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1.
ACS Med Chem Lett ; 11(10): 1863-1868, 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33062165

RESUMO

The identification and lead optimization of a series of pyrazolo[3,4-d]pyridazinone derivatives are described as a novel class of potent irreversible BTK inhibitors, resulting in the discovery of compound 8. Compound 8 exhibited high potency against BTK kinase and acceptable PK profile. Furthermore, compound 8 demonstrated significant in vivo efficacy in a mouse-collagen-induced arthritis (CIA) model.

2.
Onco Targets Ther ; 13: 10275-10285, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116608

RESUMO

Introduction: Radiotherapy is one of the most important methods in the treatment of patients with hypopharyngeal squamous cell carcinoma (HSCC). However, radioresistance will be developed after repeated irradiation. Among many key factors contributing to radioresistance, enhanced autophagy is recognized as one of the most important. The ultraviolent irradiation resistance-associated gene (UVRAG) is reported to be a crucial gene involved in the process of autophagy. Here, we test whether UVRAG has effect on the radioresistance of HSCC. Methods: HSCC cell line Fadu cells were treated with irradiation to test levels of autophagy. Tumor tissues from primary and recurrent HSCC patients were tested by immunohistochemistry. Then, we knocked down UVRAG to test its role in cell growth and the malignant behaviors. Response of cells to treatment was examined using LDH release assay, immunofluorescence, Western blot analysis and colony formation. Results: We found that irradiation induced autophagy in Fadu cells. Immunohistochemistry of primary and irradiated HSCC tumor tissues showed that UVRAG was upregulated after irradiation treatment. Inhibiting UVRAG with siRNA interfered cell growth, cell cycle, malignant behaviors and autophagic flux in Fadu cells. Knocking down UVRAG increased DNA damage and cell death induced by irradiation. Finally, we found that inhibiting UVRAG induced lysosomal membrane permeabilization, which contributed to radiosensitization of Fadu cells. Conclusion: Our findings supported the oncogenic properties of UVRAG in HSCC and inhibiting UVRAG increased radiosensitivity in HSCC by triggering lysosomal membrane permeabilization. Therefore, UVRAG might be a promising target in the treatment of HSCC.

3.
Int J Biol Macromol ; 163: 2048-2059, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32961176

RESUMO

In this work, we aimed to investigate the effect of the combination of starch nanoparticles (SNPs) and Tween 80 (TW) on the stability of oil-in-water emulsions. The emulsions prepared under different SNPs/TW ratios and different oil fraction values were characterized by means of photography, optical microscopy, laser particle size analysis, rheological measurement, quartz crystal microbalance analysis, and confocal laser scanning microscopy. At an oil fraction value of 0.4, the emulsions with a 3: 1 ratio of SNPs (1.5%, w/v) to TW (0.5%, w/v) exhibited excellent storage stability over a long period of 30 d, which was significantly better than the 2% TW stabilized emulsion and the 2% SNPs stabilized emulsion. Compared with the SNPs stable emulsions, the presence of TW decreased the emulsion droplets size, which was beneficial to reduce the aggregation of droplets. Emulsions co-stabilized by SNPs and TW can maintain good performance under harsh conditions. The results of quartz crystal microbalance analysis and isothermal titration calorimetry revealed non-covalent interactions between SNPs and TW. The results showed that SNPs and TW co-existed at the oil-water interface and improved the performance of the emulsion.

4.
Life Sci ; 262: 118480, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32980391

RESUMO

OBJECTIVE: Hypopharyngeal squamous cell carcinoma (HSCC) is a common type of malignant tumor. Long non-coding RNAs (lncRNAs) are known to participate in HSCC development, while the role of lncRNA MALAT1 in HSCC remains largely unknown. We aimed to explore function of the lncRNA MALAT1/miR-429/ZEB1 axis in HSCC progression. METHODS: Levels of MALAT1, miR-429 and ZEB1 in HSCC tissues samples were assessed. The FaDu cells were respectively treated with relative sequence or plasmid of MALAT1, miR-429, or ZEB1. Then, CCK-8 assay, colony formation assay, flow cytometry and Transwell assay were used to determine the cell proliferation, apoptosis, cell cycle, migration and invasion of the cells. The PI3K/Akt/mTOR signaling pathway-related proteins, proliferation-related proteins, cell cycle-related proteins, apoptosis-related proteins, and migration-related proteins were detected using Western blot analysis. The cell growth in vivo was observed. The targeting relationships between MALAT1 and miR-429, and between miR-429 and ZEB1 were confirmed. RESULTS: MALAT1 and ZEB1 expression in HSCC was upregulated while miR-429 expression was downregulated. Reduced MALAT1 and ZEB1, and upregulated miR-429 inactivated the PI3K/Akt/mTOR signaling pathway, suppressed in vitro viability, colony formation ability, migration and invasion, as well as cell growth in vivo, and promoted the apoptosis of FaDu cells. Downregulated miR-429 reversed the role of MALAT1 inhibition in FaDu cell growth. LncRNA MALAT1 served as a sponge of miR-429, thus regulating ZEB1 expression. CONCLUSION: Inhibition of MALAT1 was able to elevate miR-429 to suppress the progression of HSCC via reducing ZEB1. Our research provided a potential therapeutic target for HSCC.

5.
Front Oncol ; 10: 1120, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32733808

RESUMO

Radiotherapy has been used in the clinic for more than one century and it is recognized as one of the main methods in the treatment of malignant tumors. Signal Transducers and Activators of Transcription 3 (STAT3) is reported to be upregulated in many tumor types, and it is believed to be involved in the tumorigenesis, development and malignant behaviors of tumors. Previous studies also found that STAT3 contributes to chemo-resistance of various tumor types. Recently, many studies reported that STAT3 is involved in the response of tumor cells to radiotherapy. But until now, the role of the STAT3 in radioresistance has not been systematically demonstrated. In this study, we will review the radioresistance induced by STAT3 and relative solutions will be discussed.

6.
ISA Trans ; 103: 75-85, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32220533

RESUMO

The reachable set estimation and stabilization problems of large-scale switched systems have been investigated in this paper. To start with, a class of specific Lyapunov functions for the reachable set estimation of large-scale switched systems is proposed. Secondly, by the method of the proposed specific Lyapunov functions of the large-scale switched systems, the boundary of system state response is calculated under arbitrary switching, which might be used for the safety verification. Then, the concept of decentralized control is introduced and the decentralized state feedback controllers are developed to ensure the state trajectories of the closed-loop large-scale switched systems are limited within the estimated set and guarantee the system globally uniformly asymptotically stable. Finally, several numerical and practical examples are established to confirm the effectiveness and correctness of our results.

8.
Blood ; 135(13): 996-1007, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-31977002

RESUMO

Treatment options for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are limited, with no standard of care; prognosis is poor, with 4- to 6-month median survival. Avadomide (CC-122) is a cereblon-modulating agent with immunomodulatory and direct antitumor activities. This phase 1 dose-expansion study assessed safety and clinical activity of avadomide monotherapy in patients with de novo R/R DLBCL and transformed lymphoma. Additionally, a novel gene expression classifier, which identifies tumors with a high immune cell infiltration, was shown to enrich for response to avadomide in R/R DLBCL. Ninety-seven patients with R/R DLBCL, including 12 patients with transformed lymphoma, received 3 to 5 mg avadomide administered on continuous or intermittent schedules until unacceptable toxicity, disease progression, or withdrawal. Eighty-two patients (85%) experienced ≥1 grade 3/4 treatment-emergent adverse events (AEs), most commonly neutropenia (51%), infections (24%), anemia (12%), and febrile neutropenia (10%). Discontinuations because of AEs occurred in 10% of patients. Introduction of an intermittent 5/7-day schedule improved tolerability and reduced frequency and severity of neutropenia, febrile neutropenia, and infections. Among 84 patients with de novo R/R DLBCL, overall response rate (ORR) was 29%, including 11% complete response (CR). Responses were cell-of-origin independent. Classifier-positive DLBCL patients (de novo) had an ORR of 44%, median progression-free survival (mPFS) of 6 months, and 16% CR vs an ORR of 19%, mPFS of 1.5 months, and 5% CR in classifier-negative patients (P = .0096). Avadomide is being evaluated in combination with other antilymphoma agents. This trial was registered at www.clinicaltrials.gov as #NCT01421524.


Assuntos
Antineoplásicos/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Piperidonas/uso terapêutico , Quinazolinonas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Biomarcadores , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imunofenotipagem , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Piperidonas/administração & dosagem , Piperidonas/efeitos adversos , Piperidonas/farmacocinética , Prognóstico , Quinazolinonas/administração & dosagem , Quinazolinonas/efeitos adversos , Quinazolinonas/farmacocinética , Recidiva , Retratamento , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
9.
Cancer Discov ; 10(3): 406-421, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31857391

RESUMO

Hodgkin lymphoma is characterized by an extensively dominant tumor microenvironment (TME) composed of different types of noncancerous immune cells with rare malignant cells. Characterization of the cellular components and their spatial relationship is crucial to understanding cross-talk and therapeutic targeting in the TME. We performed single-cell RNA sequencing of more than 127,000 cells from 22 Hodgkin lymphoma tissue specimens and 5 reactive lymph nodes, profiling for the first time the phenotype of the Hodgkin lymphoma-specific immune microenvironment at single-cell resolution. Single-cell expression profiling identified a novel Hodgkin lymphoma-associated subset of T cells with prominent expression of the inhibitory receptor LAG3, and functional analyses established this LAG3+ T-cell population as a mediator of immunosuppression. Multiplexed spatial assessment of immune cells in the microenvironment also revealed increased LAG3+ T cells in the direct vicinity of MHC class II-deficient tumor cells. Our findings provide novel insights into TME biology and suggest new approaches to immune-checkpoint targeting in Hodgkin lymphoma. SIGNIFICANCE: We provide detailed functional and spatial characteristics of immune cells in classic Hodgkin lymphoma at single-cell resolution. Specifically, we identified a regulatory T-cell-like immunosuppressive subset of LAG3+ T cells contributing to the immune-escape phenotype. Our insights aid in the development of novel biomarkers and combination treatment strategies targeting immune checkpoints.See related commentary by Fisher and Oh, p. 342.This article is highlighted in the In This Issue feature, p. 327.

10.
Cytometry A ; 97(6): 620-629, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31637838

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma and is notorious for its clinical heterogeneity. Patient outcomes can be predicted by cell-of-origin (COO) classification, demonstrating that the underlying transcriptional signature of malignant B-cells informs biological behavior in the context of standard combination chemotherapy regimens. In the current study, we used mass cytometry (CyTOF) to examine tumor phenotypes at the protein level with single cell resolution in a collection of 27 diagnostic DLBCL biopsy specimens from treatment naïve patients. We found that malignant B-cells from each patient occupied unique regions in 37-dimensional phenotypic space with no apparent clustering of samples into discrete subtypes. Interestingly, variable MHC class II expression was found to be the greatest contributor to phenotypic diversity. Within individual tumors, a subset of cases showed multiple phenotypic subpopulations, and in one case, we were able to demonstrate direct correspondence between protein-level phenotypic subsets and DNA mutation-defined subclones. In summary, CyTOF analysis can resolve both intertumoral and intratumoral heterogeneity among primary samples and reveals that each case of DLBCL is unique and may be comprised of multiple, genetically distinct subclones. © 2019 International Society for Advancement of Cytometry.

11.
Nat Methods ; 16(10): 1007-1015, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31501550

RESUMO

Single-cell RNA sequencing has enabled the decomposition of complex tissues into functionally distinct cell types. Often, investigators wish to assign cells to cell types through unsupervised clustering followed by manual annotation or via 'mapping' to existing data. However, manual interpretation scales poorly to large datasets, mapping approaches require purified or pre-annotated data and both are prone to batch effects. To overcome these issues, we present CellAssign, a probabilistic model that leverages prior knowledge of cell-type marker genes to annotate single-cell RNA sequencing data into predefined or de novo cell types. CellAssign automates the process of assigning cells in a highly scalable manner across large datasets while controlling for batch and sample effects. We demonstrate the advantages of CellAssign through extensive simulations and analysis of tumor microenvironment composition in high-grade serous ovarian cancer and follicular lymphoma.


Assuntos
Perfilação da Expressão Gênica , Linfoma Folicular/patologia , Probabilidade , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Microambiente Tumoral , Humanos , Linfoma Folicular/imunologia
12.
Nat Commun ; 10(1): 2913, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266935

RESUMO

Mechanistic studies in human cancer have relied heavily on cell lines and mouse models, but are limited by in vitro adaptation and species context issues, respectively. More recent efforts have utilized patient-derived xenografts; however, these are hampered by variable genetic background, inability to study early events, and practical issues with availability/reproducibility. We report here an efficient, reproducible model of T-cell leukemia in which lentiviral transduction of normal human cord blood yields aggressive leukemia that appears indistinguishable from natural disease. We utilize this synthetic model to uncover a role for oncogene-induced HOXB activation which is operative in leukemia cells-of-origin and persists in established tumors where it defines a novel subset of patients distinct from other known genetic subtypes and with poor clinical outcome. We show further that anterior HOXB genes are specifically activated in human T-ALL by an epigenetic mechanism and confer growth advantage in both pre-leukemia cells and established clones.


Assuntos
Proteínas de Homeodomínio/metabolismo , Leucemia/metabolismo , Família Multigênica , Animais , Proliferação de Células , Epigênese Genética , Feminino , Xenoenxertos , Proteínas de Homeodomínio/genética , Humanos , Leucemia/genética , Leucemia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Modelos Genéticos , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo
13.
Thorac Cancer ; 9(12): 1583-1593, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30307120

RESUMO

BACKGROUND: We investigated the effect of micro-RNA 24 (miR-24) and WWOX on non-small cell lung cancer (NSCLC) cell proliferation and migration in vitro and in vivo. METHODS: We performed bioinformatics analysis and 3' untranslated region luciferase assay to investigate the direct target of miR-24. Proliferation, apoptosis, and transwell invasion assays were employed to evaluate the effect of WWOX overexpression with pcDNA3-WWOX and knocking down miR-24 with miR-24 small interfering RNA. Quantitative real-time PCR, Western blot, and immunohistochemistry were also used to investigate miR-24 and c-Kit expression, and apoptosis and invasion-related proteins. Finally, we constructed a tumor xenograft model in nude mice to confirm the effect of miR-24 on NSCLC cell proliferation in vivo. RESULTS: According to our experimental data, miR-24 inhibition could induce apoptosis by activating caspase 3 and suppress the viability and proliferation of NSCLC cells in vitro and in vivo. MiR-24 downregulation could reduce the invasive ability of NSCLC cells by downregulating MMP9. WWOX was identified as a functional target of miR-24. WWOX overexpression generated the same effect with antagonizing miR-24, while blocking WWOX counteracted the tumor suppressive effect caused by miR-24 inhibition. MiR-24 may function as an oncogene and play an important role in the cell growth and migration of NSCLC. CONCLUSIONS: Our findings enhance understanding of the miR-24 regulatory network and the molecular mechanism that underlies the oncogenesis and development of NSCLC. Suppressing the effect of miR-24 on cancer cells using a miR-24 inhibitor may be an attractive therapeutic strategy against NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , MicroRNAs/genética , Interferência de RNA , Proteínas Supressoras de Tumor/genética , Oxidorredutase com Domínios WW/genética , Regiões 3' não Traduzidas , Adulto , Idoso , Animais , Apoptose/genética , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Humanos , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Pessoa de Meia-Idade , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Cell Physiol Biochem ; 49(6): 2511-2520, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30261503

RESUMO

BACKGROUND/AIMS: Researchers have shown that long noncoding RNAs are closely associated with the pathogenesis of laryngeal squamous cell carcinoma (LSCC). However, the role of the long noncoding RNA taurine-upregulated gene 1 (TUG1) in the pathogenesis of LSCC remains unclear, although it is recognized as an oncogenic regulator for several types of squamous cell carcinoma. METHODS: qRT-PCR was performed to measure the expression of TUG1 in LSCC tissues and cell lines. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) was used to measure the effect of TUG1 on cell proliferation. Transwell assay and flow cytometry were employed to determine the effect of TUG1 on cell migration and invasion. Western-blot were performed to explore the relation of TUG1 and p53 mRNA. RESULTS: Higher TUG1 expression in LSCC than in paired normal tumor-adjacent tissue specimens (N = 64) was observed using quantitative real-time polymerase chain reaction. Also, high TUG1 expression was positively associated with advanced T category, worse lymph node metastasis and late clinical stage. Furthermore, in vitro experiments demonstrated that silencing of TUG1 markedly inhibited proliferation, cell-cycle progression, migration, and invasion of LSCC cells, whereas depletion of TUG1 led to increased apoptosis. CONCLUSION: These findings demonstrated that upregulated TUG1 expression exerted oncogenic effects by promoting proliferation, migration, and invasion, and inhibiting apoptosis in LSCC cells.


Assuntos
Carcinoma de Células Escamosas/patologia , Proliferação de Células , Neoplasias Laríngeas/patologia , RNA Longo não Codificante/metabolismo , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Neoplasias Laríngeas/genética , Masculino , Pessoa de Meia-Idade , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Pontos de Checagem da Fase S do Ciclo Celular , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
15.
Biomed Pharmacother ; 107: 390-396, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30099343

RESUMO

Resistance to adjuvant radiotherapy is a major cause of treatment failure in patients with glioblastoma (GBM). Recently, the role of lysosome, especially lysosomal proteases, in radioresistance is being paid more and more attention to. Here, we investigated the radioresistant role of Cathepsin B (CTSB), one important member of cysteine proteases, in GBM cell lines. A protease array kit was used to test GBM cells before and after irradiation. Nude mice were implanted with GBM cells to generate orthotopic xenografts for in vivo studies. Response of U87 and U251 cells to treatment was examined using cell viability, flow cytometry. Cells were transfected with siRNA knockdown and gene expression constructs and molecules potentially mediating response were examined through western blot analysis, PCR and EdU assay. The results from protease array kit showed that CTSB was up-regulated the most among all proteases after irradiation. And this was verified by western blot analysis and immunohistochemistry of tumor samples both from in vivo study and clinical patients. Compared to negative control group, knocking down CTSB led to radiosensitivity. And this radiosensitive effect was achieved by decreasing homologous recombination (HR) efficiency. Further study showed that knocking down CTSB caused cell cycle arrested in G0/G1 phases, in which HR efficiency was impaired. Knocking down CTSB contributed to radiosensitivity in GBM cells by causing cell cycle arrest and down-regulating HR efficiency.


Assuntos
Neoplasias Encefálicas/genética , Catepsina B/metabolismo , Glioblastoma/genética , Recombinação Homóloga , Tolerância a Radiação , Animais , Neoplasias Encefálicas/patologia , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Glioblastoma/patologia , Humanos , Camundongos Nus , Regulação para Cima/genética
16.
Oncol Lett ; 15(6): 8983-8990, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29844815

RESUMO

To uncover the genes associated with the development of esophageal squamous cell carcinoma (ESCC), an ESCC microarray dataset was used to identify genes differentially expressed between ESCC and normal control tissues. The dataset GSE17351 was downloaded from the Gene Expression Omnibus, containing 5 tumor esophageal mucosa samples and 5 adjacent normal esophageal mucosa samples from 5 male patients with ESCC. The differentially expressed genes (DEGs) were identified using the Linear Models for Microarray Data R package. Then, a co-expression network was constructed using the Weighted Correlation Network Analysis (WGCNA) package, and co-expression network modules were obtained with a hierarchical clustering algorithm. Additionally, functional enrichment analyses for DEGs in the top 2 modules with the highest significance were respectively conducted using the WGCNA package and the cluster Profiler package. In total, 487 upregulated and 468 downregulated DEGs were identified. A total of 24 modules were obtained from the co-expression network, and the top 2 modules with the highest significance, designated as 'blue4' and 'magenta', were further analyzed. In the module blue4, DEGs were significantly enriched in a number of Gene Ontology terms, including 'spindle organization' [e.g., ubiquitin conjugating enzyme E2 C (UBE2C) and SAC3 domain containing 1] and 'cell cycle process' [e.g., UBE2C, minichromosome maintenance complex component 6 (MCM6) and cell division cycle 20 (CDC20)]. Furthermore, a number of DEGs (e.g., UBE2C, CDC20 and MCM6) were enriched in the 'cell cycle' and 'ubiquitin mediated proteolysis' pathways. In the module 'magenta', a number of DEGs [e.g., transferrin receptor (TFRC) and TEA domain transcription factor 4 (TEAD4)] were enriched in the primary metabolic process and intracellular membrane-bounded organelle. Additionally, 308 upregulated genes and 215 downregulated genes were differentially expressed in the same pattern in another dataset, GSE20347, including UBE2C, CDC20, MCM6, TFRC, TEAD4, protein phosphatase 1 regulatory subunit 3C and MAL, T-cell differentiation protein. These DEGs may function in the development of ESCC.

17.
Mol Med Rep ; 17(5): 6456-6464, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29512696

RESUMO

Celecoxib is an inhibitor of cyclooxygenase-2, a gene that is often aberrantly expressed in the lung squamous cell carcinoma (LSQCC). The present study aims to provide novel insight into chemoprevention by celecoxib treatment. The human LSQCC cell line SK­MES­1 was treated with or without celecoxib and RNA­sequencing (RNA­seq) was performed on the Illumina HiSeq 2000 platform. Expression levels of genes or long non­coding RNAs (lncRNAs) were calculated by Cufflinks software. Subsequently, differentially expressed genes (DEGs) and differentially expressed lncRNAs (DE­LNRs) between the two groups were selected using the limma package and LNCipedia 3.0, respectively; followed by co­expression analysis based on their expression correlation coefficient (CC). Enrichment analysis for the DEGs and co­expressed DE­LNRs were performed. Protein­protein interaction (PPI) network analysis for DEGs was performed using STRING database. A set of 317 DEGs and 25 DE­LNRs were identified between celecoxib­treated and non­treated cell lines. A total of 12 pathways were enriched by the DEGs, including 'protein processing in endoplasmic reticulum' for activating transcription factor 4 (ATF4), 'mammalian target of rapamycin (mTOR) signaling pathway' for vascular endothelial growth factor A (VEGFA) and 'ECM­receptor interaction' for fibronectin 1 (FN1). Genes such as VEGFA, ATF4 and FN1 were highlighted in the PPI network. VEGFA was linked with lnc­AP000769.1­2:10 (CC= ­0.99227), whereas ATF4 and FN1 were closely correlated with lnc­HFE2­2:1 (CC=0.996159 and ­0.98714, respectively). lncRNAs were also enriched in pathways such as 'mTOR signaling pathway' for lnc­HFE2­2:1. Several important molecules were identified in celecoxib­treated LSQCC cell lines, such as VEGFA, ATF4, FN1, lnc­AP000769.1­2:10 and lnc­HFE2­2:1, which may enhance the anti­cancer effects of celecoxib on LSQCC.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Celecoxib/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , RNA Longo não Codificante/biossíntese , RNA Neoplásico/biossíntese , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , RNA Longo não Codificante/genética , RNA Neoplásico/genética
18.
J Transl Med ; 16(1): 79, 2018 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-29571296

RESUMO

BACKGROUND: Radiotherapy constitutes a standard arm of therapy in the multimodal treatment of patients with glioblastoma (GBM). Ironically, studies have recently revealed that radiation can augment malignant progression, by promoting migration and invasion, which make the disease especially difficult to cure. Here, we investigated the anticancer effects of YM155, a purported radiosensitizer, in GBM cell lines. METHODS: GBM cell lines U251 and U87 were treated with YM155 to assess cytotoxicity and activity of the molecule in vitro. Nude mice were implanted with cells to generate orthotopic xenografts for in vivo studies. Response of cells to treatment was examined using cell viability, immunofluorescence, wound healing, and the Transwell invasion assay. Molecules potentially mediating response were examined through western blot analysis, phospho-kinase arrays, and qPCR. Cells were transfected with siRNA knockdown and gene expression constructs to identify molecular mediators of response. RESULTS: YM155 reduced viability of U251 and U87 cells and enhanced radiosensitivity through inhibition of homologous recombination. Besides, YM155 decreased invasion caused by radiation and led to expression changes in molecular markers associated with EMT. STAT3 was one of 10 molecules identified on a phosphokinase array exhibiting significant change in phosphorylation under YM155 treatment. Transfection with STAT3 siRNAs or expression constructs demonstrated that EMT changes were achieved by inhibiting the phosphorylation of STAT3 and were survivin-independent. Finally, combining YM155 and radiation in orthotopic xenografts reduced growth and prolonged overall survival of animals. CONCLUSIONS: YM155 decreased radiation-induced invasion in GBM cell lines in vitro and in vivo through inhibition of STAT3.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Glioblastoma/metabolismo , Glioblastoma/radioterapia , Imidazóis/farmacologia , Naftoquinonas/farmacologia , Fator de Transcrição STAT3/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Glioblastoma/patologia , Recombinação Homóloga/genética , Humanos , Camundongos Nus , Invasividade Neoplásica , Survivina/metabolismo
19.
Cancer Cell Int ; 18: 27, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29483846

RESUMO

Background: Lung cancer is a malignant tumor with the highest incidence and mortality around the world. Recent advances in RNA sequencing technology have enabled insights into long non-coding RNAs (lncRNAs), a previously largely overlooked species in dissecting lung cancer pathology. Methods: In this study, we used a comprehensive bioinformatics analysis strategy to identify lncRNAs closely associated with lung adenocarcinoma, using the RNA sequencing datasets collected from more than 500 lung adenocarcinoma patients and deposited at The Cancer Genome Atlas (TCGA) database. Results: Differential expression analysis highlighted lncRNAs CTD-2510F5.4 and CTB-193M12.5, both of which were significantly upregulated in cancerous specimens. Moreover, network analyses showed highly correlated expression levels of both lncRNAs with those of differentially expressed protein-coding genes, and suggested central regulatory roles of both lncRNAs in the gene co-expression network. Importantly, expression of CTB-193M12.5 showed strong negative correlation with patient survival. Conclusions: Our study mined existing TCGA datasets for novel factors associated with lung adenocarcinoma, and identified a largely unknown lncRNA as a potential prognostic factor. Further investigation is warranted to characterize the roles and significance of CTB-193M12.5 in lung adenocarcinoma biology.

20.
Biomed Pharmacother ; 96: 899-904, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29223553

RESUMO

Chronic rhinosinusitis (CRS) is a well-known disease encountered in the department of otorhinolaryngology, yet little is known about its pathogenesis. Autophagy, a lysosome-dependent degradation process, has been reported to be involved in the process of many chronic inflammatory diseases. Here we tried to evaluate the function of autophagy in CRS as well as explore the related mechanisms. We first stained light chain 3B (LC3B) with immunohistochemistry in uncinate tissues (UT) from patients with and without CRS and found that its expression was up-regulated in CRS patients. Then, Human Nasal Epithelial Cells (HNEpC) were treated with lipopolysaccharide (LPS), one of the most common pathogenic elements in CRS, and we found that autophagy was induced in a dose- and time-dependent manner. This is supported by a rise in the expression of light chain 3B-II (LC3B-II), accumulation of GFP-LC3 vesicles, as well as decreased p62 expression. Furthermore, we found that LPS promoted AMPK phosphorylation and inactived mTOR, while AMPK inhibition by compound C significantly attenuated LPS-induced autophagy. Besides, treatment of HNEpC with LPS increased the amount of Toll-like receptor 4 (TLR4) while inhibiting TLR4 by Polymyxin B (PMB) declined autophagy caused by LPS. Taken together, our study first demonstrated that LPS caused autophagy in HNEpC, and this process was AMPK-mTOR dependent. These data suggested the relationship between LPS and autophagy in the pathogenesis of CRS.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Nariz/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Linhagem Celular , Células Epiteliais/metabolismo , Humanos , Mucosa Nasal/metabolismo , Fosforilação/efeitos dos fármacos , Sinusite/tratamento farmacológico , Sinusite/metabolismo , Receptor 4 Toll-Like/metabolismo
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