability with and induction of cell apoptosis of SCC-25 cell line after transfection. Moreover, the expression of miR-221, Epidermal growth factor receptor (EGFR) and CDKNIB/p27 were downregulated without significant difference. Transfection of SCC-25 by inhibitor of miR-221 resulting in blockage of its expression leading to arresting of tumor growth. These results proved the effective role of micro-RNA inhibitors as novel therapeutic agent for oral cancers.


Assuntos
Carcinoma de Células Escamosas , MicroRNAs , Neoplasias Bucais , Apoptose , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/terapia , Linhagem Celular Tumoral , Proliferação de Células , Terapia Genética , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , MicroRNAs/uso terapêutico , Neoplasias Bucais/genética , Neoplasias Bucais/terapia
13.
Nat Commun ; 11(1): 5671, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168804

RESUMO

To establish whether 4-nitroquinoline N-oxide-induced carcinogenesis mirrors the heterogeneity of human oral squamous cell carcinoma (OSCC), we have performed genomic analysis of mouse tongue lesions. The mutational signatures of human and mouse OSCC overlap extensively. Mutational burden is higher in moderate dysplasias and invasive SCCs than in hyperplasias and mild dysplasias, although mutations in p53, Notch1 and Fat1 occur in early lesions. Laminin-α3 mutations are associated with tumour invasiveness and Notch1 mutant tumours have an increased immune infiltrate. Computational modelling of clonal dynamics indicates that high genetic heterogeneity may be a feature of those mild dysplasias that are likely to progress to more aggressive tumours. These studies provide a foundation for exploring OSCC evolution, heterogeneity and progression.


Assuntos
Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Genômica , Neoplasias Bucais/genética , 4-Nitroquinolina-1-Óxido/efeitos adversos , Animais , Caderinas/genética , Carcinogênese/induzido quimicamente , Carcinoma de Células Escamosas/patologia , Modelos Animais de Doenças , Progressão da Doença , Exoma/genética , Genes Neoplásicos , Genes p53/genética , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Bucais/patologia , Mutação , Invasividade Neoplásica , Receptor Notch1/genética
14.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 38(5): 550-557, 2020 Oct 01.
Artigo em Chinês | MEDLINE | ID: mdl-33085241

RESUMO

OBJECTIVE: To investigate the mechanism underlying the regulation of the invasion and metastasis of oral squamous cell carcinoma (OSCC) by long-chain noncoding RNA (lncRNA) PCGEM1 through the transforming growth factor (TGF) ß2/Smad2 signaling pathways. METHODS: A total of 60 OSCC cases were collected. Cancer tissues and normal tissues more than 2 cm away from cancer tissues were also collected. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-148a and lncRNA PCGEM1 in OSCC, adjacent normal tissues, oral mucosa epithelial cells, KB, BcaCD885, SCC-4, CAL27, and SCC-15. The relationship between the expression of lncRNA PCGEM1 and miR-148a and the clinicopathological information of patients was analyzed. The lncRNA PCGEM1-silenced cell line KB-siPCGEM1 and negative control (KB-NC) group were constructed, and KB was used as the blank control group. The effects of lncRNA PCGEM1 on the proliferation, invasion, and migration of KB cells were determined via MTT, Transwell, and scratch assays. The bioinformatics website starBase was used to predict the complementary binding microRNA (miRNA) of lncRNA PCGEM1. Furthermore, the genes that the miRNA could target and bind were predicted in accordance with the website www.microRNA.org. Western blotting analysis was used to detect the expression of TGF ß2/Smad2 signaling pathway proteins. RESULTS: qRT-PCR results showed that the expression level of lncRNA PCGEM1 and miR-148a in OSCC tissues was higher than that in normal tissues (P<0.05). The expression of lncRNA PCGEM1 and miR-148a in the cancer tissues of patients with different TNM grades, lymph node metastasis, and tissue differentiation was statistically significant (P<0.05). Compared with those in the blank control group and the KB-NC group, OD492 nm value was significantly decreased and cell mobility was significantly reduced in the KB-siPCGEM1 group (P<0.05). Bioinformatics predictions showed that lncRNA PCGEM1 could bind to miR-148a in a complementary manner and that miR-148a had a targeted binding site with TGF ß2. qRT-PCR and Western blotting analysis results showed that the expression levels of miR-148a, TGF ß2, and p-Smad2 in the KB-siPCGEM1 group were significantly lower than those in the blank control and KB-NC groups (P<0.05), and no statistically significant difference between the blank control group and the KB-NC group was observed (P>0.05). CONCLUSIONS: LncRNA PCGEM1 is highly expressed in OSCC. The high expression of lncRNA PCGEM1 may enhance the TGF ß2/Smad2 signaling pathway by upregulating miR-148a, thus promoting the development of OSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , RNA Longo não Codificante , Carcinoma de Células Escamosas/genética , Proliferação de Células , Células Epiteliais , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Bucais/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/fisiologia , Transdução de Sinais , Proteína Smad2 , Fator de Crescimento Transformador beta2
15.
Anticancer Res ; 40(11): 6101-6113, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109548

RESUMO

BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC) is a common malignancy with poor prognosis. Therefore, novel therapeutic options are needed to improve prognosis of OSCC. Recently, microRNAs (miRs) have received increasing attention as a potential therapeutic tool for carcinomas. However, no definitive miR-based drugs for patients with OSCC have been reported to date. The aim of this study was to identify new miRs potentially involved in cellular processes associated with OSCC malignancy, which could lead to novel therapeutic strategies. MATERIALS AND METHODS: We identified miRs that are modulated in OSCC and possibly regulate OSCC malignancy, using miR microarray on OSCC cell lines. RESULTS: miR-935 and miR-509-3p were down-regulated in OSCC cell lines and patient tissues. When miR-935 was overexpressed in HSC-3-M3 cells, proliferation, migration, and invasion of the cell line was suppressed, whereas apoptosis was increased. Moreover, we showed that the gene inositol polyphosphate-4-phosphatase type I A (INPP4A) is a potential target whose expression is positively regulated by miR-935. CONCLUSION: miR-935 may function as a tumor suppressor by inhibiting OSCC malignancy via INPP4A induction. Therefore, miR-935 can be a new therapeutic candidate for OSCC treatment.


Assuntos
Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/genética , MicroRNAs/metabolismo , Neoplasias Bucais/enzimologia , Neoplasias Bucais/genética , Monoéster Fosfórico Hidrolases/metabolismo , Apoptose/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Neoplasias Bucais/patologia , Invasividade Neoplásica , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
16.
Anticancer Res ; 40(11): 6355-6366, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109573

RESUMO

BACKGROUND/AIM: p16 and PTEN are tumor suppressor genes. Loss of these molecules in oral squamous cell carcinoma (OSCC) has been studied worldwide. In this study, we explored whether p16 cooperates with inactive PTEN during the pathogenesis of OSCC, especially in regard to tumor aggressiveness and proliferation. MATERIALS AND METHODS: Immunocytochemistry and western blot analysis were used to examine the levels of p16 and PTEN. Sequencing analysis was performed to identify mutations in the PTEN gene and HPV infection. Fluorescence in situ hybridization was used to examine the presence of the PTEN locus. RESULTS: PTEN analysis showed high positivity in T4 samples. HPV-positive tumors correlated with tabagism, tumor size 3 and 4, disease stages 3 and 4, presence of lymph node metastasis (N1) and poor differentiation. Immunoexpression of p16 was strongly correlated with the presence of HPV. CONCLUSION: PTEN demonstrated a higher reactivity in advanced disease stages and p16 was strongly associated with HPV. Viral presence decreases tumor aggressiveness. Patients with advanced stage lesions demonstrated lower survival rate.


Assuntos
Carcinoma de Células Escamosas/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Neoplasias Bucais/genética , PTEN Fosfo-Hidrolase/genética , Adulto , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Hibridização in Situ Fluorescente , Perda de Heterozigosidade/genética , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Neoplasias Bucais/virologia , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia
17.
PLoS One ; 15(9): e0238420, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32931492

RESUMO

BACKGROUND: Patients diagnosed with Oral Floor Squamous Cell Carcinoma (OFSCC) face considerable challenges in physiology and psychology. This study explored prognostic signatures to predict prognosis in OFSCC through a detailed transcriptomic analysis. METHOD: We built an interactive competing endogenous RNA (ceRNA) network that included lncRNAs, miRNAs and mRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to predict the gene functions and regulatory pathways of mRNAs. Least absolute shrinkage and selection operator algorithm (LASSO) analysis and Cox regression analysis were used to screen prognosis factors. The Kaplan-Meier method was used to analyze the survival rate of prognosis factors. Risk score was used to assess the reliability of the prediction model. RESULTS: A specific ceRNA network consisting of 56 mRNAs, 16 miRNAs and 31 lncRNAs was established. Three key genes (HOXC13, TGFBR3, KLHL40) and 4 clinical factors (age, gender, TNM, and clinical stage) were identified and effectively predicted the for survival time. The expression of a gene signature was validated in two external validation cohorts. The signature (areas under the curve of 3 and 5 years were 0.977 and 0.982, respectively) showed high prognostic accuracy in the complete TCGA cohort. CONCLUSIONS: Our study successfully developed an extensive ceRNA network for OFSCC and further identified a 3-mRNA and 4-clinical-factor signature, which may serve as a biomarker.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Neoplasias Bucais/genética , RNA Neoplásico/genética , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Bases de Dados de Ácidos Nucleicos , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Proteínas de Homeodomínio/genética , Humanos , Estimativa de Kaplan-Meier , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Soalho Bucal , Neoplasias Bucais/mortalidade , Proteínas Musculares/genética , Prognóstico , Proteoglicanas/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Fatores de Risco
18.
Artigo em Inglês | MEDLINE | ID: mdl-32981864

RESUMO

OBJECTIVES: Tissue hypoxia in oral submucous fibrosis (OSMF) induces hypoxia-inducible factor (HIF)-1 α and vascular endothelial growth factor (VEGF), causing angiogenesis. Single nucleotide polymorphisms (SNPs) may predict susceptibility to environmental carcinogens and to development of OSMF, as well as its severity and malignant transformation. This study aimed to determine the serologic levels and frequencies of SNPs of HIF-1 α and VEGF in OSMF. STUDY DESIGN: In this prospective pilot study, the frequencies of SNPs of HIF-1 α (C1772 T, G1790 A); VEGF-A 936 C/T; and VEGF-C (rs7664413, rs1485766) in patients with OSMF or oral squamous cell carcinoma (OSCC) and in healthy controls were determined by using polymerase chain reaction (PCR) (n = 100 each), and serologic levels were determined by using enzyme-linked immunosorbent assay (ELISA (n = 50 each), in a North Indian population. RESULTS: Heterozygous forms of HIF-1 α C1772 T (CT: odds ratio [OR] 5.0; 95% confidence interval [CI] 2.24-11.16; P < .001); HIF-1 α G1790 A (GA: OR 2.8; 95% CI 1.62-5.16; P < .001); and VEGF-C rs1485766 (AC: OR 2.18; 95% CI 1.19-3.99; P < .05) were associated with OSMF. The mean serologic levels of HIF-1 α, VEGF-A, and VEGF-C were significantly raised in patients with OSMF compared with healthy controls (P < .001). CONCLUSIONS: The SNPs of HIF-1 α, VEGF-A, and VEGF-C and their serologic levels can act as prognostic biomarkers and aid in the development of specialized anti-HIF-1 α or anti-VEGF drugs for the management and prevention of OSCC in patients with OSMF.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Fibrose Oral Submucosa , Tabaco sem Fumaça , Humanos , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Bucais/genética , Fibrose Oral Submucosa/genética , Projetos Piloto , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fator A de Crescimento do Endotélio Vascular
19.
Life Sci ; 261: 118372, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32882268

RESUMO

Despite remarkable progress in understanding and treating oral cancer (OC), it still remains one of the life-threatening diseases and predominant cancers in the world. Therefore, deciphering the molecular mechanisms of this disease would help us to develop highly efficacious therapies. Multiple lines of evidence suggest that calcium and its dysregulation play significant role in the development of various cancers. As an adaptation of survival mechanism, upon depletion of ER calcium stores, store-operated calcium entry (SOCE) has been induced via SOCE channels (SOCC) in various mammalian cells. SOCC are regulated by Orai-1, Orai-2 and Orai-3 located on plasma membrane and two calcium-sensing ER membrane proteins known as stromal interaction molecules (STIM-1 and STIM-2). Hence, the present study was aimed at analysing the role of Orai-1 and Orai-2 in oral cancer and the underlying mechanism. Our results suggest that both Orai-1 and Orai-2 proteins were overexpressed in oral cancer tissues and cell lines (SAS) compared to normal epithelial tissues and cell lines respectively. In addition, silencing of Orai-1 and Orai-2 via chemical SOCE inhibitors and siRNAs inhibited calcium uptake and suppressed oral cancer cell proliferation, colony formation and migration. Furthermore, silencing of Orai-1 and Orai-2 inhibited Akt/mTOR/NF-κB pathway in oral cancer cells. Interestingly, tobacco carcinogen NNN and synthetic carcinogen 4-NQO, enhanced the expression of Orai-1 and Orai-2 in SAS cells. Therefore, we conclude that Orai-1 and Orai-2 have significant role in oral cancer and can be further explored to develop novel therapies for the treatment of this disease.


Assuntos
Movimento Celular , Neoplasias Bucais/patologia , NF-kappa B/metabolismo , Proteína ORAI1/metabolismo , Proteína ORAI2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Cálcio/metabolismo , Sinalização do Cálcio , Carcinógenos/toxicidade , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Humanos , Neoplasias Bucais/genética , Transdução de Sinais/efeitos dos fármacos , Tabaco/química , Ensaio Tumoral de Célula-Tronco
20.
Artigo em Inglês | MEDLINE | ID: mdl-32773350

RESUMO

OBJECTIVES: The aim of this study was to evaluate the prevalence of CYP2 C9 polymorphism among healthy controls and patients with oral squamous cell carcinoma (OSCC) and to analyze the risk of disease development. We also investigated the interaction between CYP2 C9 wild type and the polymorphic variants with benzo[a]pyrene by using molecular docking analysis. STUDY DESIGN: The study included 46 patients with OSCC and 46 controls. Amplification of the genomic DNA was done by using allele-specific polymerase chain reaction and then analyzed by using agarose gel electrophoresis. Molecular docking was then carried out to determine the interaction of CYP2 C9*1, CYP2 C9*2, and CYP2 C9*3 with benzo[a]pyrene. RESULTS: In the OSCC group, CYP2 C9*2 and CYP2 C9*3 polymorphisms were 17.4% and 15.2%, respectively, and in the control group, they were 8.7% and 6.5%, respectively. The OSCC group showed a statistically significant (P = .043) increase in the prevalence of CYP2 C9 polymorphic variants compared with the control group. The docking analysis showed benzo[a]pyrene to bind specifically to the altered single nucleotide catalytic site in the polymorphic CYP2 C9*3 enzyme. CONCLUSIONS: This study demonstrates that functionally important CYP2 C9 polymorphism exists among patients with OSCC, with a modest increase in the risk of disease development in those individuals who acquire these poor metabolizing variants. The modified docking of CYP2 C9*3 with benzo[a]pyrene signifies altered metabolism in vivo.


Assuntos
Benzo(a)pireno/metabolismo , Carcinoma de Células Escamosas , Neoplasias Bucais , Alelos , Carcinoma de Células Escamosas/genética , Estudos de Casos e Controles , Humanos , Simulação de Acoplamento Molecular , Neoplasias Bucais/genética , Polimorfismo de Nucleotídeo Único/genética
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