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1.
World J Surg Oncol ; 19(1): 123, 2021 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-33865399

RESUMEN

BACKGROUND: Pancreatic cancer (PAC) is one of the most devastating cancer types with an extremely poor prognosis, characterized by a hypoxic microenvironment and resistance to most therapeutic drugs. Hypoxia has been found to be one of the factors contributing to chemoresistance in PAC, but also a major driver of the formation of the tumor immunosuppressive microenvironment. However, the method to identify the degree of hypoxia in the tumor microenvironment (TME) is incompletely understood. METHODS: The mRNA expression profiles and corresponding clinicopathological information of PAC patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, respectively. To further explore the effect of hypoxia on the prognosis of patients with PAC as well as the tumor immune microenvironment, we established a hypoxia risk model and divided it into high- and low-risk groups in line with the hypoxia risk score. RESULTS: We established a hypoxia risk model according to four hypoxia-related genes, which could be used to demonstrate the immune microenvironment in PAC and predict prognosis. Moreover, the hypoxia risk score can act as an independent prognostic factor in PAC, and a higher hypoxia risk score was correlated with poorer prognosis in patients as well as the immunosuppressive microenvironment of the tumor. CONCLUSIONS: In summary, we established and validated a hypoxia risk model that can be considered as an independent prognostic indicator and reflected the immune microenvironment of PAC, suggesting the feasibility of hypoxia-targeted therapy for PAC patients.


Asunto(s)
Hipoxia/genética , Neoplasias Pancreáticas/genética , Microambiente Tumoral , Biomarcadores de Tumor/genética , Bases de Datos Genéticas , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Pancreáticas/patología , Pronóstico
2.
Int J Mol Sci ; 22(6)2021 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-33799364

RESUMEN

Epithelial membrane proteins (EMP1-3) are involved in epithelial differentiation and carcinogenesis. Dysregulated expression of EMP2 was observed in various cancers, but its role in human lung cancer is not yet clarified. In this study, we analyzed the expression of EMP1-3 and investigated the biological function of EMP2 in non-small cell lung cancer (NSCLC). The results showed that lower expression of EMP1 was significantly correlated with tumor size in primary lung tumors (p = 0.004). Overexpression of EMP2 suppressed tumor cell growth, migration, and invasion, resulting in a G1 cell cycle arrest, with knockdown of EMP2 leading to enhanced cell migration, related to MAPK pathway alterations and disruption of cell cycle regulatory genes. Exosomes isolated from transfected cells were taken up by tumor cells, carrying EMP2-downregulated microRNAs (miRNAs) which participated in regulation of the tumor microenvironment. Our data suggest that decreased EMP1 expression is significantly related to increased tumor size in NSCLC. EMP2 suppresses NSCLC cell growth mainly by inhibiting the MAPK pathway. EMP2 might further affect the tumor microenvironment by regulating tumor microenvironment-associated miRNAs.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Proliferación Celular/genética , Glicoproteínas de Membrana/genética , Proteínas de Neoplasias/genética , Receptores de Superficie Celular/genética , Microambiente Tumoral/genética , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Exosomas/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Transducción de Señal/genética
3.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33803949

RESUMEN

Invasive urothelial carcinomas of the bladder (UCB) characteristically show a loss of differentiation markers. The transcription factor Grainyhead-like 3 (GRHL3) plays an important role in the development and differentiation of normal urothelium. The contribution to UCB progression is still elusive. Differential expression of GRHL3 was assessed in normal human urothelium and in non-invasive and invasive bladder cancer cell lines. The contribution of GRHL3 to cell proliferation, viability and invasion in UCB cell lines was determined by gain- and loss-of-function assays in vitro and in an organ culture model using de-epithelialized porcine bladders. GRHL3 expression was detectable in normal human urothelial cells and showed significantly higher mRNA and protein levels in well-differentiated, non-invasive RT4 urothelial carcinoma cells compared to moderately differentiated RT112 cells. GRHL3 expression was absent in anaplastic and invasive T24 cells. Ectopic de novo expression of GRHL3 in T24 cells significantly impaired their migration and invasion properties in vitro and in organ culture. Its downregulation improved the invasive capacity of RT4 cells. The results indicate that GRHL3 may play a role in progression and metastasis in UCB. In addition, this work demonstrates that de-epithelialized porcine bladder organ culture can be a useful, standardized tool to assess the invasive capacity of cancer cells.


Asunto(s)
Carcinoma/genética , Proteínas de Unión al ADN/genética , Factores de Transcripción/genética , Neoplasias de la Vejiga Urinaria/genética , Urotelio/metabolismo , Animales , Carcinoma/patología , Carcinoma de Células Transicionales , Diferenciación Celular/genética , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Metástasis de la Neoplasia , Técnicas de Cultivo de Órganos , Porcinos , Neoplasias de la Vejiga Urinaria/patología , Urotelio/patología
4.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33803955

RESUMEN

MicroRNAs (miRs) are non-coding master regulators of transcriptome that could act as tumor suppressors (TSs) or oncogenes (oncomiRs). We aimed to systematically investigate the relevance of miRs as prognostic biomarkers in primary glioblastoma multiforme (GBM) treated with postoperative radio(chemo)therapy (PORT). For hypothesis generation, tumor miR expression by Agilent 8x15K human microRNA microarrays and survival data from 482 GBM patients of The Cancer Genome Atlas (TCGA cohort) were analyzed using Cox-PH models. Expression of candidate miRs with prognostic relevance (miR-221/222; miR-17-5p, miR-18a, miR-19b) was validated by qRT-PCR using Taqman technology on an independent validation cohort of GBM patients (n = 109) treated at Heidelberg University Hospital (HD cohort). In TCGA, 50 miRs showed significant association with survival. Among the top ranked prognostic miRs were members of the two miR families miR-221/222 and miR-17-92. Loss of miR-221/222 was correlated with improved prognosis in both cohorts (TCGA, HD) and was an independent prognostic marker in a multivariate analysis considering demographic characteristics (age, sex, Karnofsky performance index (KPI)), molecular markers (O-6-methylguanine-DNA methyltransferase (MGMT) methylation, IDH mutation status) and PORT as co-variables. The prognostic value of miR-17-92 family members was ambiguous and in part contradictory by direct comparison of the two cohorts, thus warranting further validation in larger prospective trials.


Asunto(s)
Glioblastoma/radioterapia , MicroARNs/genética , ARN Largo no Codificante/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Glioblastoma/genética , Glioblastoma/patología , Glioblastoma/cirugía , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Regiones Promotoras Genéticas/genética , Análisis de Matrices Tisulares , Transcriptoma/genética
5.
Molecules ; 26(6)2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33804111

RESUMEN

In this work, a simple enzyme-free flow cytometric assay (termed as TSDR-based flow cytometric assay) has been developed for the detection of papillary thyroid carcinoma (PTC)-related microRNA (miRNA), hsa-miR-146b-5p with high performance through the toehold-mediated strand displacement reaction (TSDR) on magnetic beads (MBs). The complementary single-stranded DNA (ssDNA) probe of hsa-miR-146b-5p was first immobilized on the surface of MB, which can partly hybridize with the carboxy-fluorescein (FAM)-modified ssDNA, resulting in strong fluorescence emission. In the presence of hsa-miR-146b-5p, the TSDR is trigged, and the FAM-modified ssDNA is released form the MB surface due to the formation of DNA/RNA heteroduplexes on the MB surface. The fluorescence emission change of MBs can be easily read by flow cytometry and is strongly dependent on the concentration of hsa-miR-146b-5p. Under optimal conditions, the TSDR-based flow cytometric assay exhibits good specificity, a wide linear range from 5 to 5000 pM and a relatively low detection limit (LOD, 3σ) of 4.21 pM. Moreover, the practicability of the assay was demonstrated by the analysis of hsa-miR-146b-5p amounts in different PTC cells and clinical PTC tissues.


Asunto(s)
Citometría de Flujo/métodos , MicroARNs/genética , Cáncer Papilar Tiroideo/diagnóstico , Cáncer Papilar Tiroideo/genética , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/genética , Línea Celular Tumoral , Movimiento Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Fenómenos Magnéticos
6.
Medicine (Baltimore) ; 100(14): e25369, 2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33832120

RESUMEN

ABSTRACT: Colon cancer patients suffer from high incidence and mortality rates worldwide. More novel molecular biomarkers should be used for the diagnosis and treatment of colon cancer. Long noncoding RNAs (lncRNAs) are found to be involved in colon cancer tumorigenesis and metastasis. This study aimed to identify novel lncRNAs in colon cancer.Two independent datasets (GSE70880 and GSE110715) were downloaded from the Gene Expression Omnibus database and merged with the sva package. R software was used to distinguish differentially expressed lncRNAs and mRNAs in the merged dataset. The competing endogenous RNA (ceRNA) network was constructed using differentially expressed lncRNAs and mRNAs with Cytoscape. Differentially expressed RNAs in the ceRNA network were further verified using the Cancer Genome Atlas database. Gene oncology analysis, Kyoto Encyclopedia of Genes and Genomes pathway enrichment and survival analysis were also performed to identify hub genes.A total of 99 differentially expressed lncRNAs and 95 differentially expressed mRNAs were identified in the merged database. Ten lncRNAs, 8 miRNAs, and 6 mRNAs were involved in the ceRNA network, in which LINC00114 and UCA1 were highly expressed in colon cancer. They were both associated with early tumor stages and might be used for the early diagnosis of colon cancer. High expression of LINC00114 can lead to poor overall survival of colon cancer patients. Furthermore, new pathways such as LINC00114/miR-107/PCKS5, UCA1/miR-107/PCKS5, and UCA1/miR-129-5p/SEMA6A were identified.Two novel lncRNAs (LINC00114 and UCA1) in colon cancer were identified by bioinformatics analysis. They might contribute to the occurrence and development of colon cancer. In addition, LINC00114 may be involved in the overall survival of colon cancer patients.


Asunto(s)
Neoplasias del Colon/genética , Biología Computacional/métodos , ARN Largo no Codificante/genética , ARN Mensajero/genética , Anciano , Biomarcadores de Tumor/genética , Carcinogénesis/genética , Carcinogénesis/patología , Neoplasias del Colon/epidemiología , Neoplasias del Colon/mortalidad , Bases de Datos Genéticas/estadística & datos numéricos , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Incidencia , Masculino , MicroARNs/genética , Persona de Mediana Edad , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Estadificación de Neoplasias/métodos , Análisis de Supervivencia
7.
Medicine (Baltimore) ; 100(16): e25246, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879658

RESUMEN

ABSTRACT: Lung adenocarcinoma (LUAD) is a lethal malignancy worldwide and a major public health concern. We explored the potential clinical significance for LUAD of ATP-binding cassette (ABC), sub-family C, consisting of ABCC1-6, 8-12, and cystic fibrosis transmembrane conductance regulator (CFTR).Five hundred LUAD patients from The Cancer Genome Atlas database were used for analysis, including differential expression and diagnostic and prognostic significance. Oncomine and MERAV databases were used to validate differential expression and diagnostic significance. A risk score model was constructed using prognosis-related ABCC members. Prognosis-related genes were further explored to correlate their expression with tumor stage progression. Interaction networks, including biological processes and metabolic pathways, were constructed using Cytoscape software and STRING website.ABCC1-3 consistently showed high expression in tumor tissues (all P ≤ 0.05). Most datasets indicated that ABCC5, 10, and 11 were highly expressed in tumor tissues whereas ABCC6, 9, and CFTR were highly expressed in nontumor tissues (all P ≤ 0.05). Diagnostic significance of ABCC3 and ABCC5 was consistently assessed and validated in three datasets (all area under the curve > 0.700) whereas ABCC6, 8, 10, 11, and CFTR were assessed in The Cancer Genome Atlas dataset and validated in one dataset (all area under the curve > 0.700). Prognostic analysis indicated that ABCC2, 6, and 8 mRNA expression was associated with survival of LUAD (all adjusted P ≤ .037). The risk score model constructed using ABCC2, 6, and 8 suggested prognostic significance for survival predictions. ABCC2 expression was associated with tumor stage, whereas ABCC6 and 8 were not. Interaction networks indicated that they were involved in establishment of localization, ion transport, plasma membrane, apical plasma membrane, adenylyl nucleotide binding, ABC transporters, ABC transporter disorders, ABC-family-protein-mediated transport, and bile secretion.Differentially expressed ABCC2 and ABCC5 might be diagnostic whereas ABCC2, 6, and 8 may be prognostic biomarkers for LUAD, possibly through ABC-family-mediated transporter disorders.


Asunto(s)
Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/mortalidad , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Anciano , Biomarcadores de Tumor/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Bases de Datos Genéticas , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , Medición de Riesgo , Factores de Riesgo , Análisis de Supervivencia
8.
Medicine (Baltimore) ; 100(16): e25244, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879657

RESUMEN

ABSTRACT: A newly discovered long non-coding RNA (lncRNA) is associated with the progression of a variety of tumors. The purpose of this meta-analysis is to explore further the relationship between clinicopathological features and the prognostic value of LINC00675 in caners.We searched the various database, including PubMed, Web of Science, Cochrane Library, Embase together with Wanfang, and China National Knowledge Infrastructure for articles on LINC00675 and clinicopathological characteristics and prognosis of patients with cancers before February 20, 2020. According to the inclusion and exclusion criteria, the studies that meet the criteria were systematically collected through search keywords. The Newcastle Ottawa document quality assessment system was used to evaluate the quality of documents. The required data from literature were extracted, and the hazard ratio (HR), odds ratio (OR), and 95confidence interval (CI) were calculated using stata12.0 software and RevMan5.3 software.A total of 5 studies covering 462 patients were included in this meta-analysis to evaluate the prognostic value of LINC00675 in cancers. Our results showed that high LINC00675 expression was significantly correlated with poor overall survival (OS) (HR = 1.60, 95% CI: 1.23-2.08, P = .0005). Additionally, upregulated expression of LINC00675 was significantly associated with tumor node metastasis stage (OR = 1.74, 95% CI: 1.18-2.58, P = .006) and distant metastasis (OR = 2.22, 95% CI: 1.21-4.08, P = .01).Our study suggests that LINC00675 could be used as a biomarker to evaluate the prognosis of cancer patients. More studies to further confirm that the clinical value of LINC00675 in cancers will be required.


Asunto(s)
Neoplasias/genética , Neoplasias/mortalidad , ARN Largo no Codificante/metabolismo , Biomarcadores de Tumor/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Metástasis de la Neoplasia/genética , Oportunidad Relativa , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Sensibilidad y Especificidad , Análisis de Supervivencia , Regulación hacia Arriba/genética
9.
Medicine (Baltimore) ; 100(16): e25414, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879671

RESUMEN

ABSTRACT: Single-cell RNA-seq has become a powerful tool to understand tumor cell heterogenicity. This study tried to screen prognosis-related genes in basal-like breast tumors and evaluate their correlations with cellular states at the single-cell level.Bulk RNA-seq data of basal-like tumor cases from The Cancer Genome Atlas-Breast Cancer (TCGA-BRCA) and single-cell RNA-seq from GSE75688 were retrospectively reviewed. Kaplan-Meier survival curves, univariate and multivariate analysis based on Cox regression model were conducted for survival analysis. Gene set enrichment analysis (GSEA) and single-cell cellular functional state analysis were performed.Twenty thousand five hundred thirty genes with bulk RNA-seq data in TCGA were subjected to screening. Preliminary screening identified 10 candidate progression-related genes, including CDH19, AQP5, SDR16C5, NCAN, TTYH1, XAGE2, RIMS2, GZMB, LY6D, and FAM3B. By checking their profiles using single-cell RNA-seq data, only CDH19, SDR16C5, TTYH1, and RIMS2 had expression in primary triple-negative breast cancer (TNBC) cells. Prognostic analysis only confirmed that RIMS2 expression was an independent prognostic indicator of favorable progression free survival (PFS) (HR: 0.78, 95%: 0.64-0.95, P  = .015). GSEA analysis showed that low RIMS2 group expression had genes significantly enriched in DNA Repair, and MYC Targets V2. Among the 89 basal-like cells, RIMS2 expression was negatively correlated with DNA repair and epithelial-to-mesenchymal transition (EMT).RIMS2 expression was negatively associated with DNA repair capability of basal-like breast tumor cells and might serve as an independent indicator of favorable PFS.


Asunto(s)
Neoplasias de la Mama/genética , Proteínas de la Membrana/genética , Neoplasias Basocelulares/genética , RNA-Seq , Proteínas de Unión al GTP rab3/genética , Adulto , Biomarcadores de Tumor/genética , Simulación por Computador , Reparación del ADN/genética , Bases de Datos Genéticas , Detección Precoz del Cáncer/métodos , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Análisis de Supervivencia , Neoplasias de la Mama Triple Negativas/genética
10.
Medicine (Baltimore) ; 100(16): e25541, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879700

RESUMEN

ABSTRACT: Thyroid cancer is a common endocrine malignancy; however, surgery remains its primary treatment option. A novel targeted drug for the development and application of targeted therapy in thyroid cancer treatment remain underexplored.We obtained RNA sequence data of thyroid cancer from The Cancer Genome Atlas database and identified differentially expressed genes (DEGs). Then, we constructed co-expression network with DEGs and combined it with differentially methylation analysis to screen the key genes in thyroid cancer. PockDrug-Server, an online tool, was applied to predict the druggability of the key genes. Finally, we constructed protein-protein interaction (PPI) network to observe potential targeted drugs for thyroid cancer.We identified 3 genes correlated with altered DNA methylation level and oncogenesis of thyroid cancer. According to the druggable analysis and PPI network, we predicted TRAF2 and NCK-interacting protein kinase (TNIK) sever as the drug targeted for thyroid cancer. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that genes in protein-protein interaction network of TNIK enriched in mitogen-activated protein kinase signaling pathway. For drug repositioning, we identified a targeted drug of genes in PPI network.Our study provides a bioinformatics method for screening drug targets and provides a theoretical basis for thyroid cancer targeted therapy.


Asunto(s)
Desarrollo de Medicamentos/métodos , Proteínas Serina-Treonina Quinasas/genética , Factor 2 Asociado a Receptor de TNF/genética , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/genética , Biomarcadores de Tumor/genética , Carcinogénesis/genética , Biología Computacional/métodos , Metilación de ADN/genética , Bases de Datos Genéticas , Regulación Neoplásica de la Expresión Génica/genética , Ontología de Genes , Humanos , Sistema de Señalización de MAP Quinasas/genética , Mapas de Interacción de Proteínas/genética
11.
Medicine (Baltimore) ; 100(16): e25603, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33879726

RESUMEN

ABSTRACT: Gliomas have the highest incidence among primary brain tumors, and the extracellular matrix (ECM) plays a vital role in tumor progression. We constructed a risk signature using ECM-related genes to predict the prognosis of patients with gliomas.mRNA and clinical data from glioma patients were downloaded from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) and Chinese Glioma Genome Atlas (CGGA) databases. Differentially expressed ECM-related genes were screened, and a risk signature was built using least absolute shrinkage and selection operator (LASSO) Cox regression. Cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT) was used to assess immune infiltration in different risk groups. Gene set enrichment analysis (GSEA) was performed to explore the molecular mechanisms of the genes employed in the risk score.Differentially expressed ECM-related genes were identified, and their associated regulatory mechanisms were predicted via analysis of protein-protein interaction (PPI), transcription factor (TF) regulatory and TF coexpression networks. The established risk signature considered 17 ECM-related genes. The prognosis of the high-risk group was significantly worse than that of the low-risk group. We used the CGGA database to validate the signature. CIBERSORT indicated that the levels of naive B cells, activated memory CD4 T cells, regulatory T cells, gamma delta T cells, activated NK cells, monocytes, activated dendritic cells and activated mast cells were higher in the high-risk group. The levels of plasma cells, CD8 T cells, naive CD4 T cells, resting memory CD4 T cells, M0 macrophages, M1 macrophages, resting mast cells, and neutrophils were lower in the high-risk group. Ultimately, GSEA showed that the terms intestinal immune network for IgA production, primary immunodeficiency, and ECM receptor interaction were the top 3 terms enriched in the high-risk group. The terms Wnt signaling pathway, ErbB signaling pathway, mTOR signaling pathway, and calcium signaling pathway were enriched in the low-risk group.We built a risk signature to predict glioma prognosis using ECM-related genes. By evaluating immune infiltration and biofunctions, we gained a further understanding of this risk signature. This risk signature could be an effective tool for predicting glioma prognosis.This study did not require ethical approval. We will disseminate our findings by publishing results in a peer-reviewed journal.


Asunto(s)
Neoplasias Encefálicas/genética , Matriz Extracelular/genética , Glioma/genética , Medición de Riesgo/normas , Adulto , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/mortalidad , Bases de Datos Genéticas , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , Glioma/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Mapas de Interacción de Proteínas/genética , ARN Mensajero/genética , Reproducibilidad de los Resultados , Factores de Riesgo , Transducción de Señal/genética , Factores de Transcripción/genética
12.
World J Surg Oncol ; 19(1): 131, 2021 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-33882945

RESUMEN

BACKGROUND: Radiotherapy is a main therapeutic method for cancers, including colon cancer. In the current study, we aim to explore the effects of circular RNA (circRNA) circ_0055625 in the progression and radiosensitivity of colon cancer and the underlying mechanism. METHODS: The expression of circ_0055625 and musashi homolog 1 (MSI1) mRNA was detected by quantitative real-time polymerase chain reaction (qRT-PCR). MSI1 protein expression was determined by Western blot. Cell proliferation was assessed by cell counting kit-8 (CCK-8) and colony formation assays. Cell survival fraction, apoptosis, and invasion were investigated by colony formation assay, flow cytometry analysis, and transwell invasion assay, respectively. Cell migration was detected by wound-healing and transwell migration assays. The binding relationship between microRNA-338-3p (miR-338-3p) and circ_0055625 or MSI1 was predicted by online databases and identified by Dual-Luciferase Reporter Assay. The effects of circ_0055625 silencing on the tumor formation and radiosensitivity of colon cancer in vivo were explored by in vivo tumor formation assay. RESULTS: Circ_0055625 and MSI1 were upregulated in colon cancer tissues and cells relative to control groups. Radiation treatment apparently increased the expression of circ_0055625 and MSI1 in colon cancer cells. Circ_0055625 knockdown or MSI1 silencing repressed cell proliferation, migration, and invasion and promoted cell apoptosis and radiosensitivity in colon cancer. Also, circ_0055625 silencing-mediated effects were attenuated by MSI1 overexpression. Additionally, circ_0055625 silencing reduced MSI1 expression, which could be attenuated by miR-338-3p inhibitor. Mechanically, circ_0055625 acted as a sponge for miR-338-3p to regulate MSI1. Furthermore, circ_0055625 knockdown hindered tumor growth and improved radiosensitivity in vivo. CONCLUSION: Circ_0055625 repression inhibited the progression and radioresistance of colon cancer by downregulating MSI1 through sponging miR-338-3p. This result might provide a theoretical basis for improving the therapy of colon cancer with radiation.


Asunto(s)
Neoplasias del Colon , MicroARNs/genética , Proteínas del Tejido Nervioso/genética , ARN Circular/genética , Proteínas de Unión al ARN/genética , Carcinogénesis/genética , Línea Celular Tumoral , Neoplasias del Colon/genética , Neoplasias del Colon/radioterapia , Regulación Neoplásica de la Expresión Génica/genética , Técnicas de Inactivación de Genes , Silenciador del Gen , Humanos , Proteínas del Tejido Nervioso/biosíntesis , Pronóstico , Proteínas de Unión al ARN/biosíntesis , Tolerancia a Radiación/genética , Tolerancia a Radiación/efectos de la radiación , Transfección
13.
Int J Mol Sci ; 22(7)2021 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-33807419

RESUMEN

Osteosarcoma (OSA) represents the most common bone tumor in dogs. The malignancy is highly aggressive, and most of the dogs die due to metastasis, especially to the lungs. The metastatic process is complex and consists of several main steps. Assessment of the molecular mechanisms of metastasis requires in vitro and especially in vivo studies for a full evaluation of the process. The molecular and biological resemblance of canine OSA to its human counterpart enables the utilization of dogs as a spontaneous model of this disease in humans. The aim of the present review article is to summarize the knowledge of genes and proteins, including p63, signal transducer and activator of transcription 3 (STAT3), Snail2, ezrin, phosphorylated ezrin-radixin-moesin (p-ERM), hepatocyte growth factor-scatter factor (HGF-SF), epidermal growth factor receptor (EGFR), miR-9, and miR-34a, that are proven, by in vitro and/or in vivo studies, to be potentially involved in the metastatic cascade of canine OSA. The determination of molecular targets of metastatic disease may enhance the development of new therapeutic strategies.


Asunto(s)
Metástasis de la Neoplasia/fisiopatología , Osteosarcoma/metabolismo , Animales , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Neoplasias Óseas/fisiopatología , Línea Celular Tumoral , Proteínas del Citoesqueleto/metabolismo , Modelos Animales de Enfermedad , Perros , Receptores ErbB/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Factor de Crecimiento de Hepatocito/metabolismo , MicroARNs , Metástasis de la Neoplasia/genética , Osteosarcoma/veterinaria , Fosforilación , Factor de Transcripción STAT3/metabolismo , Factores de Transcripción de la Familia Snail/metabolismo , Proteínas Supresoras de Tumor/metabolismo
14.
Mol Cell Biol ; 41(5)2021 04 22.
Artículo en Inglés | MEDLINE | ID: mdl-33722958

RESUMEN

Exosomes are microvesicles secreted by body cells for intercellular communication. The circular RNA circ_0000338 was found to be present in extracellular vesicles and improve the chemoresistance of colorectal cancer (CRC) cells. However, the role of exosomal circ_0000338 in 5-fluorouracil (5-FU) resistance in CRC is largely unknown. The levels of circ_0000338, microRNA 217 (miR-217), and miR-485-3p were detected using quantitative real-time PCR (qRT-PCR). The 50% inhibitory concentration (IC50) values of cells for 5-FU, cell proliferation, and apoptosis were evaluated using cell counting kit 8 (CCK-8), colony formation, flow cytometry, and Western blot assays. The interaction between miR-217 or miR-485-3p and circ_0000338 was confirmed by RNA immunoprecipitation (RIP), dual-luciferase reporter, and pulldown assays. Exosomes were isolated by ultracentrifugation and qualified by transmission electron microscopy (TEM), Nanosight tracking analysis (NTA), and Western blotting. Xenograft models were performed to analyze whether circ_0000338-loaded exosomes could increase resistance of CRC cells to 5-FU in vivo The circ_0000338 level was elevated in 5-FU-resistant CRC tissues and cells, and circ_0000338 knockdown sensitized 5-FU-resistant CRC cells to 5-FU through enhancing apoptosis and decreasing proliferation in vitro Mechanistically, circ_0000338 directly bound to miR-217 and miR-485-3p, and the inhibition of miR-217 or miR-485-3p reversed the effects of circ_0000338 knockdown on cell 5-FU resistance in CRC. Additionally, extracellular circ_0000338 could be incorporated into secreted exosomes and transmitted to 5-FU-sensitive cells. Treatment-sensitive cells with exosomes containing circ_0000338 reduced the 5-FU response in CRC both in vitro and in vivo Besides that, the exosomal circ_0000338 concentration was higher in patients exhibiting resistance to 5-FU and showed good diagnostic efficiency in 5-FU-resistant CRC. The delivery of circ_0000338 via exosomes enhanced 5-FU resistance in CRC through negative regulation of miR-217 and miR-485-3p, indicating a promising diagnostic and therapeutic marker for 5-FU-based chemotherapy in CRC patients.


Asunto(s)
Neoplasias Colorrectales/genética , Exosomas/metabolismo , Fluorouracilo/farmacología , MicroARNs/genética , ARN Circular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Neoplasias Colorrectales/metabolismo , Resistencia a Antineoplásicos/genética , Exosomas/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos
15.
Mol Med Rep ; 23(5)2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33760104

RESUMEN

Gastric cancer (GC) is a common malignant tumor in the digestive system, which presents without specific symptoms. Circular RNAs (circRNAs) play important roles in tumor progression and cellular functions; however, the relationship between GC and hsa_circ_0072309 remains unclear. The aim of the present study was to investigate the molecular mechanisms of hsa_circ_0072309 and the role that hsa_circ_0072309 plays in proliferation, invasion and migration of GC cells. The expression of hsa_circ_0072309 was evaluated using reverse transcription­quantitative PCR. A series of functional experiments were performed to study the role that hsa_circ_0072309 has in survival and metastasis of GC cells. In the present study, hsa_circ_0072309 was downregulated in GC cell lines and its overexpression inhibited the proliferation, migration and invasion of GC cells. In addition, hsa_circ_0072309 overexpression induced activation of the peroxisome proliferator­activated receptor γ (PPARγ)/PTEN pathway and inhibition of PI3K/AKT signaling. Moreover, pioglitazone, a PPARγ agonist, strengthened the effects of abundant hsa_circ_0072309 on the proliferative, migratory and invasive capabilities of GC cells, while GW9662, a PPARγ antagonist, abolished the effects of hsa_circ_0072309 overexpression on cell proliferation, migration and invasion. The present findings suggested that hsa_circ_0072309 inhibited proliferation, invasion and migration of gastric cancer cells via the inhibition of PI3K/AKT signaling by activating the PPARγ/PTEN signaling pathway. Targeting hsa_circ_0072309 may be an innovative therapeutic strategy for the treatment of GC.


Asunto(s)
PPAR gamma/genética , Fosfohidrolasa PTEN/genética , ARN Circular/genética , Neoplasias Gástricas/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal/genética , Neoplasias Gástricas/patología
16.
Mol Med Rep ; 23(5)2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33760109

RESUMEN

Increasing evidence suggests that long noncoding RNAs (lncRNAs) influence the pathogenesis and progression of hepatocellular carcinoma (HCC). The authors of the present study previously reported that abnormal upregulation of lncRNA DQ786243 (lncDQ) was associated with poor prognoses for patients with HCC. However, the elucidation of underlying mechanisms which influenced these results was not completed. Thus, the current study aimed to characterize the mechanisms and functions of lncDQ that facilitate its promotion of HCC progression. lncDQ, miR­15b­5p and Wnt3A expression levels were characterized in HCC and portal vein tumor thrombus tissue samples and for liver cancer and liver cancer cell lines using reverse transcription­quantitative PCR. Bioinformatics software was used for the analysis of interactions between lncDQ and miR­15b­5p, miR­15b­5p and Wnt3A. Luciferase assays confirmed the binding relationships between miR­15b­5p and the 3' untranslated region (UTR) of Wnt3A. Using online databases, prognostic values of miR­15b­5p and Wnt3A were also assessed. Proliferation and invasion assays were used to assess liver cancer and HCC cell functions after individually silencing lncDQ and miR­15b­5p expression in the cells. Western blotting was used for the investigation of alterations of the expression of Wnt3A/ß­catenin and epithelial­mesenchymal transition (EMT) signal pathways. lncDQ and Wnt3A expression were significantly increased in HCC tissues, whereas miR­15b­5p was downregulated in HCC tissues. Low expression of miR­15b­5p was also associated with poor prognoses for patients with HCC. lncDQ was able to bind with miR­15b­5p and served as a competing endogenous RNA. As the target gene of miR­15b­5p, Wnt3A was correlated with poor prognoses for patients with HCC. Silencing of lncDQ expression significantly attenuated proliferation and invasion of liver cancer and HCC cells, however the inhibition of miR­15b­5p was able to reverse this effect. However, silencing of lncDQ and miR­15b­5p expression simultaneously resulted in the partial rescue of the inhibitory effect in the liver cancer and HCC cells. lncDQ inhibited miR­15b­5p so as to promote HCC cell invasion and proliferation through activation of the Wnt3A/ß­catenin/EMT pathway. Taken together, the results of the present study suggested that the lncDQ/miR­15b­5p axis modulates the progression of HCC.


Asunto(s)
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , ARN Largo no Codificante/genética , Proteína Wnt3A/genética , Animales , Apoptosis , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Células Hep G2 , Humanos , Neoplasias Hepáticas/patología , Masculino , Ratones , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología
17.
Mol Med Rep ; 23(5)2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33760113

RESUMEN

Pancreatic mucinous cystadenocarcinoma (MCC) is a rare malignant tumor, with a limited number of studies. The present study aimed to investigate the function and mechanism of microRNA (miR)­224­5p on proliferation, migration and invasion of MCC of the pancreas. Reverse transcription­quantitative PCR was used to explorethe expression of miR­224­5p and the PTEN gene. MTT, wound healing, Transwell and tumorigenesis assays were conducted to investigate the proliferation, migration and invasion of MCC1 cells in vitro and in vivo. Western blot analysis was employed to test the protein expression of PTEN. The target gene of miR­224­5p was assessed and verified by luciferase assay. miR­224­5p expression was notably higher, while PTEN expression was lower, in MCC1 cells compared with normal tissues and cells. Overexpression of miR­224­5p promoted the proliferation, migration and invasion of MCC and knockdown of miR­224­5p inhibited these functions. Bioinformatics analysis and luciferase assay indicated that PTEN was the direct target gene of miR­224­5p. The negative correlation between miR­224­5p and PTEN was confirmed both in vitro and in vivo. PTEN reversed the effects of miR­224­5p on proliferation, migration and invasion of MCC1 cells. The present study revealed for the first time, to the best of the authors' knowledge, that miR­224­5p was highly expressed and served an oncogenic role in MCC. miR­224­5p not only regulated the proliferation, migration and invasion of pancreatic MCC but may also be a potential therapeutic target for MCC.


Asunto(s)
Cistadenocarcinoma Mucinoso/genética , MicroARNs/genética , Fosfohidrolasa PTEN/genética , Neoplasias Pancreáticas/genética , Anciano , Animales , Apoptosis , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Cistadenocarcinoma Mucinoso/patología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Xenoinjertos , Humanos , Masculino , Ratones , Persona de Mediana Edad , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Neoplasias Pancreáticas/patología
18.
Mol Med Rep ; 23(5)2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33760117

RESUMEN

The aim of the present study was to identify the differentially expressed microRNAs (miRs) in cervical carcinoma (CC) tissues and cells and to explore the function of miR­302c­3p and miR­520a­3p in the proliferation of CC cells. Potential dysregulated miRNAs in CC tissues and tumour­adjacent tissues were detected. Reverse transcription­quantitative PCR (RT­qPCR) was performed to determine the expression of miR­302c­3p, miR­520a­3p and CXCL8 in CC tissues and cell lines. The target genes of the miRNAs were predicted using miRTarBase and verified by luciferase reporter assays. RT­qPCR and western blotting were performed to measure the expression of C­X­C motif ligand (CXCL)8 after transfection. The effect on proliferation was verified by Cell Counting Kit assay and ethynyl­2­deoxyuridine staining. Flow cytometry was utilised to assess the effect on apoptosis. In the present study, miR­302c­3p and miR­520a­3p were markedly downregulated in CC cell lines compared to the normal cervical cell line H8. Functionally, overexpression of miR­302c­3p and/or miR­520a­3p inhibited proliferation and promoted the apoptosis of CC cell lines in vitro, while the knockdown of miR­302c­3p and/or miR­520a­3p had the opposite effect. Furthermore, miR­302c­3p and miR­520a­3p could both bind to CXCL8. Inhibition of CXCL8 in combination with miR­302c­3p and/or miR­520a­3p overexpression exerted proliferation­suppressive and apoptosis­stimulating effects on CC cells, whereas restoring CXCL8 attenuated the miR­302c­3p­ and miR­520a­3p­induced anti­proliferative and pro­apoptotic effects. miR­302c­3p and miR­520a­3p suppress the proliferation of CC cells by downregulating the expression of CXCL8, which may provide a novel target for the treatment of CC.


Asunto(s)
Carcinoma/genética , Interleucina-8/genética , MicroARNs/genética , Neoplasias del Cuello Uterino/genética , Adulto , Anciano , Antagomirs/farmacología , Apoptosis/genética , Carcinoma/patología , Línea Celular Tumoral , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Persona de Mediana Edad , Neoplasias del Cuello Uterino/patología
19.
Mol Med Rep ; 23(5)2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33760126

RESUMEN

The present study aimed to elucidate the biological function of circular RNAs (circRNA) 0074027 in colorectal cancer (CRC). The expression of circRNA­0074027 in CRC tissues and cells was determined by reverse transcription­quantitative PCR. The in vitro experiments, including Cell Counting Kit­8 (CCK­8) assay, 5­Ethynyl­2'­deoxyuridine assay, flow cytometry and Transwell assay, were applied to evaluate cell proliferation, apoptosis and metastasis ability respectively following downregulation of circRNA­0074027. The correlation between circRNA­0074027 and micro (mi)RNA­525­3p was determined via dual­luciferase reporter assay. Finally, western blotting was used to explore the possible regulatory mechanism. CircRNA­0074027 was upregulated in CRC tissues, while miR­525­3p expression was reduced. In addition, patients with CRC and circRNA­0074027 overexpression were more likely to have low tumor differentiation, lymph node metastasis and advanced TMN stage. Deletion of circRNA­0074027 could suppress cell proliferation and metastasis through up-regulating p53 expression and forbidding epithelial­mesenchymal transition signaling pathway. The addition of miRNA­525­3p inhibitors could reverse the anti­tumor effects induced by the deletion of circRNA­0074027. The downregulation of cirRNA_0074027 inhibited tumor progression via sponging miR­525­3p, which could be a promising treatment bio­marker for CRC.


Asunto(s)
Proliferación Celular/genética , Neoplasias Colorrectales/genética , MicroARNs/genética , ARN Circular/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/genética , Células CACO-2 , Línea Celular Tumoral , Movimiento Celular/genética , Neoplasias Colorrectales/patología , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Vía de Señalización Wnt/genética , Adulto Joven
20.
Mol Med Rep ; 23(5)2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33760133

RESUMEN

Esophageal squamous cell carcinoma (ESCC) is one of the most debilitating and invasive tumors. Although previous reports have demonstrated the critical role microRNA­181a (miR­181a) serves in the progression of ESCC, how miR­181a induces epithelial­mesenchymal transition (EMT) remains to be elucidated. In the present study, the expression profiles of TGF­ß1 and Smad4 proteins in 88 patients with ESCC and 21 adjacent non­cancerous tissues were analyzed using immunohistochemistry. The expression of miR­181a in ESCC cells (ECA109 and TE­1) and HEEC was analyzed using reverse transcription­quantitative polymerase chain reaction (RT­qPCR). The role of miR­181a in ESCC was analyzed using miR­181a mimics and inhibitor in the same system. Migration, proliferation and apoptosis of cells were assessed using wound­healing assays and cell proliferation assays and flow cytometry, respectively. The expression levels of TGF­ß1 and Smad4 in ESCC cell lines transfected with miR­181a mimics and inhibitor were measured using RT­qPCR and western blotting. The expression of E­cadherin and vimentin was also assessed following transfection. The findings demonstrated that expression of TGF­ß1 was upregulated, in contrast to Smad4 expression which was downregulated. Expression levels of Smad4 affected the prognosis of patients with ESCC. Higher expression of miR­181a promoted migration and proliferation but inhibited apoptosis of ESCC cells. miR­181a promoted EMT by modulating Smad4 expression in ESCC cells. Overall, these findings revealed that miR­181a induced EMT in ESCC via the TGF­ß/Smad pathway in ESCC. Consequently, miR­181a is a potential novel target against ESCC.


Asunto(s)
Carcinoma de Células Escamosas de Esófago/genética , MicroARNs/genética , Pronóstico , Proteína Smad4/genética , Factor de Crecimiento Transformador beta/genética , Adulto , Anciano , Apoptosis/genética , Cadherinas/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Supervivencia sin Enfermedad , Transición Epitelial-Mesenquimal/genética , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología
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