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1.
Gene ; 723: 144142, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31589957

RESUMO

DNA methylation is an epigenetic alteration that may lead to carcinogenesis by silencing key tumor suppressor genes. Hypermethylation of the paired box gene 1 (PAX1) promoter is important in cervical cancer development. Here, PAX1 methylation levels were compared between Uyghur and Han patients with cervical lesions. Data on PAX1 methylation in different cervical lesions were obtained from the Gene Expression Omnibus (GEO) database, whereas data on survival and PAX1 mRNA expression in invasive cervical cancer (ICC) were retrieved from the Cancer Genome Atlas (TCGA) database. MassARRAY spectrometry was used to detect methylation of 19 CpG sites in the promoter region of PAX1, whereas gene mass spectrograms were drawn by Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry. Human papillomavirus (HPV) 16 infection was detected by polymerase chain reaction. PAX1 methylation in high-grade squamous intraepithelial lesion (HSIL) and ICC was significantly higher than in normal tissues. PAX1 hypermethylation was associated with poor prognosis and reduced transcription. ICC-specific PAX1 promoter methylation involved distinct CpG sites in Uyghur and Han patients HPV16 infection in HSIL and ICC patient was significantly higher than in normal women (p < 0.05). Our study revealed a strong association between PAX1 methylation and the development of cervical cancer. Moreover, hypermethylation of distinct CpG sites may induce HSIL transformation into ICC in both Uyghur and Han patients. Our results suggest the existence of ethnic differences in the genetic susceptibility to cervical cancer. Finally, PAX1 methylation and HPV infection exhibited synergistic effects on cervical carcinogenesis.


Assuntos
Carcinoma de Células Escamosas/virologia , Metilação de DNA , Papillomavirus Humano 16/patogenicidade , Fatores de Transcrição Box Pareados/genética , Infecções por Papillomavirus/diagnóstico , Lesões Intraepiteliais Escamosas Cervicais/virologia , Neoplasias do Colo do Útero/virologia , Carcinoma de Células Escamosas/genética , China/etnologia , DNA Viral/genética , Bases de Dados Factuais , Regulação para Baixo , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Papillomavirus Humano 16/genética , Humanos , Infecções por Papillomavirus/genética , Prognóstico , Regiões Promotoras Genéticas , Lesões Intraepiteliais Escamosas Cervicais/genética , Análise de Sobrevida , Neoplasias do Colo do Útero/genética
2.
Anticancer Res ; 39(10): 5573-5579, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570452

RESUMO

BACKGROUND/AIM: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer, frequently infected with Merkel cell polyomavirus (MCPyV). H3K27me3 acts as a repressive histone modification that epigenetically controls gene transcription. The aim of this study was to examine H3K27me3 expression in MCC. MATERIALS AND METHODS: H3K27me3 expression levels were immunohistochemically analyzed in 20 MCPyV-positive MCCs, 15 MCPyV-negative MCCs with squamous cell carcinoma (SCC) (combined MCCs), and six MCPyV-negative pure MCCs. RESULTS: Reduced H3K27me3 expression was variously observed in MCCs. H3K27me3 H-score was significantly lower in MCPyV-negative MCCs than in MCPyV-positive MCCs (p=0.002). H3K27me3 expression was significantly lower in MCPyV-negative combined MCC component than in MCPyV-positive MCCs (p<0.001), MCPyV-negative pure MCCs (p=0.036), or pure MCC histology (p<0.001). Kaplan-Meier analysis showed no association of H3K27me3 with outcome. CONCLUSION: Differential reduction in H3K27me3 expression was observed based on MCPyV status and morphological type. These results implicate H3K27me3-mediated epigenetic changes in tumorigenesis of MCC, especially in MCPyV-negative MCC combined with SCC.


Assuntos
Carcinoma de Célula de Merkel/genética , Carcinoma de Células Escamosas/genética , Histonas/genética , Neoplasias Cutâneas/genética , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/genética , Carcinoma de Célula de Merkel/virologia , Carcinoma de Células Escamosas/virologia , Epigênese Genética/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Poliomavírus das Células de Merkel/patogenicidade , Pessoa de Meia-Idade , Infecções por Polyomavirus/genética , Infecções por Polyomavirus/virologia , Neoplasias Cutâneas/virologia , Infecções Tumorais por Vírus/genética , Infecções Tumorais por Vírus/virologia
3.
Anticancer Res ; 39(10): 5623-5630, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570459

RESUMO

BACKGROUND: This study aimed to investigate p16 and COX2 expression in oropharyngeal squamous cell carcinoma (OPSCC), and evaluate the prognostic role of COX2 expression under the new TNM classification. MATERIALS AND METHODS: Biopsy specimens obtained from 75 patients with OPSCC were stained for p16 and COX2 expression immunohistochemically. The results and clinical records were analyzed retrospectively. RESULTS: Fifty-nine patients (79%) were positive for p16. COX2 expression was correlated with poor relapse-free survival in patients overall, and in p16-positive patients. Smoking was positively associated with COX2 expression. Moreover, both positive COX2 expression and anterior wall tumor subsite were independently correlated with lymph node metastasis, which was the only independent prognostic factor in p16-positive OPSCC. CONCLUSION: The p16-positive rate in this study was comparable with that in the USA and Europe, and higher than that in other Asian countries. COX2 expression might affect the prognosis of p16-positive OPSCC through promoting lymph node metastasis.


Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Metástase Linfática/genética , Metástase Linfática/patologia , Neoplasias Orofaríngeas/genética , Neoplasias Orofaríngeas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidor p16 de Quinase Dependente de Ciclina/genética , Ciclo-Oxigenase 2/genética , Intervalo Livre de Doença , Feminino , Humanos , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias/métodos , Prognóstico , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
4.
Medicine (Baltimore) ; 98(43): e17651, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651887

RESUMO

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the leading histological type among head and neck cancers. Several studies have explored an association between aberrant methylation of MutL homolog-1 (MLH1) promoter and HNSCC risk. We aimed to explore the associations between MLH1 promoter methylation and HNSCC by using a meta-analysis. METHODS: Systematic literature search was conducted among PubMed, Google Scholar, Web of Science, and China National Knowledge Infrastructure, and Wanfang databases to retrieve relevant articles published up to June 30, 2018. A total of 12 studies were included in this meta-analysis (including 717 HNSCC and 609 controls). RESULTS: The results demonstrated that MLH1 promoter methylation was notably higher in patients with HNSCC than in controls (odds ratios [ORs] = 2.52, 95% confidence intervals [CIs] = 1.33-4.79). Besides, MLH1 promoter methylation was not associated with tumor stage, lymph node status, smoking behavior, age, clinical stage, gender, and differentiation grade (all P > .05). The pooled sensitivity and specificity rates of MLH1 methylation for HNSCC were 0.23 (95% CI = 0.12-0.38) and 0.95 (95% CI, 0.82-0.99), respectively. The area under the receiver operating characteristic (ROC) curve was presented as 0.64 (95% CI = 0.60-0.68). CONCLUSION: The results of this meta-analysis suggested that hypermethylation of MLH1 promoter was associated with HNSCC. Methylated MLH1 could be a potential diagnostic biomarker for diagnose of HNSCC.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias de Cabeça e Pescoço/genética , Proteína 1 Homóloga a MutL/genética , Biomarcadores Tumorais/genética , Metilação de DNA , Humanos , Regiões Promotoras Genéticas
5.
Medicine (Baltimore) ; 98(38): e17225, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31567982

RESUMO

The present study is to analyze the difference of gene methylation in early cervical adenocarcinoma and to find molecular markers for predicting the occurrence and development of cervical adenocarcinoma.A total of 15 cases of primary cervical adenocarcinoma and 10 cases of primary cervical squamous cell carcinoma at stages IB1 or IIA1 were included in the study. Infinium MethylationEPIC BeadChip (850K) was used to screen specifically expressed genes in cervical adenocarcinoma tissues. Bisulfite sequencing polymerase chain reaction (BSP) and quantitative real-time polymerase chain reaction (qRT-PCR) were used to verify the methylation levels in cervical adenocarcinoma, cervical squamous cell carcinoma, and normal cervical tissues.Sex determining region Y-box 1 (SOX1) and cyclin D1 (CCND1) genes participated in multiple signaling pathways, being the central nodes of gene regulatory networks. SOX1 gene, but not CCND1 gene, was a specifically methylated gene in cervical adenocarcinoma according to BSP. According to qRT-PCR, methylation level of SOX1 in cervical adenocarcinoma tissues is significantly different from that in cervical squamous cell carcinoma tissues or normal cervical tissues, and the methylation level of CCND1 in cervical adenocarcinoma tissues or cervical squamous cell carcinoma tissues is significantly different from that in normal cervical tissues.The present study demonstrates that tumor-suppressor gene SOX1 is a methylation-specific expression gene of cervical adenocarcinoma and is expected to become a specific molecular marker for the diagnosis of cervical adenocarcinoma. However, CCND1 gene was not proven to be a specific methylation expression gene in cervical adenocarcinoma in the present study.


Assuntos
Adenocarcinoma/genética , Metilação de DNA/genética , Fatores de Transcrição SOXB1/genética , Neoplasias do Colo do Útero/genética , Adenocarcinoma/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Colo do Útero/metabolismo , Ciclina D1/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/genética , Marcadores Genéticos/genética , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias do Colo do Útero/metabolismo
6.
J Cancer Res Clin Oncol ; 145(11): 2663-2674, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31541338

RESUMO

BACKGROUND: It is known that there are insufficient prognostic factors for non-small cell lung cancer (NSCLC). It was reported that PD-L1 was a prognostic factor for NSCLC,and c-Myc regulated the expression of PD-L1. Herein, we investigated c-Myc and PD-L1 expression and their association with overall survival (OS) in NSCLC. METHODS: Formalin-fixed paraffin-embedded specimens were obtained from 128 patients with surgically resected primary NSCLC. Immunohistochemistry was used to assess the expression of PD-L1 and c-Myc in this study. Pearson's Chi squared test or Fisher's exact test was used to analyze the correlation of the expression of PD-L1 and c-Myc with clinicopathologic features. The relationship between OS and the expression of PD-L1 and c-Myc was evaluated by the Kaplan-Meier method and Cox proportional hazards model, respectively. RESULTS: Positive expression of PD-L1 was detected in 59 patients (46.1%). Patients with negative expression of PD-L1 had remarkably longer OS than those with positive expression of PD-L1. The positive expression rate of c-Myc in NSCLC accounted for 58.6% (75/128) and its expression was significantly more frequent in males (p = 0.002) and patients with lymph node metastasis (p = 0.029). PD-L1 expression was positively correlated with c-Myc expression (r = 0.459, p < 0.001). The PD-L1 and c-Myc double-positive group had a worse prognosis than other subgroups (p < 0.05), and the PD-L1 and c-Myc double-negative group had a better OS than other subgroups (p < 0.05). CONCLUSION: Conjoint analysis of the expression of PD-L1 and c-Myc was a better prognostic approach for NSCLC patients.


Assuntos
Adenocarcinoma/secundário , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/secundário , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-myc/genética , Taxa de Sobrevida
7.
Shanghai Kou Qiang Yi Xue ; 28(3): 225-230, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31489406

RESUMO

PURPOSE: To investigate the mechanism of ANXA1 in TPF chemotherapy of oral squamous cell carcinoma (OSCC). METHODS: ANXA1 overexpression and low-expression cell lines were constructed. The role of ANXA1 in TPF chemotherapy was analyzed by cell proliferation, cytotoxicity test, real-time PCR and Western blot, and the mechanism of ANXA1 in TPF chemotherapy through EMT (epithelial-mesenchymal transition) pathway was discussed. The data were analyzed with SPSS 18.0 software package. RESULTS: After overexpression of ANXA1, cell growth rate decreased, cell cycle slowed down, sensitivity to TPF-induced drugs decreased, and EMT occurred in OSCC. After underexpression of ANXA1, cell growth rate increased, cell cycle accelerated, sensitivity to TPF chemotherapeutic drugs increased, and reverse EMT occurred in OSCC. CONCLUSIONS: In TPF chemotherapy of OSCC, overexpression of ANXA1 results in EMT of cells, which leads to decreased chemosensitivity.


Assuntos
Anexina A1 , Antineoplásicos , Carcinoma de Células Escamosas , Transição Epitelial-Mesenquimal , Neoplasias Bucais , Anexina A1/metabolismo , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/genética
8.
Artigo em Chinês | MEDLINE | ID: mdl-31446726

RESUMO

Objective:The aim of this study is to explore the relative expression level of LINC00152 in laryngeal squamous cell carcinoma(LSCC) and its clinical significance. Method:The relative expression levels of LINC00152 in LSCC cell lines and 36 paired LSCC specimens were measured by qRT-PCR method. And the correlations between the expression level of LINC00152 and the clinical features derived from LSCC patients were analyzed and compared through the independent sample t-test. Result:The relative expression level of LINC00152 was over-expressed in LSCC cell lines and cancerous tissues than that in paired adjacent normal tissues, and the difference was statistically significant(P=0.006). Even the associations between LINC00152 expression level and clinicopathological features(P=0.044 for clinical stage, P=0.032 for pathological differentiation degree) were significantly. Conclusion:LINC00152 is highly expressed in LSCC and it may become a new tumor marker for the diagnosis and prognosis of LSCC.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Laríngeas/genética , RNA Longo não Codificante/genética , Biomarcadores Tumorais/genética , Humanos , Prognóstico
9.
Anticancer Res ; 39(8): 4129-4136, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366497

RESUMO

BACKGROUND/AIM: 5-Aza-2-deoxycytidine (5-Aza-CdR) enhances the sensitivity to 5-fluorouracil (5-FU), but the molecular mechanism is not fully understood. The aim of this study was to investigate the molecular mechanism that enhances the sensitivity to 5-FU treated with 5-Aza-CdR via thymidine phosphorylase (TP). MATERIALS AND METHODS: The sensitivity to drugs was determined on several cancer cell lines by the MTT assay. Protein and mRNA levels were examined by immunoblot and RT-PCR, respectively. Gene silencing, binding of Sp1 to DNA and methylation of DNA was performed by siRNA, ChIP assay and sodium bisulfate genomic sequencing, respectively. RESULTS: Sp1-binding sites in the TP promoter were methylated in epidermoid carcinoma. 5-Aza-CdR demethylated Sp1-binding sites and enhanced sensitivity to 5-FU. CONCLUSION: Demethylation of Sp1-binding sites by 5-Aza-CdR was a key factor enhancing 5-FU sensitivity, which may enable more effective treatments for cancer patients with the combination of 5-Aza-CdR and 5-FU.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Metilação de DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Fator de Transcrição Sp1/genética , Timidina Fosforilase/genética , Sítios de Ligação/efeitos dos fármacos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Decitabina/metabolismo , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Humanos , Regiões Promotoras Genéticas/efeitos dos fármacos , RNA Mensageiro/genética , Timidina Fosforilase/química
10.
Anticancer Res ; 39(8): 4137-4142, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366498

RESUMO

BACKGROUND: P53 is a key regulator of genomic stability and function, acting as a tumor suppressor protein. Our aim was to correlate P53 expression with murine double minute 2 (MDM2), a proto-oncogene that interacts with P53 and forms an auto-regulatory pathway, in laryngeal squamous cell carcinoma (LSCC). MATERIALS AND METHODS: A total of 50 LSCC cases were included in the study. Immunohistochemistry was applied by using antibodies to P53 and MDM2 in the corresponding tissue sections. Protein expression levels for both molecules were measured by implementing a digital image analysis assay (immunostaining intensity levels, densitometric evaluation). RESULTS: Overexpression of P53 protein was observed in 16/50 (32%) LSCC cases, while 22/50 (44%) cases strongly expressed MDM2 protein. Interestingly, in 13/50 (26%) cases, combined overexpression of P53/MDM2 was detected. Overall P53 was strongly positively correlated with MDM2 expression (p=0.001). Both P53 and MDM2 overexpression were significantly correlated with advanced stage of LSCC (p=0.032 and p=0.001, respectively). Additionally, MDM2 was found to be associated with poorer survival of patients (p=0.046). CONCLUSION: Aberrant co-expression of P53 and MDM2 is associated with advanced stage in LSCC. Furthermore, MDM2 overexpression is a frequent and critical genetic event in LSCC and seems to negatively affect survival.


Assuntos
Carcinoma de Células Escamosas/diagnóstico por imagem , Neoplasias Laríngeas/diagnóstico por imagem , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteína Supressora de Tumor p53/genética , Idoso , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Neoplasias Laríngeas/tratamento farmacológico , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Anticancer Res ; 39(8): 4285-4289, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366519

RESUMO

BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC) is a cancer with poor prognosis due to therapy resistance, locoregional recurrences, and distant metastases. There is on increased interest in profiling the androgen receptor (AR) in cancer biology. The aim of this study was to compare AR and Ki-67 levels in the neoplastic epithelium and stroma between non-metastatic and metastatic stages of OSCC. PATIENTS AND METHODS: Tissue specimens of 101 non-metastatic and 95 metastatic OSCC patients were analyzed by immunohistochemistry. RESULTS: More than 20% of AR-positive cytoplasmic staining of OSCC epithelium was significantly associated with nuclear AR levels in the epithelium and increased AR levels in the stroma. In metastatic OSCC patients, Ki-67 was significantly higher than in non-metastatic OSCC patients. CONCLUSION: More than 20% of AR-positive cytoplasmic staining in neoplastic OSSC epithelium is a significant predictor of OSCC progression risk.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Antígeno Ki-67/genética , Neoplasias Bucais/genética , Receptores Androgênicos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Fatores de Risco
12.
Cancer Sci ; 110(10): 3215-3224, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432603

RESUMO

Patient-derived xenograft (PDX) models are a useful tool in cancer biology research. However, the number of lung cancer PDX is limited. In the present study, we successfully established 10 PDX, including three adenocarcinoma (AD), six squamous cell carcinoma (SQ) and one large cell carcinoma (LA), from 30 patients with non-small cell lung cancer (NSCLC) (18 AD, 10 SQ, and 2 LA), mainly in SCID hairless outbred (SHO) mice (Crlj:SHO-Prkdcscid Hrhr ). Histology of SQ, advanced clinical stage (III-IV), status of lymph node metastasis (N2-3), and maximum standardized uptake value ≥10 when evaluated using a delayed 18 F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scan was associated with successful PDX establishment. Histological analyses showed that PDX had histology similar to that of patients' surgically resected tumors (SRT), whereas components of the microenvironment were replaced with murine cells after several passages. Next-generation sequencing analyses showed that after two to six passages, PDX preserved the majority of the somatic mutations and mRNA expressions of the corresponding SRT. Two out of three PDX with AD histology had epidermal growth factor receptor (EGFR) mutations (L858R or exon 19 deletion) and were sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and osimertinib. Furthermore, in one of the two PDX with an EGFR mutation, osimertinib resistance was induced that was associated with epithelial-to-mesenchymal transition. This study presented 10 serially transplantable PDX of NSCLC in SHO mice and showed the use of PDX with an EGFR mutation for analyses of EGFR-TKI resistance.


Assuntos
Adenocarcinoma de Pulmão/patologia , Carcinoma de Células Grandes/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma de Células Grandes/tratamento farmacológico , Carcinoma de Células Grandes/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Camundongos , Camundongos Pelados , Camundongos SCID , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Life Sci ; 233: 116708, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31369759

RESUMO

AIMS: Cervical cancer seriously affects women's health. The function of methylated alterations in the long non-coding RNAs (lncRNAs) promote the progression and metastasis of cancer. Our study aims to identify the functional effects of lncRNA methylation in cervical carcinogenesis. MAIN METHODS: Genome-wide DNA methylation of 6 samples was assessed using the Illumina Infinium MethylationEPIC BeadChip. RNA sequencing (RNA-seq) data and survival follow-up time of 307 samples from The Cancer Genome Atlas (TCGA) dataset were enrolled in this study. The statistical analysis and graphical work were mainly realized by R language. KEY FINDINGS: Methylation map identified 3962 hypermethylated CpG sites and 4484 hypomethylated CpG sites in cervical cancer (|Δß| ≥ 0.20). Bioinformatic analysis of the lncRNA expression identified 363 upregulated and 664 downregulated lncRNAs with log2 (fold change) ≥ 1.00 in squamous cervical carcinoma (SCC) samples. Weighted gene co-expression network analysis (WGCNA) and Venn diagram revealed that lncRNA MAGI2 antisense RNA 3 (lncRNA MAGI2-AS3), lncRNA WT1 antisense RNA (lncRNA WT1-AS) and lncRNA SOX21 antisense divergent transcript 1 (lncRNA SOX21-AS1) were important methylation changed lncRNAs. Kaplan-Meier survival curves showed only lncRNA SOX21-AS1 had clinical prognostic value in cervical cancer. Gene set enrichment analysis (GSEA) suggest that lncRNA SOX21-AS1 involve in the multiple cellular processes and might significantly suppress cervical tumorigenesis. SIGNIFICANCE: These insights into the functional role of lncRNA SOX21-AS1 DNA methylome alterations in cervical cancer might promote clinically new applicable in diagnosis and prognosis.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , RNA Longo não Codificante/genética , Neoplasias do Colo do Útero/patologia , Adulto , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Estudos de Casos e Controles , Proliferação de Células , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/genética
14.
Medicine (Baltimore) ; 98(31): e16715, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31374065

RESUMO

Chromosome 8 open reading frame 4 (C8orf4) is an activator of Wnt signaling pathway, and participates in the tumorigenesis and progression of many tumors. The expression levels of C8orf4 and ß-catenin were assessed via immunohistochemical staining in 100 cervical squamous cell carcinoma (CSCC) tissues, 50 high-grade squamous intraepithelial lesions (HSILs), 50 low-grade squamous intraepithelial lesions (LSILs), and 50 normal cervical tissues. Bisulfite sequencing polymerase chain reaction analysis was used to examine the methylation status of the C8orf4 locus in CSCC and normal cervical tissues. The expression rates of C8orf4 and ß-catenin were significantly higher in CSCCs or HSILs than in LSILs or normal cervical tissues (P < .05). C8orf4 expression was positively correlated with the poor differentiation of CSCCs (P = .009), and with aberrant expression of ß-catenin in CSCCs (P = .002) and squamous intraepithelial lesions (P < .001). The methylation rate of C8orf4 in CSCCs was significantly lower than that in normal cervical tissues (P = .001). The Cancer Genome Atlas genomics data also confirmed that the mRNA expression of C8orf4 was positively associated with the copy number alteration of C8orf4 (correlation coefficient = 0.213, P < .001), and negatively correlated with the methylation level of C8orf4 (correlation coefficient = -0.408, P < .001). In conclusion, the expressions of C8orf4 and ß-catenin were synergistically increased in CSCCs and HSILs and higher than those in LSILs and normal cervical tissues. The methylation level of C8orf4 is decreased in CSCCs and is responsible for the increased expression of C8orf4.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasia Intraepitelial Cervical/genética , Proteínas de Neoplasias/biossíntese , Neoplasias do Colo do Útero/genética , beta Catenina/biossíntese , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Neoplasia Intraepitelial Cervical/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Reação em Cadeia da Polimerase , Neoplasias do Colo do Útero/patologia , Via de Sinalização Wnt , Adulto Jovem , beta Catenina/genética
15.
Gynecol Oncol ; 155(1): 151-160, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31375269

RESUMO

OBJECTIVE: Toll-like receptors constitute an important component of innate immune mechanism. HPV is a known etiological factor of cervical cancer and is known to interfere with the expression of TLRs and downstream signaling pathway. It remains poorly understood whether HPV modulates the expression of TLRs. Hence, understanding HPV mediated immune alterations might aid in identifying novel therapeutic targets. The aim was to study the relative gene expression of TLRs & downstream signaling pathway in cervical carcinoma. METHODS: Cervical squamous cell carcinoma (CSCC) and normal cervical tissues were obtained. Subsequent to HPV genotyping, mRNA expression profiling using PCR Array was performed. Protein expression of relevant genes with western blot was studied. Levels of cytokines in cervicovaginal washes were estimated using a Luminex multiplex platform. RESULTS: All cases of cervical cancer were HR-HPV positive and predominant subtype was HPV16 (71.1%). Significant TLR4 upregulation and TLR2,7 downregulation were observed in HR-HPV infected cervix. TLR4,7 demonstrated low expression in CSCC. Molecules from cancer allied pathways; RELA, AKT, CDKN2A, and MDM2 demonstrated upregulation in CSCC. Protein expression data corroborated with gene expression profile. A diminished level of Th1 cytokines TNF-α, IFN-É£, IL-17, and IL-12 was observed in CSCC. Significantly increased levels of IL-1ß, IL-6 and IL-2 were detected in HR-HPV infected cervix. Kaplan Meier curve demonstrated high TLR4 and low TLR7 expression was associated with poor prognosis. CONCLUSION: The study demonstrates the HPV mediated dampening of the innate immune response in CSCC and provides support for exploring potential TLR2, 7 agonists as an adjunct therapy in CSCC patients.


Assuntos
Carcinoma de Células Escamosas/virologia , Papillomavirus Humano 16/fisiologia , Infecções por Papillomavirus/virologia , Receptores Toll-Like/metabolismo , Neoplasias do Colo do Útero/virologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Regulação para Baixo , Feminino , Expressão Gênica , Humanos , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/metabolismo , Transdução de Sinais , Taxa de Sobrevida , Receptores Toll-Like/biossíntese , Receptores Toll-Like/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo
16.
Cancer Sci ; 110(9): 2794-2805, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31336010

RESUMO

SALL4 is overexpressed in many cancers and is found to be involved in tumorigenesis and tumor progression. However, the function of SALL4 in cervical cancer remains unknown. Here, we showed that the expression of SALL4 was gradually increased from normal cervical tissue to high-grade squamous intraepithelial lesions and then to squamous cervical carcinoma. SALL4 was upregulated or downregulated in cervical cancer cells by stably transfecting a SALL4-expressing plasmid or a shRNA plasmid targeting SALL4, respectively. In vitro, cell growth curves and MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) assays showed that SALL4 promoted the cell proliferation of cervical cancer cells. In vivo, xenograft experiments verified that SALL4 enhanced the tumor formation of cervical cancer cells in female BALB/c Nude mice. Cell cycle analysis by fluorescence-activated cell sorting found that SALL4 accelerates cell cycle transition from the G0 /G1 phase to the S phase. TOP/FOP-Flash reporter assay revealed that SALL4 significantly upregulates the activity of Wnt/ß-catenin pathway. Western blotting showed that the expression levels of ß-catenin and important downstream genes, including c-Myc and cyclin D1, were increased by SALL4 in cervical cancer cells. Furthermore, dual-luciferase reporter and chromatin immunoprecipitation assays confirmed that SALL4 transcriptionally activated CTNNB1 by physically interacting with its promoters. Taken together, The results of this study demonstrated that SALL4 may promote cell proliferation and tumor formation of cervical cancer cells by upregulating the activity of the Wnt/ß-catenin signaling pathway by directly binding to the CTNNB1 promoter and trans-activating CTNNB1.


Assuntos
Carcinoma de Células Escamosas/genética , Transformação Celular Neoplásica/genética , Lesões Intraepiteliais Escamosas Cervicais/patologia , Fatores de Transcrição/metabolismo , Neoplasias do Colo do Útero/genética , Via de Sinalização Wnt/genética , beta Catenina/genética , Animais , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Colo do Útero/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Regiões Promotoras Genéticas/genética , RNA Interferente Pequeno/metabolismo , Lesões Intraepiteliais Escamosas Cervicais/genética , Fatores de Transcrição/genética , Regulação para Cima , Neoplasias do Colo do Útero/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/metabolismo
17.
Arkh Patol ; 81(3): 12-18, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31317926

RESUMO

OBJECTIVE: To identify the expression of the molecular markers p53 and p16INK4A in head and neck squamous cell carcinoma (HNSCC) and to assess their impact on its clinical and morphological characteristics and overall survival (OS) rates in patients with HNSCC. MATERIAL AND METHODS: Histological blocks were immunohistochemically studied using anti-p16 and p53 monoclonal antibodies in Krasnodar Clinical Oncology Dispensary One in 2011 to 2016. Overexpression of p16INK4A was established in the presence of 3 and 4 staining points (nuclear and/or cytoplasmic staining in 40% or more tumor cells). That of p53 was determined in the presence of nuclear staining (3+) in more than 50% of tumor cells. RESULTS: Overexpression of p16 was found in 15 (27%) patients (9 (60%) men and 6 (40%) women). The p16-positive tumor status was associated with the female sex (p=0.023), which was characteristic of tonsil cancer (p<0.001) and represented by the nonkeratinizing type (p=0.008). Overexpression of p16 was associated with more frequent regional lymph node metastases (p=0.029). Overexpression of p53 was related to G2 tumor (p=0.021) and expression of p53 was less than 50% associated with tongue body cancer (p=0.004). Kaplan-Meier analysis showed that the 3-year OS in p16-positive HNSCC patients was significantly higher than that in p16-negative ones (p=0.048). Significantly higher OS rates were observed in p16-positive HNSCC patients than in p16INK4A-negative ones for Stage III-IV (p=0.021). OS rates in HNSCC patients with co-expression of p16INK4A (3 and 4 points) and p53 (3+) were significantly higher than in the absence of a combination of these molecular markers (p=0.049). At the same time, OS in HNSCC patients with co-expression of p16INK4A (3 and 4 points), p53 (3+) was significantly higher than in the absence of a set of these molecular markers for stage III-IV (p=0.01). OS in patients with Stages I-II HNNSCC and co-expression of p16INK4A (3 and 4 points) and p53 (3+) did not significantly differ from that in the absence of a set of these molecular markers (p=0.960). CONCLUSION: Overexpression of p16INK4A (3 and 4 points) can be used as a prognostic marker to divide patients into subgroups with different clinical and morphological characteristics. The data on the correlation of p53 overexpression as a marker of mutations in the TP53 gene are contradictory and the study has not revealed the worst overall survival rates. A set of markers for the expression of p16 (≥40%) and p53 (≥50%) has been proposed for use as a favorable prognostic sign.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Escamosas , Inibidor p16 de Quinase Dependente de Ciclina , Genes p53 , Neoplasias de Cabeça e Pescoço , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Células Epiteliais , Feminino , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Prognóstico , Proteína Supressora de Tumor p53/metabolismo
18.
Comput Biol Chem ; 82: 74-79, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302411

RESUMO

We use a newly developed feature extraction and classification method to analyze previously published gene expression data sets in Oral Squamous Cell Carcinoma and in healthy oral mucosa in order to find a gene set sufficient for diagnoses. The feature selection technology is based on the relative dichotomy power concept published by us earlier. The resulting biomarker panel has 100% sensitivity and 95% specificity, is enriched in genes associated with oncogenesis and invasive tumor growth, and, unlike marker panels devised in earlier studies, shows concordance with previously published marker genes.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/diagnóstico , Expressão Gênica , Neoplasias Bucais/diagnóstico , Algoritmos , Carcinoma de Células Escamosas/genética , Biologia Computacional/métodos , Marcadores Genéticos , Humanos , Mucosa Bucal , Neoplasias Bucais/genética
19.
J Cancer Res Clin Oncol ; 145(9): 2241-2250, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31342168

RESUMO

PURPOSE: The tripartite motif (TRIM)16 acts as a tumour suppressor in both squamous cell carcinoma (SCC) and melanoma. TRIM16 is known to be secreted by keratinocytes, but no studies have been reported yet to assess the relationship between TRIM16 keratinocyte expression and melanoma development. METHODS: To study the role of TRIM16 in skin cancer development, we developed a keratinocyte TRIM16-specific knockout mouse model, and used the classical two-stage skin carcinogenesis challenge method, to assess the loss of keratinocyte TRIM16 on both papilloma, SCC and melanoma development in the skin after topical carcinogen treatment. RESULTS: Heterozygous, but not homozygous, TRIM16 knockout mice exhibited an accelerated development of skin papillomas and melanomas, larger melanoma lesions and an increased potential for lymph node metastasis. CONCLUSION: This study provides the first evidence that keratinocyte loss of the putative melanoma tumour suppressor protein, TRIM16, enhances melanomagenesis. Our data also suggest that TRIM16 expression in keratinocytes is involved in cross talk between keratinocytes and melanocytes, and has a role in melanoma tumorigenesis.


Assuntos
Proteínas de Transporte/genética , Queratinócitos/metabolismo , Perda de Heterozigosidade/fisiologia , Linfonodos/metabolismo , Melanócitos/metabolismo , Melanoma/genética , Neoplasias Cutâneas/genética , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proteínas de Transporte/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Células Cultivadas , Regulação Neoplásica da Expressão Gênica , Queratinócitos/patologia , Linfonodos/patologia , Metástase Linfática , Melanócitos/patologia , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Knockout , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
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