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1.
Int J Cancer ; 146(4): 1042-1051, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31396961

RESUMO

Esophageal squamous cell carcinoma (ESCC) occurs with highest frequency in China with over 90% mortality, highlighting the need for early detection and improved treatment strategies. We aimed to identify ESCC cancer predisposition gene(s). Our study included 4,517 individuals. The discovery phase using whole-exome sequencing (WES) included 186 familial ESCC patients from high-risk China. Targeted gene sequencing validation of 598 genes included 3,289 Henan and 1,228 moderate-risk Hong Kong Chinese. A WES approach identified BRCA2 loss-of-function (LOF) mutations in 3.23% (6/186) familial ESCC patients compared to 0.21% (9/4300) in the ExAC East Asians (odds ratio [OR] = 15.89, p = 2.48 × 10-10 ). BRCA2 LOF mutation frequency in the combined Henan cohort has significantly higher prevalence (OR = 10.55, p = 0.0035). Results were independently validated in an ESCC Hong Kong cohort (OR = 10.64, p = 0.022). One Hong Kong pedigree was identified to carry a BRCA2 LOF mutation. BRCA2 inactivation in ESCC was via germline LOF mutations and wild-type somatic allelic loss via loss of heterozygosity. Gene-based association analysis, including LOF mutations and rare deleterious missense variants defined with combined annotation dependent depletion score ≥30, confirmed the genetic predisposition role of BRCA2 (OR = 9.50, p = 3.44 × 10-5 ), and provided new evidence for potential association of ESCC risk with DNA repair genes (POLQ and MSH2), inflammation (TTC39B) and angiogenesis (KDR). Our findings are the first to provide compelling evidence of the role of BRCA2 in ESCC genetic susceptibility in Chinese, suggesting defective homologous recombination is an underlying cause in ESCC pathogenesis, which is amenable to therapeutic options based on synthetic lethality approaches such as targeting BRCA2 with PARP1 inhibitors in ESCC.


Assuntos
Proteína BRCA2/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Genes BRCA2 , Mutação em Linhagem Germinativa , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , China , Estudos de Coortes , Exoma , Feminino , Predisposição Genética para Doença , Humanos , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Penetrância
2.
Cancer Sci ; 111(3): 795-806, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31883400

RESUMO

Esophageal cancer is currently one of the most fatal cancers. However, there is no effective treatment. Increasing evidence suggests that interleukin (IL)-33 has a significant role in tumor progression and metastasis. Currently, the underlying cellular and molecular mechanism of IL-33 in promoting esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we investigated whether IL-33 could induce the epithelial-mesenchymal transition (EMT) in ESCC. Interleukin-33 expression was examined in ESCC and corresponding adjacent normal tissues by immunohistochemistry and quantitative real-time PCR experiments. Elevated IL-33 levels were observed in ESCC tissues. Further in vitro experiments were undertaken to elucidate the effect of IL-33 on migration and invasion in KYSE-450 and Eca-109 esophageal cancer cells. Knockdown of IL-33 decreased the metastasis and invasion capacity in esophageal cancer cells, whereas IL-33 overexpression showed the opposite effect. We then screened CCL2 which is a downstream molecule of IL-33, and proved that IL-33 could promote tumor development and metastasis by recruiting regulatory T cells (Tregs) through CCL2, and IL-33 regulated the expression of CCL2 through transforming growth factor-ß in Treg cells. Knockdown of IL-33 decreased the development of human ESCC xenografts in BALB/c nude mice. Collectively, we found that the IL-33/nuclear factor-κB/CCL2 pathway played an essential role in human ESCC progress. Hence, IL-33 should be considered as an effective therapy target for ESCC.


Assuntos
Quimiocina CCL2/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Interleucina-33/genética , NF-kappa B/genética , Transdução de Sinais/genética , Linfócitos T Reguladores/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus
3.
Zhonghua Yu Fang Yi Xue Za Zhi ; 53(11): 1176-1182, 2019 Nov 06.
Artigo em Chinês | MEDLINE | ID: mdl-31683410

RESUMO

Abnormal genomic DNA methylation is an important epigenetic change in malignant tumors. Esophageal squamous cell cancer is one of common malignant tumors in our country. In this paper summarized and discussed the progress of genomic DNA methylation in the esophageal squamouscell cancer, including the level of genomic DNA methylation, frequent abnormally methylated genes, methylation markers and potential targets, etc. This paper might provide candidate biomarkers and targets for further studies on the mechanism of the tumorigenesis and development of the esophagealsquamouscell cancer, as well as for the clinical application of esophageal cancer.


Assuntos
Metilação de DNA , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Biomarcadores Tumorais , Epigênese Genética , Genômica , Humanos , Regiões Promotoras Genéticas
4.
Anticancer Res ; 39(11): 5943-5951, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704819

RESUMO

BACKGROUND/AIM: To investigate the function of preferentially expressed antigen of melanoma (PRAME) in esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: mRNA expression levels of PRAME were analyzed in resected esophageal tissues of 150 ESCC patients and correlated with clinicopathological parameters. We also investigated the potential function of PRAME by analyzing coordinately expressed genes in 13 ESCC cell lines. RESULTS: RT-qPCR analysis of clinical samples revealed aberrantly high PRAME expression in tumors compared with normal esophageal tissues. High PRAME expression was significantly associated with shorter disease-specific survival and hematogenous recurrence, but not with overall recurrence. The cumulative incidence of hematogenous recurrence was significantly greater for patients with high compared to those with low PRAME expression. In vitro, PCR array analysis revealed that PRAME was coordinately expressed with EGFR, ITGB, and TCF3. CONCLUSION: PRAME is overexpressed in ESCC tissues and may serve as a novel biomarker for predicting hematogenous recurrence.


Assuntos
Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/secundário , Recidiva Local de Neoplasia/patologia , RNA Mensageiro/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Estudos de Coortes , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Prognóstico , RNA Mensageiro/genética , Taxa de Sobrevida
5.
Bioengineered ; 10(1): 679-688, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31679450

RESUMO

MiR-25 is a well-documented oncogenic miRNA implicated in esophageal squamous cell carcinoma (ESCC) development, progression and metastasis. However, whether and how miR-25 is involved in the development and metastasis of ESCC remain un-addressed. By using qRT-PCR analysis to compare levels of miR-25 in ESCC tissues with or without lymph node metastasis (LNM), it showed that ESCC tissues with LNM had increased levels of miR-25, which was correlated with tumor metastasis and poor prognosis. Gain- and loss-of-function assays indicated that targeting miR-25 could reverse EMT, and reduce in vitro cell migration and invasion, but not apoptosis and proliferation of ESCC. Furthermore, targeting miR-25 inhibited in vivo lung metastasis, and vice versa. And E-cadherin was a direct target of miR-25 through which affected EMT process and metastasis of ESCC. It is therefore indicated that miR-25 promotes metastasis of ESCC through E-cadherin and EMT events, thus may serves as a negative prognostic factor and possible target for treatment of ESCC patients.


Assuntos
Antígenos CD/genética , Caderinas/genética , Transição Epitelial-Mesenquimal/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , MicroRNAs/genética , Animais , Antígenos CD/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/secundário , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Camundongos , Camundongos Nus , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Prognóstico , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Technol Cancer Res Treat ; 18: 1533033819877977, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31578133

RESUMO

OBJECTIVE: Our aim of the study was to investigate the expression level and methylation status of the secreted frizzled-related protein 2 in esophageal squamous cell carcinoma and to evaluate the clinical utility of the marker. MATERIAL AND METHODS: We first used Immunohistochemistry (ICH) to explore the expression level of secreted frizzled-related protein 2 protein in esophageal squamous cell carcinoma tissues and adjacent normal tissues and then used methylation-specific polymerase chain reaction and bisulfite sequencing polymerase chain reaction to detect methylation status of secreted frizzled-related protein 2. RESULTS: Secreted frizzled-related protein 2 expression was notably reduced in patients with esophageal squamous cell carcinoma, whereas methylation of secreted frizzled-related protein 2 was increased in the majority of esophageal squamous cell carcinoma specimens. CONCLUSION: Sum up, we have demonstrated the abnormal DNA hypermethylation, causing reduced or absent gene expression. Methylation testing of secreted frizzled-related protein 2 using epigenetic marker may be a significative screening method for patients with esophageal squamous cell carcinoma.


Assuntos
Metilação de DNA , Carcinoma de Células Escamosas do Esôfago/genética , Inativação Gênica , Proteínas de Membrana/genética , Regiões Promotoras Genéticas , Adulto , Idoso , Biomarcadores Tumorais , Linhagem Celular Tumoral , Ilhas de CpG , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/mortalidade , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Carga Tumoral
7.
World J Gastroenterol ; 25(37): 5604-5618, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31602161

RESUMO

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the main causes of human death. It is usually already in middle or advanced stage when diagnosed due to its hidden symptoms in early stage. Therefore, patients have already lost the best surgical timing when diagnosed. Radiotherapy and chemotherapy are standard treatment methods for ESCC clinically, but the efficacy and prognosis of patients from them are still unsatisfactory. Therefore, it is of great clinical significance to seek for biomarkers that can predict the radiotherapy and chemotherapy response and prognosis of ESCC patients. AIM: To explore the clinical value of plasma miR-21 and miR-93 in ESCC. METHODS: A total of 128 ESCC patients admitted to the First Affiliated Hospital of Zhenzhou University were enrolled as a study group and treated with concurrent radiotherapy and chemotherapy, and other 45 healthy people during the same period were enrolled as a control group. The expression of plasma miR-21 and miR-93 was determined using quantitative real-time polymerase chain reaction, and the correlation of expression of plasma miR-21 and miR-93 with clinical pathological parameters about the patients was analyzed. The receiver operating characteristic (ROC) curve was adopted to assess the diagnostic value of plasma miR-21 and miR-93 for clinical pathological features of ESCC patients, the Logistic regression analysis adopted to analyze the risk factors for radiotherapy and chemotherapy efficacy in ESCC patients, and the Cox regression analysis to identify the prognostic factors for ESCC patients. RESULTS: The study group showed significantly higher relative expression of plasma miR-21 and miR-93 than the control group (P < 0.01). The area under the ROC curve (AUC) of plasma miR-21 for diagnosing T stage, N stage, M stage, and pathological differentiation of ESCC was 0.819, 0.758, 0.824, and 0.725, respectively, and that of plasma miR-93 for diagnosing T stage, N stage, and M stage of ESCC was 0.827, 0.815, and 0.814, respectively. The AUC of combined plasma miR-21 and miR-93 for predicting radiotherapy and chemotherapy efficacy before radiotherapy and chemotherapy was 0.894, and the AUCs of them for predicting the 3-year overall survival (OS) were 0.861 and 0.807, respectively. T stage (P < 0.05), M stage (P < 0.05), miR-21(P < 0.01), and miR-93 (P < 0.05) were independent risk factors for radiotherapy and chemotherapy efficacy, and T stage (P < 0.01), N stage (P < 0.05), M stage (P < 0.01), miR-21 (P < 0.01), and miR-93 (P < 0.01) were independent prognostic factors for ESCC patients. CONCLUSION: MiR-21 and miR-93 can be adopted as effective biomarkers for predicting radiotherapy and chemotherapy efficacy in ESCC and the 3-year OS of ESCC patients.


Assuntos
Biomarcadores Tumorais/sangue , Quimiorradioterapia/métodos , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/terapia , MicroRNAs/sangue , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Estudos de Casos e Controles , Cisplatino/administração & dosagem , Esquema de Medicação , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Carcinoma de Células Escamosas do Esôfago/sangue , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/mortalidade , Feminino , Fluoruracila/administração & dosagem , Regulação Neoplásica da Expressão Gênica , Voluntários Saudáveis , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Curva ROC , Radioterapia Conformacional/métodos , Fatores de Risco , Resultado do Tratamento
8.
Cancer Sci ; 110(12): 3677-3688, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31646712

RESUMO

5-Fluorouracil (5-FU) is a chemotherapeutic agent commonly used to treat esophageal squamous cell carcinoma (ESCC), but acquisition of chemoresistance frequently occurs and the underlying mechanisms are not fully understood. We found that microRNA (miR)-338-5p was underexpressed in ESCC cells with acquired 5-FU chemoresistance. Forced expression of miR-338-5p in these cells resulted in downregulation of Id-1, and restoration of both in vitro and in vivo sensitivity to 5-FU treatment. The effects were abolished by reexpression of Id-1. In contrast, miR-338-5p knockdown induced 5-FU resistance in chemosensitive esophageal cell lines, and knockdown of both miR-338-5p and Id-1 resensitized the cells to 5-FU. In addition, miR-338-5p had suppressive effects on migration and invasion of ESCC cells. Luciferase reporter assay confirmed a direct interaction between miR-338-5p and the 3'-UTR of Id-1. We also found that miR-338-5p was significantly downregulated in tumor tissue and serum samples of patients with ESCC. Notably, low serum miR-338-5p expression level was associated with poorer survival and poor response to 5-FU/cisplatin-based neoadjuvant chemoradiotherapy. In summary, we found that miR-338-5p can modulate 5-FU chemoresistance and inhibit invasion-related functions in ESCC by negatively regulating Id-1, and that serum miR-338-5p could be a novel noninvasive prognostic and predictive biomarker in ESCC.


Assuntos
Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Proteína 1 Inibidora de Diferenciação/genética , MicroRNAs/fisiologia , Adulto , Idoso , Animais , Linhagem Celular Tumoral , Movimento Celular , Resistencia a Medicamentos Antineoplásicos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Fluoruracila/farmacologia , Humanos , Masculino , Camundongos , MicroRNAs/sangue , Pessoa de Meia-Idade , Invasividade Neoplásica
9.
BMC Cancer ; 19(1): 875, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481019

RESUMO

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most frequent malignant digestive tumors around the world. We previously demonstrated that eIF3b could promote the progression of ESCC. The exact mechanisms underlying these effects remained unknown. METHODS: Quantitative proteomics was applied to detect the potential targets of Eukaryotic translation initiation factor 3 subunit b (eIF3b). RT-qPCR and Western blot were performed to detect the expression of targeted gene and pathway related genes. RNA-immunoprecipitation was applied to verify the binding of eIF3b with targeted gene. Moreover, CCK-8 assay, colony-formation assay, transwell assay, flow cytometry for cell apoptosis and tumor xenograft assay were performed to analyze the regulation of the targeted gene on the bio-function of ESCC cells. RESULTS: Quantitative proteomics data showed that Testis-expressed protein 9 (TEX9) expression was positively associated with eIF3b expression. RT-qPCR and Western blot results confirmed the quantitative proteomics data and demonstrated that TEX9 expression was positively correlated with TNM stage in ESCC. Furtherly, RNA-immunoprecipitation confirmed that eIF3b binding to TEX9 mRNA. The bio-function related assay demonstrated that TEX9 and eIF3b functionally synergized to promote the proliferation and migration, and inhibited the apoptosis of ESCC cells. In the analysis of mechanism, we revealed that TEX9 and eIF3b promoted the progression of ESCC through the activation of AKT signaling pathway. CONCLUSIONS: The synergized promoting role of TEX9 and eIF3b in the progression of ESCC may provide a novel mechanism for exploring viable therapeutic strategies for ESCC.


Assuntos
Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Fator de Iniciação 3 em Eucariotos/metabolismo , Proteínas de Neoplasias/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Fator de Iniciação 3 em Eucariotos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Nus , Proteínas de Neoplasias/genética , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Pathol Res Pract ; 215(10): 152604, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31495606

RESUMO

Esophageal squamous cell carcinoma (ESCC) is one of the major global health problems, especially in Asia. Long non-coding RNAs (lncRNAs) have been increasingly identified and characterized in almost every aspect of biology, especially in cancer biology. This research desires to explore the regulatory mechanism of lncRNA PANDA (PANDA) on ESCC process. Quantitative real-time PCR (qRT-PCR) was carried out to detect the PANDA expression, which was up-regulated in matched cancerous tissues and adjacent noncancerous tissues from 134 patients and 9 ESCC cell lines. Higher expression of PANDA in ESCC tissues was associated with TNM stage, advanced clinical stage, and shorter overall survival of ESCC patients by MTT, EDU, colony formation assay and flow cytometry in KYSE180 and KYSE450 cells. Exogenous down-regulation of PANDA expression significantly suppressed ESCC cells proliferation and colony formation by arresting G1-S checkpoint transition in vitro, and retarded the development of tumors in vivo. Meanwhile, qRT-PCR and western blot assays showed that depletion of PANDA reduced E2F1, cyclinD1, cyclinD2, cyclinE1 and Bcl-2 expression. RIP showed the interaction between PANDA and NF-YA or SAFA. Our findings suggested that, PANDA drifted away from NF-YA to promote the expression of NF-YA-E2F1 co-regulated proliferation-promoting genes, and to limit the cell apoptosis. In addition, PANDA binds SAFA to switch on the tumor proliferation program through CyclinD1/2-Cyclin E1 and Bcl-2 pathways. PANDA could serve as a potential prognostic biomarker and therapeutic target for ESCC.


Assuntos
Fator de Ligação a CCAAT/metabolismo , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo U/metabolismo , RNA Longo não Codificante/metabolismo , Apoptose/genética , Fator de Ligação a CCAAT/genética , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Ribonucleoproteínas Nucleares Heterogêneas Grupo U/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , RNA Longo não Codificante/genética , Taxa de Sobrevida , Regulação para Cima
11.
Diagn Pathol ; 14(1): 97, 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31470870

RESUMO

BACKGROUND: Esophageal cancer is one of the leading causes of cancer related deaths among the Iranians. There is still a high ratio of mortality and low 5 years survival which are related to the late onset and diagnosis. Majority of patients refer for the treatment in advanced stages of tumor progression. MAIN BODY: It is required to define an efficient local panel of diagnostic and prognostic markers for the Iranians. Indeed such efficient specific panel of markers will pave the way to decrease the mortality rate and increase the 5 years survival among the Iranian patients via the early diagnosis and targeted therapy. CONCLUSION: in present review we have reported all of the molecular markers in different signaling pathways and cellular processes which have been assessed among the Iranian esophageal cancer patients until now.


Assuntos
Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Humanos , Irã (Geográfico)
12.
Mol Med Rep ; 20(4): 3649-3660, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485619

RESUMO

The main purpose of the present study was to recognize the integrative genomics analysis of hub genes and their relationship with prognosis and signaling pathways in esophageal squamous cell carcinoma (ESCC). The mRNA gene expression profile data of GSE38129 were downloaded from the Gene Expression Omnibus database, which included 30 ESCC and 30 normal tissue samples. The differentially expressed genes (DEGs) between ESCC and normal samples were identified using the GEO2R tool. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify the functions and related pathways of the genes. The protein­protein interaction (PPI) network of these DEGs was constructed with the Search Tool for the Retrieval of Interacting Genes and visualized with a molecular complex detection plug­in via Cytoscape. The top five important modules were selected from the PPI network. A total of 928 DEGs, including ephrin­A1 (EFNA1), collagen type IV α1 (COL4A1),  C­X­C chemokine receptor 2 (CXCR2), adrenoreceptor ß2 (ADRB2), P2RY14, BUB1B, cyclin A2 (CCNA2), checkpoint kinase 1 (CHEK1), TTK, pituitary tumor transforming gene 1 (PTTG1) and COL5A1, including 498 upregulated genes, were mainly enriched in the 'cell cycle', 'DNA replication' and 'mitotic nuclear division', whereas 430 downregulated genes were enriched in 'oxidation­reduction process', 'xenobiotic metabolic process' and 'cell­cell adhesion'. The KEGG analysis revealed that 'ECM­receptor interaction', 'cell cycle' and 'p53 signaling pathway' were the most relevant pathways. According to the degree of connectivity and adjusted P­value, eight core genes were selected, among which those with the highest correlation were CHEK1, BUB1B, PTTG1, COL4A1 and CXCR2. Gene Expression Profiling Interactive Analysis in The Cancer Genome Atlas database for overall survival (OS) was applied among these genes and revealed that EFNA1 and COL4A1 were significantly associated with a short OS in 182 patients. Immunohistochemical results revealed that the expression of PTTG1 in esophageal carcinoma tissues was higher than that in normal tissues. Therefore, these genes may serve as crucial predictors for the prognosis of ESCC.


Assuntos
Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Regulação Neoplásica da Expressão Gênica , Transcriptoma , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Carcinoma de Células Escamosas do Esôfago/metabolismo , Perfilação da Expressão Gênica , Genômica , Humanos , Prognóstico , Mapas de Interação de Proteínas , Transdução de Sinais
13.
Mol Med Rep ; 20(4): 3633-3641, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485658

RESUMO

As a tumor­associated microRNA (miR), miR­212 has dual functions; either as an oncogene or a tumor suppressor. A high expression level of miR­212 was reported to be associated with poor outcome in patients with esophageal squamous cell carcinoma (ESCC), however, its role in ESCC progression has not been explored. In the present study, an in vitro cell model of lentivirus­mediated gain­of­function demonstrated promotion of ESCC cell migration and invasion when miR­212 was overexpressed, and no effect on cell proliferation. miR­212 resulted in downregulation of the expression of E­cadherin, ß­catenin, vimentin and Twist1. Moreover, it led to increased levels of extracellular matrix (ECM)­degrading enzymes, matrix metalloproteinase­9 and urokinase­type plasminogen activator. Furthermore, berberine inhibited miR­212­induced ESCC cell migration, unlike the PI3K inhibitor LY294002, rapamycin (mTOR inhibitor), 5­(Tetradecyloxy)­2­furoic acid (TOFA; an acetyl­CoA carboxylase 1 inhibitor), metformin and propranolol. These data suggest that miR­212 activates multiple signaling cascades and facilitates ESCC cell motility and invasion by promoting the epithelial­mesenchymal transition and degrading the ECM. Berberine may be a potential therapeutic agent against metastasis in patients with ESCC, who express high levels of miR­212.


Assuntos
Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Invasividade Neoplásica/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Humanos , Regulação para Cima
14.
J Exp Clin Cancer Res ; 38(1): 389, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488217

RESUMO

BACKGROUND: In cancer progression, hypoxia, or low oxygen tension, is a major regulator of tumor aggressiveness and metastasis. However, how cancer cells adapt to the hypoxia and communicate with other mesenchymal cells in microenvironment during tumor development remains to be elucidated. Here, we investigated the involvement of exosomes in modulating angiogenesis and enhancing metastasis in esophageal squamous cell carcinoma (ESCC). METHODS: Differential centrifugation, transmission electron microscopy and nanoparticle tracking analysis were used to isolate and characterize exosomes. Colony formation and transwell assay were performed to assess the proliferation, migration and invasion of human umbilical vein endothelial cells (HUVECs). The tube formation assay and matrigel plug assay were used to evaluate the vascular formation ability of HUVECs in vitro and in vivo respectively. An in vivo nude mice model was established to detect the regulatory role of exosomes in ESCC progression. Microarray analysis was performed to analyze the transcriptome profiles in HUVECs. RESULTS: Exosomes derived from ESCC cells cultured under hypoxia played a better role in promoting proliferation, migration, invasion and tube formation of HUVECs in vitro and in vivo than exosomes from ESCC cells cultured under normoxia. Moreover, hypoxic exosomes significantly enhanced the tumor growth and lung metastasis compared with normoxic exosomes in nude mice models. Interestingly, endothelial cells were programmed by hypoxic and normoxic exosomes from ESCC cells which altered the transcriptome profile of HUVECs. CONCLUSIONS: Taken together, our data identified an angiogenic role of exosomes from ESCC cells which shed light on the further application of exosomes as valuable therapeutic target for ESCC.


Assuntos
Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Exossomos/metabolismo , Hipóxia/genética , Hipóxia/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Transcriptoma , Animais , Ciclo Celular , Linhagem Celular Tumoral , Biologia Computacional/métodos , Modelos Animais de Doenças , Progressão da Doença , Células Endoteliais , Carcinoma de Células Escamosas do Esôfago/patologia , Perfilação da Expressão Gênica , Humanos , Camundongos , Anotação de Sequência Molecular , Metástase Neoplásica , Estadiamento de Neoplasias , Fenótipo
15.
EBioMedicine ; 46: 66-78, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31383552

RESUMO

BACKGROUND: MicroRNAs (miRNAs) are involved in oncogenesis of esophageal squamous cell carcinoma (ESCC). miR-134 is reported to have a tumour-suppressive role but its role in ESCC is not known. The present study was designed to examine whether miR-134 inhibits ESCC development and further explored relevant underlying mechanisms. METHODS: Differentially expressed genes related to ESCC were identified from microarray gene expression profiles. Immunohistochemical staining and RT-qRCR assays identified elevated PLXNA1 expression levels and low miR-134. The relationship between miR-134 and PLXNA1 was predicted and further verified by a dual-luciferase reporter assay. The expression levels of miR-134 and PLXNA1 in ESCC cells were modified by miR-134 mimic/inhibitor and siRNA against PLXNA1, respectively. Thereafter, the expression of MAPK signalling pathway-related proteins, as well as the viability, migration, invasion, cell cycle and cell apoptosis of ESCC cells was investigated. FINDINGS: The results showed that miR-134 could block the MAPK signalling pathway by downregulating PLXNA1. When miR-134 was overexpressed or PLXNA1 was silenced, cell apoptosis was enhanced, the cell cycle was retarded, and the cell proliferation, migration and invasion were suppressed. In vivo experiments confirmed that miR-134 overexpression or PLXNA1 silencing restrained tumour growth and lymph node metastasis. INTERPRETATION: These findings demonstrate that cancer cell proliferation, migration, invasion, and tumour metastasis of ESCC can be suppressed by overexpression of miR-134 through downregulating PLXNA1, which subsequently blocks the MAPK signalling pathway. These results provide new potential targets and strategies for the treatment of ESCC.


Assuntos
Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Regulação Neoplásica da Expressão Gênica , Sistema de Sinalização das MAP Quinases , MicroRNAs/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores de Superfície Celular/metabolismo , Idoso , Animais , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Biologia Computacional/métodos , Progressão da Doença , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Metástase Neoplásica , Estadiamento de Neoplasias , Interferência de RNA
16.
Mol Med Rep ; 20(4): 3003-3010, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432128

RESUMO

Dysregulations of the mevalonate pathway (MVA) have been previously identified. Our previous study demonstrated that 3­hydroxy­3­methylglutaryl­coenzyme A reductase (HMGCR), the rate­limiting enzyme of the MVA pathway, was upregulated in esophageal squamous cell carcinoma (ESCC) and statin­inhibited ESCC tumorigenesis. However, the underlying mechanism of HMGCR regulation in ESCC remains unknown. In the present study, western blotting and immunohistochemistry analysis demonstrated that sterol regulatory element­binding protein 2 (SREBP2), the master regulator for HMGCR, was upregulated in ESCC clinical samples. Overexpression of SREBP2 expression in ESCC cell lines promoted the growth, migration and colony formation of cancer cells in the MTT, Boyden chamber and soft agar assays, respectively, which was inhibited by lovastatin. Downregulation of SREBP2 expression in ESCC cell lines inhibited the viability, and migration and colony formation abilities of cancer cells. Assessment of the molecular mechanism demonstrated that SREBP2 interacted with c­Myc and cooperated with c­Myc to activate HMGCR expression. Collectively, the present study identified SREBP2 as an oncogene associated with the tumorigenesis of ESCC and further demonstrated the therapeutic effects of statins in ESCC.


Assuntos
Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Regulação Neoplásica da Expressão Gênica , Hidroximetilglutaril-CoA Redutases/biossíntese , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/biossíntese , Regulação para Cima , Linhagem Celular Tumoral , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Humanos , Hidroximetilglutaril-CoA Redutases/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/genética
17.
J Exp Clin Cancer Res ; 38(1): 369, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31438989

RESUMO

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide, which lacks effective biomarkers for prognosis. Therefore, it is urgent to explore new potential molecular markers to discriminate patients with poorer survival in ESCC. METHODS: Bioinformatics analysis, qRT-PCR, and western blot were applied to investigate S1PR1 expression. CCK-8 assay, colony formation assay, flow cytometry dual staining assay, and immunofluorescence were performed to examine cell proliferation ability and apoptosis rate. Mouse xenograft model of TE-13 cells was established to confirm the roles of S1PR1 in vivo. Gene set enrichment analysis (GSEA) was used to investigate the downstream signaling pathways related to S1PR1 functions. Co-IP was performed to verify the direct binding of S1PR1 and STAT3. Western blot was applied to determine the phosphorylation level of STAT3. Immunohistochemistry was conducted to identify protein expression of S1PR1 and p- STAT3 in tumor tissues. RESULTS: In the present study, we found that S1PR1 expression was higher in ESCC patients and was a potential biomarker for poor prognosis. Silencing S1PR1 expression inhibited proliferation, and increased apoptosis of ESCC cells, while overexpression of S1PR1 had opposite effects. Mechanistically, S1PR1 played the roles of promoting proliferation and attenuating apoptosis through directly activating p-STAT3. Furthermore, in vivo experiments verified this mechanism. CONCLUSION: Our findings indicated that S1PR1 enhanced proliferation and inhibited apoptosis of ESCC cells by activating STAT3 signaling pathway. S1PR1 may serve as a prognostic biomarker for clinical applications.


Assuntos
Apoptose , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Fator de Transcrição STAT3/metabolismo , /metabolismo , Animais , Biomarcadores Tumorais/genética , Movimento Celular , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Fator de Transcrição STAT3/genética , Transdução de Sinais , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Oncol Rep ; 42(4): 1497-1506, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31364751

RESUMO

Intrinsic and acquired resistance of cancer to radio­and chemotherapy is one of the major challenges in the treatment of esophageal squamous cell carcinoma (ESCC). Elevated reactive oxygen species (ROS) play an important role in the resistance to cisplatin in ESCCs. Super dismutase [Mn], mitochondrial (SOD­2), an important primary antioxidant enzyme located in mitochondria, could regulate ROS production. Our previous study showed that tumor necrosis factor­α (TNF­α)­mediated SOD­2 through NF­κB was involved in epithelial­mesenchymal transition and migration in A549 cells. Therefore, the present study aimed to identify if TNF­α mediated SOD­2 upregulation is involved in cisplatin resistance in ESCC. It was identified that a higher expression of SOD­2 in human ESCC samples was associated with TNF­α expression and poor overall survival in patients with ESCC, suggesting that SOD­2 may act as an oncogene in ESCC. To further confirm if TNF­α could upregulate SOD­2 to contribute to cell proliferation, the human ESCC cell line Eca­109 was treated with TNF­α in vitro. TNF­α could upregulate SOD­2 and induce cell proliferation in Eca109 cells, while blocking SOD­2 using small interfering RNA (siRNA) inhibited TNF­α­induced cell proliferation. Upregulation of SOD­2 by TNF­α was inhibited by blocking the NF­κB pathway, which suggested that SOD­2 by TNF­α/NF­κB contributes to cell proliferation in Eca109 cells. Furthermore, it was observed that TNF­α could induce cisplatin resistance in Eca109 cells, while transfection with SOD­2 siRNA could significantly increase the chemosensitivity of ESCC to cisplatin. Therefore, the present results suggested that SOD­2 may serve as an oncogene, and the upregulation of SOD­2 by TNF­α/NF­κB may contribute to cisplatin resistance in ESCC.


Assuntos
Cisplatino/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/genética , Superóxido Dismutase/genética , Fator de Necrose Tumoral alfa/farmacologia , Idoso , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Humanos , Masculino , NF-kappa B/metabolismo , Oncogenes , Superóxido Dismutase/biossíntese , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos
19.
Anticancer Res ; 39(8): 4539-4548, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366557

RESUMO

BACKGROUND/AIM: The aim of this study was to investigate PD-L1 expression and its association with prognosis in esophageal squamous cell carcinoma (ESCC) before and after neoadjuvant chemotherapy (5-fluorouracil and cisplatin, NAC-FP). PATIENTS AND METHODS: Using a database of 69 ESCC patients, we analyzed PD-L1 expression on tumor cells (TCs) and immune cells (ICs), as well as the density of CD8+ tumor-infiltrating lymphocytes (TILs) in pretreatment biopsy specimens-versus-surgical specimens after resection. We determined the prognostic significance of these factors. RESULTS: The fraction of ESCC containing ICs expressing PD-L1 and having a high CD8+ TIL density was significantly increased after neoadjuvant treatment. However, PD-L1 expression on TCs or ICs, and CD8+ TIL density, was not significantly associated with patient survival in ESCC patients. CONCLUSION: NAC-FP induced PD-L1 expression on ICs and CD8+ TILs in ESCC patients. This finding suggests that PD-1/PD-L1 blockade could be combined with NAC-FP to treat ESCC patients.


Assuntos
Antígeno B7-H1/genética , Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Receptor de Morte Celular Programada 1/genética , Idoso , Antígeno B7-H1/sangue , Linfócitos T CD8-Positivos/efeitos dos fármacos , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Carcinoma de Células Escamosas do Esôfago/sangue , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Fluoruracila/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Prognóstico , Receptor de Morte Celular Programada 1/sangue , Microambiente Tumoral/efeitos dos fármacos
20.
Eur J Pharmacol ; 861: 172590, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31401160

RESUMO

Increasing evidence displays that microRNAs (miRNAs) participate in the development of various human malignancies, including esophageal squamous cell carcinoma (ESCC). MicroRNA-33a-5p (miR-33a-5p) has recently been reported to function as a tumor suppressor in many human cancers. However, the expression and role of miR-33a-5p in ESCC remains largely unknown. Herein, we discovered that miR-33a-5p was down-regulated in both ESCC tissues and cell lines, compared with their normal counterparts, and decreased expression of miR-33a-5p was found to be closely associated with poor patient prognosis of ESCC. Moreover, functional experiments revealed that up-regulation of miR-33a-5p inhibited cell proliferation and metastasis of ESCC cells. In addition, the expression level of miR-33a-5p was found to be negatively correlated with the long non-coding RNA (lncRNA) differentiation antagonizing non-protein coding RNA (DANCR), in both ESCC tissues and cell lines. Furthermore, zinc-finger-enhancer binding protein 1 (ZEB1) was predicted and confirmed to be a direct target of miR-33a-5p in ESCC. Further mechanistic investigation indicated that DANCR may function as a competing endogenous RNA (ceRNA) to sponge miR-33a-5p, and thereby up-regulate ZEB1 expression in ESCC. This study highlights the functions of miR-33a-5p in the progression of ESCC and suggests that the DANCR/miR-33a-5p/ZEB1 axis may be a potential prognostic and therapeutic target.


Assuntos
Progressão da Doença , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , RNA Longo não Codificante/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação para Baixo/genética , Transição Epitelial-Mesenquimal/genética , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico
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