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1.
Zhonghua Kou Qiang Yi Xue Za Zhi ; 55(10): 789-793, 2020 Oct 09.
Artigo em Chinês | MEDLINE | ID: mdl-33045793

RESUMO

Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignant tumors, which is prone to tumor recurrence and metastasis. At present, surgery combined with radiotherapy and chemotherapy is the conventional modality for HNSCC patients, but for patients who have tumor relapse or metastasis, the treatment outcome is not ideal and the prognosis is pretty poor. Thus, to deepen the understanding of tumor mechanism will be very crucial. Post-translational modification (PTM) refer to covalent binding of small chemical molecular groups on the amino acid side chain of proteins, which is an important way of protein function regulation as well as a research hotspot of epigenetics. In recent years, it has been found that the occurrence of tumor is often accompanied by the abnormality of PTM. The abnormality plays an important role in the development of tumor and can be used as a target of tumor diagnosis and treatment. Many types of protein PTM involve in the development of HNSCC. This paper reviews the relationship between HNSCC and several major protein PTM types, including acetylation, methylation, glycosylation, in order to provide clues for the clinicians in diagnosis and treatment of HNSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas de Cabeça e Pescoço , Carcinoma de Células Escamosas/genética , Neoplasias de Cabeça e Pescoço/genética , Humanos , Recidiva Local de Neoplasia , Processamento de Proteína Pós-Traducional
2.
Anticancer Res ; 40(10): 5417-5421, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988862

RESUMO

BACKGROUND: Type II diabetes agents have anticancer effects on head and neck squamous cell carcinoma (HNSCC). The mechanistic target of rapamycin (MTOR) pathway represents a putative target. MATERIALS AND METHODS: We interrogated an Affymetrix HNSCC dataset for MTOR-related gene expression. RESULTS: MTOR expression itself was unchanged, but various related genes demonstrated differential expression. Pathway promoters ras homolog (RHEB), MTOR-associated protein (MLST8), and ribosomal protein S6 kinase B1 (RPS6KB1) were up-regulated. Expression of growth suppressors tuberous sclerosis complex 2 (TSC2), programmed cell death 4 (PDCD4), and BCL2 apoptosis regulator-associated agonist of cell death (BAD) were reduced in HNSCC. Upstream, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), AKT serine/threonine kinase 1 (AKT1), and phosphatase and tensin homolog (PTEN) were up-regulated in cancer. CONCLUSION: Several MTOR pathway promoters and tumor suppressors were found to be differentially expressed, favoring MTOR pathway up-regulation in HNSCC. Genomic databases can be interrogated to identify intervention targets and endpoints in HNSCC trials.


Assuntos
Bases de Dados Genéticas , Neoplasias de Cabeça e Pescoço/genética , Proteínas de Neoplasias/genética , Serina-Treonina Quinases TOR/genética , Proteínas Reguladoras de Apoptose/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias de Cabeça e Pescoço/classificação , Neoplasias de Cabeça e Pescoço/patologia , Humanos , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas de Ligação a RNA/genética , Proteína Enriquecida em Homólogo de Ras do Encéfalo/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Transdução de Sinais/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteína de Morte Celular Associada a bcl/genética , Homólogo LST8 da Proteína Associada a mTOR/genética
3.
Nat Commun ; 11(1): 4788, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963234

RESUMO

Regenerative proliferation capacity and poor differentiation are histological features usually linked to poor prognosis in head and neck squamous cell carcinoma (hnSCC). However, the pathways that regulate them remain ill-characterized. Here, we show that those traits can be triggered by the RHO GTPase activator VAV2 in keratinocytes present in the skin and oral mucosa. VAV2 is also required to maintain those traits in hnSCC patient-derived cells. This function, which is both catalysis- and RHO GTPase-dependent, is mediated by c-Myc- and YAP/TAZ-dependent transcriptomal programs associated with regenerative proliferation and cell undifferentiation, respectively. High levels of VAV2 transcripts and VAV2-regulated gene signatures are both associated with poor hnSCC patient prognosis. These results unveil a druggable pathway linked to the malignancy of specific SCC subtypes.


Assuntos
Proliferação de Células , Neoplasias de Cabeça e Pescoço/metabolismo , Proteínas Proto-Oncogênicas c-vav/genética , Proteínas Proto-Oncogênicas c-vav/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Animais , Diferenciação Celular , Modelos Animais de Doenças , Epiderme/metabolismo , Epiderme/patologia , GTP Fosfo-Hidrolases , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Hiperplasia/patologia , Queratinócitos/patologia , Camundongos , Camundongos Knockout , Membrana Mucosa/metabolismo , Prognóstico , RNA Mensageiro/metabolismo , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Transcriptoma
4.
PLoS One ; 15(8): e0238120, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32833992

RESUMO

PURPOSE: Conjunctival squamous cell carcinoma (SCC) is primarily treated with surgical resection. SCC has various stages, and local recurrence is common. The purpose of this study was to determine molecular localization of epidermal growth factor receptor (EGFR) and the possibility of EGFR as a biomarker for the management of conjunctival SCC. METHODS: In this retrospective study, we performed immunohistochemistry to evaluate EGFR expression and localization in tumor cells, EGFR mutation-specific expression (E746-A750del and L858R), and human papillomavirus expression in a series of 29 conjunctival SCCs. RESULTS: All 29 tumors in our cohort were EGFR positive (100%). Twenty-one of 29 tumors (72%) showed focal EGFR staining, and seven (28%) showed diffuse EGFR staining. In addition, we calculated the percentages of the two most important mutations in EGFR (exon 19 746-A750del (8/29, 27.5%), exon 21 (L858R mutant (2/29, 6.8%)) in conjunctival SCCs. We observed that the translocation of EGFR from the membrane into the cytoplasm was related to clinical prognosis, as we detected correlations between EGFR cytoplasmic staining and final orbital exenteration and between decreased EGFR membrane staining and progression-free survival. CONCLUSIONS: EGFR is important in the pathology of ocular surface squamous neoplasia including SCC and is a prognostic factor. Increased understanding of EGFR mutations may have important implications for future treatment options.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias da Túnica Conjuntiva/genética , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/metabolismo , Estudos de Coortes , Neoplasias da Túnica Conjuntiva/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/genética , Humanos , Imuno-Histoquímica/métodos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Prognóstico , Estudos Retrospectivos
5.
Gene ; 757: 144927, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32628975

RESUMO

AIM: The incidence of head and neck cancer (HNC) is increasing but its pathogenic factors are complex. Changes in both internal (genetic) and external (environmental) causes HNC to some extent. The purpose of our study was to investigate the influence of IL1R1 polymorphisms on HNC risk in Chinese Han population. METHODS: Genotypes of 535 HNC patients and 538 healthy controls were analyzed by Agena MassARRAY. Odds ratio (ORs) and 95% confidence interval (CIs) were calculated by logistic regression analysis to evaluate the relationship between single nucleotide polymorphisms (SNPs) and HNC susceptibility. RESULTS: It was found that the rs956730 of IL1R1 reduced the risk of HNC in multiple models (allele: OR = 0.76, 95% CI: 0.62-0.93, p = 0.008; codominant: OR = 0.43, 95% CI: 0.25-0.75, p = 0.003; recessive: OR = 0.45, 95% CI: 0.26-0.77, p = 0.004; additive: OR = 0.77, 95% CI: 0.63-0.94, p = 0.01). IL1R1 rs956730 had a protective effect on HNC at age ≤ 46. However, the rs3917225 increased a 1.31-fold HNC risk in the codominant model (OR = 1.31, 95% CI: 1.00-1.70, p = 0.03). CONCLUSION: Our study showed that the rs956730 of IL1R1 gene in Chinese Han population was associated with a reduced risk of HNC, while the rs3917225 of IL1R1 might increase the risk of HNC.


Assuntos
Neoplasias de Cabeça e Pescoço/genética , Polimorfismo de Nucleotídeo Único , Receptores Tipo I de Interleucina-1/genética , Grupo com Ancestrais do Continente Asiático , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
6.
J Comput Assist Tomogr ; 44(4): 546-552, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32697524

RESUMO

PURPOSE: To determine the relationship between computed tomography (CT) radiomic features and gene expression levels in head and neck squamous cell carcinoma (HNSCC). METHODS: This retrospective study included 66 patients with HNSCC primary lesions (36 oropharyngeal, 6 hypopharyngeal, 10 laryngeal, 14 oral cavity). Gene expression information for 6 targetable genes (fibroblast growth factor receptor [FGFR]1, epidermal growth factor receptor [EGFR], FGFR2, FGFR3, EPHA2, PIK3CA) was obtained via Agilent microarrays from samples collected between 1997 and 2010. Pretreatment contrast-enhanced soft tissue neck CT scans were reviewed, and 142 radiomics features were derived. R was used to calculate Pearson correlation coefficients were calculated between gene expression levels and each radiomic feature. P values were adjusted using the false discovery rate (FDR) method. RESULTS: There were significant correlations between FGFR1 and 5 gray level cooccurrence matrix (GLCM) features with FDR-adjusted P values less than 0.05: inertia (r = 0.366, FDR-adjusted P = 0.006), absolute value (r = 0.31, FDR-adjusted P = 0.024), contrast (r = 0.366, FDR-adjusted P = 0.006), difference average (r = 0.31, FDR-adjusted P = 0.024), and difference variance (r = 0.37, FDR-adjusted P = 0.005). There was 1 correlated feature for FGFR2 with an FDR-adjusted P value less than 0.05: fractal dimension box-coarse (r = 0.33, FDR-adjusted P = 0.018). There was 1 correlated feature for EPHA2 with an FDR-adjusted P value less than 0.05: GLCM entropy (r = -0.28, FDR-adjusted P = 0.049). Six of the 7 features that showed significant correlation belonged to the GLCM class of features. CONCLUSIONS: The CT radiomic features demonstrate correlations with FGFR1 status in HNSCC and should be further investigated for their potential to predict FGFR1 status.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Efrina-A2/genética , Perfilação da Expressão Gênica/métodos , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Receptores de Fatores de Crescimento de Fibroblastos/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Receptores ErbB/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Humanos , Masculino , Pessoa de Meia-Idade , Medicina de Precisão , Interpretação de Imagem Radiográfica Assistida por Computador , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Tomografia Computadorizada por Raios X/métodos
7.
J Cancer Res Ther ; 16(3): 405-409, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719244

RESUMO

Activation of inflammasomes has a decisive role in host defense mechanism against pathogens and other intracellular risk factors, but recently, it has been revealed that they play a significant role in the pathogenesis of several diseases, including cancer. Nod-like receptor protein 3 (NLRP3) inflammasome, the best-studied inflammasome, has contrasting roles in cancer development and progressions. In head-and-neck cancers, the upregulated level of NLRP3 promotes tumor progression. The main objective of this review is to provide current knowledge on the involvement of NLRP3 inflammasome in head-and-neck cancers. Deeper understanding of the biology of this dynamic protein complex provides new scope for the development of more effective anticancer therapies.


Assuntos
Neoplasias de Cabeça e Pescoço/patologia , Imunidade Inata , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais
8.
J Cancer Res Ther ; 16(3): 410-424, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719245

RESUMO

Development of human genetic and proteomic research has increased the interest in alternative head-and-neck cancer (HNC) detection methods. The aim of this article, the second of two-part series, was to review the scientific literature about novel HNC genetic and proteomic biomarkers. A comprehensive review of the current literature was conducted according to the Preferred Reporting Item for Systematic Review and Meta-analyses guidelines by accessing the NCBI PubMed database. Authors conducted the search of articles in English language published from 2004 to 2015. A total of 50 relevant studies were included in the review. Thirty of them concerned proteomic and twenty genetic alterations in HNC. The present systematic review discovered 242 genes and 44 proteins associated with HNC. Due to inconsistent and sparse results, novel biomarkers cannot be firmly established. Prognostic capacity of genetic markers was not evaluated. Proteins (14-3-3γ, extracellular matrix metalloproteinase inducer, and PA28γ) were described as most valuable for prognostic observation of HNC. A strict methodological protocol for molecular studies must be established.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/patologia , Mutação , Proteômica/métodos , Perfilação da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Prognóstico
9.
DNA Cell Biol ; 39(10): 1789-1798, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32716650

RESUMO

Head and neck squamous cell carcinoma (HNSCC) is a malignancy with relatively high incidence and poor prognosis. RNA-binding proteins (RBPs) were reported to be dysregulated in multiple cancers and were closely associated with tumor initiation and progression. However, an integrated analysis of the roles of RBPs in HNSCC has not been conducted. In the present study, we obtained transcriptome data and corresponding clinical information of HNSCC patients from The Cancer Genome Atlas database and screened out differentially expressed RBPs between tumor and normal tissues. Subsequently, we utilized a series of bioinformatics analyses to elucidate the potential functions and prognostic value of these RBPs in HNSCC. As a result, a total of 88 aberrantly expressed RBPs were identified, including 63 downregulated and 25 upregulated RBPs. Functional enrichment analysis suggested that the differentially expressed RBPs mainly participated in mRNA metabolic processes, RNA processing, RNA transport, regulation of RNA stability, RNA degradation, and mRNA surveillance pathway. Three RBP genes (NOVA1, EZH2, and RBM24) were determined as prognosis-related hub genes from which EZH2 and NOVA1 were selected to construct a prognostic signature based on LASSO Cox regression algorithm. Further analysis demonstrated that the high-risk patient group stratified by the risk signature has advanced tumor grade and poorer overall survival when compared with low-risk group. Moreover, univariate analysis showed that the risk score, tumor stage, T stage, and N stage were significantly associated with patient overall survival and the multivariate analysis results indicated that the risk score and age were greatly correlated with patient prognosis. Overall, this study provided a comprehensive landscape of RBPs in HNSCC and identified an effective gene signature for predicting the clinical outcomes of HNSCC patient, which may contribute to clinical decision making and individualized cancer treatment.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeça e Pescoço/genética , Proteínas de Ligação a RNA/genética , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Feminino , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a RNA/metabolismo , Análise de Sobrevida
10.
Mol Cell ; 79(3): 425-442.e7, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32615088

RESUMO

Double-strand breaks (DSBs) are the most deleterious DNA lesions, which, if left unrepaired, may lead to genome instability or cell death. Here, we report that, in response to DSBs, the RNA methyltransferase METTL3 is activated by ATM-mediated phosphorylation at S43. Phosphorylated METTL3 is then localized to DNA damage sites, where it methylates the N6 position of adenosine (m6A) in DNA damage-associated RNAs, which recruits the m6A reader protein YTHDC1 for protection. In this way, the METTL3-m6A-YTHDC1 axis modulates accumulation of DNA-RNA hybrids at DSBs sites, which then recruit RAD51 and BRCA1 for homologous recombination (HR)-mediated repair. METTL3-deficient cells display defective HR, accumulation of unrepaired DSBs, and genome instability. Accordingly, depletion of METTL3 significantly enhances the sensitivity of cancer cells and murine xenografts to DNA damage-based therapy. These findings uncover the function of METTL3 and YTHDC1 in HR-mediated DSB repair, which may have implications for cancer therapy.


Assuntos
Adenosina/análogos & derivados , Neoplasias de Cabeça e Pescoço/genética , Metiltransferases/genética , Proteínas do Tecido Nervoso/genética , Fatores de Processamento de RNA/genética , Reparo de DNA por Recombinação/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Adenosina/metabolismo , Animais , Antibióticos Antineoplásicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Bleomicina/farmacologia , Linhagem Celular Tumoral , DNA/genética , DNA/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Células HEK293 , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Metiltransferases/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas do Tecido Nervoso/metabolismo , Hibridização de Ácido Nucleico , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/patologia , Fosforilação , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Fatores de Processamento de RNA/metabolismo , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo , Ribonuclease H/genética , Ribonuclease H/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Gene ; 754: 144880, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32526260

RESUMO

Cancer secretion can change the properties of adjacent cells, including peripheral blood mononuclear cells (PBMCs). We investigated whether such secretion influences messenger RNA expression in PBMCs of patients with head and neck squamous cell carcinoma (HNSCC). In the present study, co-culture model of normal PBMCs and HNSCC cell lines were established. The PBMCs were subsequently subjected to RNA sequencing for transcriptome analysis. Furthermore, expression data from the Gene Expression Omnibus repository, platform GPL4133, series GSE39400, were gathered to analyze, afterward identify zinc finger CysCysHisCys (CCHC)-type domain-containing protein 6 (ZCCHC6) as the main gene involved in HNSCC. This gene was then validated by a quantitative real-time polymerase chain reaction. The results showed that ZCCHC6 was expressed at significantly higher levels in the patients with HNSCC than in the healthy controls, and the sensitivity and specificity of these findings for diagnostic purposes were 100.00% and 70.83%, respectively. In summary, our findings demonstrated that the secretion of HNSCC cells could cause the alterations in messenger RNA expression by PBMCs. The ZCCHC6 expression level may apply in HNSCC screening.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias de Cabeça e Pescoço/sangue , Leucócitos Mononucleares/metabolismo , RNA Nucleotidiltransferases/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/sangue , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
12.
PLoS One ; 15(5): e0233380, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32437477

RESUMO

Alternative mRNA splicing increases protein diversity, and alternative splicing events (ASEs) drive oncogenesis in multiple tumor types. However, the driving alterations that underlie the broad dysregulation of ASEs are incompletely defined. Using head and neck squamous cell carcinoma (HNSCC) as a model, we hypothesized that the genomic alteration of genes associated with the spliceosome may broadly induce ASEs across a broad range of target genes, driving an oncogenic phenotype. We identified 319 spliceosome genes and employed a discovery pipeline to identify 13 candidate spliceosome genes altered in HNSCC using The Cancer Genome Atlas (TCGA) HNSCC data. Phenotypic screens identified amplified and overexpressed CPSF1 as a target gene alteration that was validated in proliferation, colony formation, and apoptosis assays in cell line and xenograft systems as well as in primary HNSCC. We employed knockdown and overexpression assays followed by identification of ASEs regulated by CPSF1 overexpression to identify changes in ASEs, and the expression of these ASEs was validated using RNA from cell line models. Alterations in expression of spliceosome genes, including CPSF1, may contribute to HNSCC by mediating aberrant ASE expression.


Assuntos
Fator de Especificidade de Clivagem e Poliadenilação/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Processamento Alternativo , Biomarcadores Tumorais , Fator de Especificidade de Clivagem e Poliadenilação/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
13.
Anticancer Res ; 40(5): 2627-2635, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366407

RESUMO

BACKGROUND/AIM: Head and neck squamous cell carcinoma (HNSCC) is an aggressive head and neck malignancy. The aim of this study was to elucidate the role of periostin (POSTN) in the epithelial-to-mesenchymal transition (EMT) process mediating the acquisition of radioresistance in HNSCC. MATERIALS AND METHODS: The expression levels of EMT hallmark genes including POSTN and Erk/Akt signaling pathways were compared between radiosensitive and radioresistant HNSCC cells. RESULTS: POSTN mRNA expression was higher in radioresistant HNSCC cells, and silencing POSTN significantly impaired their invasiveness under the effect of EMT process represented by up-regulation of mesenchymal markers and down-regulation of an epithelial marker. Expression levels of Erk and Akt were higher in radioresistant cells. CONCLUSION: POSTN in association with the Erk and Akt signaling pathways was up-regulated during the EMT process, leading to the conversion of radiosensitive to radioresistant HNSCC cells. POSTN may be a key marker for predicting the radioresistance and therapeutic target of HNSCC.


Assuntos
Moléculas de Adesão Celular/metabolismo , Transição Epitelial-Mesenquimal , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Tolerância a Radiação , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Epitélio/metabolismo , Epitélio/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Humanos , Mesoderma/patologia , Invasividade Neoplásica , Tolerância a Radiação/genética , Transdução de Sinais/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
14.
Medicine (Baltimore) ; 99(11): e19491, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176088

RESUMO

PROM1 has played a pivotal role in the identification and isolation of tumor stem cells. This study aimed to assess the association between PROM1 promoter methylation and head and neck squamous cell carcinoma (HNSCC), and its diagnostic and prognostic value.Bioinformatic analysis was performed using data from the Cancer Genome Atlas-HNSC and Gene Expression Omnibus datasets.The results showed that PROM1 promoter was hypermethylated in HNSCCs compared with normal head and neck tissues (P = 4.58E-37). The area under the receiver-operating characteristic curve based on methylated PROM1 data was 0.799. In addition, PROM1 hypermethylation independently predicted poor overall survival (hazard ratio [HR]: 1.459, 95% confidence interval [CI]: 1.071-1.987, P = .016) and recurrence-free survival (HR: 1.729, 95% CI: 1.088-2.749, P = .021) in HNSCC patients. Moreover, PROM1 methylation was weakly negatively correlated with its mRNA expression (Pearson r = -0.148, P < .001).In summary, our study reveals that methylated PROM1 might serve as a valuable diagnostic biomarker and predictor of poor survival for HNSCC patients. PROM1 hypermethylation might partially contribute to its downregulation in HNSCC.


Assuntos
Antígeno AC133/genética , Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço/genética , Recidiva Local de Neoplasia/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Grupo com Ancestrais do Continente Asiático , Biomarcadores Tumorais/genética , China/epidemiologia , Mineração de Dados , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Análise de Sobrevida
15.
Asian Pac J Cancer Prev ; 21(3): 663-665, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32212791

RESUMO

BACKGROUND AND OBJECTIVE: X-ray repair cross-complementing group1 (XRCC1) is a key protein in base excision repair and closely associated with the coordination of the base excision repair pathway. Many studies have focused on XRCC1 SNPs and have shown an associated between these SNPs and the risk of several types of cancers, including head and neck cancer. There are many single nucleotide polymorphisms XRCC1 gene (SNPs) and the most common SNP that result in amino acid substitutions is exon 10 (Arg399Gln). This study aimed to investigate the association between Arg399Gln SNP and the risk of squamous cell carcinoma of the head and neck. MATERIAL AND METHOD: Ninety nine patients with squamous cell carcinomas of the head and neck and 89 healthy adult controls were enrolled in this study. The Arg399Gln in XRCC1 allele was genotyped using polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: In the single-locus analyses, Arg399Gln SNP showed a significant association with head and neck cancer risk (p value = 0.016 and odd ratio of 1.8). On the genotype level, we applied three analysis models, namely co-dominant, dominant, and recessive genotypes. Arg/Arg homozygous major genotype was significantly (p value <0.05) associated with head and neck squamous cell carcinoma incidence with odd ratio of 2.23 and 2.24 for the co-dominant and recessive models, respectively. CONCLUSION: The findings indicated that Arg399Gln allele was associated with squamous cell carcinoma of the head and neck among Jordanian patients. This allele might be used as a genetic biomarker of squamous cell carcinoma of the head and neck.


Assuntos
Neoplasias de Cabeça e Pescoço/genética , Polimorfismo de Nucleotídeo Único , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Adulto , Idoso , Arginina/genética , Feminino , Glutamina/genética , Humanos , Masculino , Pessoa de Meia-Idade
16.
Science ; 367(6483): 1264-1269, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32165588

RESUMO

In most human cancers, only a few genes are mutated at high frequencies; most are mutated at low frequencies. The functional consequences of these recurrent but infrequent "long tail" mutations are often unknown. We focused on 484 long tail genes in head and neck squamous cell carcinoma (HNSCC) and used in vivo CRISPR to screen for genes that, upon mutation, trigger tumor development in mice. Of the 15 tumor-suppressor genes identified, ADAM10 and AJUBA suppressed HNSCC in a haploinsufficient manner by promoting NOTCH receptor signaling. ADAM10 and AJUBA mutations or monoallelic loss occur in 28% of human HNSCC cases and are mutually exclusive with NOTCH receptor mutations. Our results show that oncogenic mutations in 67% of human HNSCC cases converge onto the NOTCH signaling pathway, making NOTCH inactivation a hallmark of HNSCC.


Assuntos
Genes Supressores de Tumor , Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Proteínas Supressoras de Tumor/genética , Proteína ADAM10/genética , Secretases da Proteína Precursora do Amiloide/genética , Animais , Sistemas CRISPR-Cas , Feminino , Testes Genéticos , Células HEK293 , Humanos , Proteínas com Domínio LIM/genética , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Mutação , Receptores Notch/genética , Transdução de Sinais/genética
17.
PLoS One ; 15(3): e0221779, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32208417

RESUMO

BACKGROUNDS: MicroRNAs (miRNA) are a class of non-protein-coding RNAs that have significant biological and pathological functions. The importance of miRNAs as potential cancer diagnostic biomarkers is gaining attention due to their influence in the regulation of cellular processes such as cell differentiation, proliferation and apoptosis. The aim of this study was to identify significant miRNAs from saliva as potential diagnostic biomarkers in the early diagnosis and prognosis of head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Five differentially expressed miRNAs (miR-7703, miR- let-7a-5p, miR- 345-5p, miR- 3928 and miR- 1470) were selected from Next Generation Sequencing (NGS) miRNA data generated from our previous study using saliva of 12 HNSCC patients and 12 healthy controls. Their differential expressed miRNAs were subsequently validated by RT-qPCR using saliva samples from healthy controls (n = 80) and HNSCC patients (n = 150). Total RNA was isolated from 150 saliva samples of HNSCC patients and was transcripted into cDNA by TaqMan MicroRNA Reverse Transcription Kit. Using quantitative RT-PCR analysis, salivary miRNAs were identified in HNSCC patients (n = 150) and healthy controlled cases (n = 80). T-tests were used to compare the differences among the various clinical variants. RESULTS: On average 160 ng/µl was isolated from 500 µl of saliva. Overall, a good correlation observed between the HNSCC and some of miRNAs expression levels. Salivary miR-let-7a-5p (P<0.0001) and miR-3928 (P< 0.01) were significantly down regulated in saliva of HNSCC patients relative to age and sex-matched healthy controls. A number of salivary miRNAs (miR-let-7a-5p and miR-3928) were correlated with lymph node metastasis (p = 0.003, p = 0.049) and tumour size (p = 0.01, p = 0.02), respectively. However, our preliminary analysis showed no significant differences in salivary miR-1470, miR-345-5p or miR-7703 expression between patients and healthy controls. Most notably, our analysis showed that salivary miR-let-7a-5p and miR-3928 expression levels have significant sensitivity and specificity to distinguish between patients with HNSCC and healthy controls. CONCLUSION: This study concluded that salivary miR-let-7a-5p and miR-3928 has the potential to be novel non-invasive biomarkers for early detection and prognosis of HNSCC.


Assuntos
Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/genética , MicroRNAs/genética , Saliva/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Biomarcadores Tumorais/genética , Regulação para Baixo , Detecção Precoce de Câncer , Feminino , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Metástase Linfática/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma , Carga Tumoral/genética
18.
DNA Cell Biol ; 39(5): 909-917, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32150689

RESUMO

The aims of this study were to investigate the expression of prolyl 4-hydroxylase subunit alpha-1 (P4HA1) and its relationship with clinicopathological features in lung cancer (LC), breast cancer (BC), and head and neck cancer (HNSC) and to discuss the possibility of P4HA1 being a potential diagnostic and prognostic biomarker. Data on the RNA expression profile, protein expression profile, and relevant clinical information were downloaded from The Cancer Genome Atlas (TCGA) and The Human Protein Atlas databases. The relationship between P4HA1 mRNA expression and clinicopathological features was evaluated. Survival analysis was performed to assess overall survival (OS) and relapse-free survival (RFS). The multivariate Cox regression model was employed to analyze the independent prognostic factors. Finally, protein-protein interaction networks were constructed and enrichment analysis was performed to identify the latent P4HA1-related terms and pathways. This study showed that P4HA1 was upregulated in three types of tumor tissues (p < 0.05) and high P4HA1 was significantly relevant to the clinical features of patients with LC, BC, or HNSC. Survival analysis indicated that patients with high P4HA1 had unfavorable clinical outcomes. Multivariate analysis showed that the high P4HA1 expression was an independent prognostic factor for poor OS and RFS in LC and HNSC patients. Bioinformatic analysis was performed to predict P4HA1-interacted proteins and further evaluate possible signal pathways. In the current study, the rising P4HA1 was identified in LC, BC, and HNSC and significantly correlated with the clinicopathological features of patients. High P4HA1, suggesting poor clinical outcomes, could be used as an early diagnostic and prognostic biomarker for patients with aforementioned tumors.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias/diagnóstico , Neoplasias/genética , Pró-Colágeno-Prolina Dioxigenase/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Genômica , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Prognóstico , Análise de Sobrevida
19.
Am J Surg Pathol ; 44(5): 607-616, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32187044

RESUMO

Rhabdomyosarcoma (RMS) encompasses a heterogenous collection of tumors in which new groups have recently been identified that improved the World Health Organization (WHO) classification. While performing RNA-sequencing in our routine practice, we identified 3 cases of well-differentiated RMS harboring new fusion genes. We also analyzed these tumors through array-comparative genomic hybridization. Clinically, these tumors were deep paraspinal tumors, occurring in neo-nat and young children. The patients underwent resection and adjuvant therapy. At the time of last follow-up (ranging from 12 to 108 mo), they were alive without disease. Histologically, these tumors consisted of well-differentiated rhabdomyoblastic proliferations with nuclear atypia, infiltrative borders, and a specific growth pattern. These tumors harbored new fusion genes involving SRF and either FOXO1 or NCOA1. We compared the expression profiles of these 3 tumors to the expression data of a series of 33 skeletal muscle tumors including embryonal RMSs, alveolar rhandomyosarcomas, RMSs with VGLL2 fusions, RMSs with the myoD1 mutation, EWSR1/FUS-TFCP2 epithelioid and spindle cell RMSs of the bone, and rhabdomyomas with PTCH1 loss. According to clustering analyses, the 3 SRF-fused tumors formed a distinct group with a specific expression profile different from that of the other types of skeletal muscle tumors. Array-comparative genomic hybridization showed a recurrent gain of chromosome 11. These 3 tumors define a new group of RMS associated with a fusion of the SRF gene. FOXO1 rearrangements, usually used to confirm the diagnosis of alveolar RMS and identify poor-outcome RMSs, were identified in a nonalveolar RMS for the first time.


Assuntos
Biomarcadores Tumorais/genética , Proteína Forkhead Box O1/genética , Fusão Gênica , Neoplasias de Cabeça e Pescoço/genética , Coativador 1 de Receptor Nuclear/genética , Rabdomiossarcoma/genética , Fator de Resposta Sérica/genética , Diferenciação Celular , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço/classificação , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Músculos do Pescoço/patologia , Músculos Paraespinais/patologia , Fenótipo , Rabdomiossarcoma/classificação , Rabdomiossarcoma/patologia , Rabdomiossarcoma/terapia , Análise de Sequência de RNA , Resultado do Tratamento
20.
Nat Commun ; 11(1): 1556, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32214092

RESUMO

c-MET receptors are activated in cancers through genomic events like tyrosine kinase domain mutations, juxtamembrane splicing mutation and amplified copy numbers, which can be inhibited by c-MET small molecule inhibitors. Here, we discover that the most common polymorphism known to affect MET gene (N375S), involving the semaphorin domain, confers exquisite binding affinity for HER2 and enables METN375S to interact with HER2 in a ligand-independent fashion. The resultant METN375S/HER2 dimer transduces potent proliferative, pro-invasive and pro-metastatic cues through the HER2 signaling axis to drive aggressive squamous cell carcinomas of the head and neck (HNSCC) and lung (LUSC), and is associated with poor prognosis. Accordingly, HER2 blockers, but not c-MET inhibitors, are paradoxically effective at restraining in vivo and in vitro models expressing METN375S. These results establish METN375S as a biologically distinct and clinically actionable molecular subset of SCCs that are uniquely amenable to HER2 blocking therapies.


Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptor ErbB-2/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Linhagem Celular Tumoral , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Camundongos , Mutação , Fenótipo , Fosforilação/efeitos dos fármacos , Polimorfismo Genético , Prognóstico , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/química , Receptor ErbB-2/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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