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1.
Med Oncol ; 41(6): 141, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38714554

RESUMO

IGFBP-3 is aberrantly expressed in many tumor types, and its serum and tumor tissue levels provide auxiliary information for assessing the degree of tumor malignancy and patient prognosis, making it a potential therapeutic target for human malignancies and conferring it remarkable clinical value for determining patient prognosis. In this review, we provide a comprehensive overview of the aberrant expression, diverse biological effects, and clinical implications of IGFBP-3 in tumors and its role as a potential prognostic marker and therapeutic target for tumors. In addition, we summarize the signaling pathways through which IGFBP-3 exerts its effects. IGFBP-3 comprises an N-terminal, an intermediate region, and a C-terminal structural domain, each exerting different biological effects in several tumor cell types in an IGF-dependent/non-independent manner. IGFBP-3 shares an intricate relationship with the tumor microenvironment, thereby affecting tumor growth. Overall, IGFBP-3 is an essential regulatory factor that mediates tumor occurrence and progression. Gaining deeper insights into the fundamental characteristics of IGFBP-3 and its role in various tumor types will provide new perspectives and allow for the development of novel strategies for cancer diagnosis, treatment, and prognostic evaluation.


Assuntos
Biomarcadores Tumorais , Progressão da Doença , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina , Neoplasias , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Neoplasias/metabolismo , Neoplasias/diagnóstico , Neoplasias/patologia , Neoplasias/terapia , Biomarcadores Tumorais/metabolismo , Prognóstico , Transdução de Sinais , Microambiente Tumoral , Animais
2.
Hum Immunol ; 85(3): 110795, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38582657

RESUMO

The coronavirus disease 2019 (COVID-19) has merged as a global health threat since its outbreak in December 2019. Despite widespread recognition, there has been a paucity of studies focusing on the T cell receptor (TCR) bias in adaptive immunity induced by SARS-CoV-2. This research conducted a comparative analysis of the TCR immune repertoire to identify notable αß TCR bias sequences associated with the SARS-CoV-2 virus antigen. The present study encompassed 73 symptomatic COVID-19 patients, categorized as moderate/mild or severe/critical, along with 9 healthy controls. Our findings revealed specific TCR chains prominently utilized by moderate and severe patients, identified as TRAV30-J34-TRBV3-1-J2-7 and TRAV12-3-J6-TRBV28-J1-1, respectively. Additionally, our research explored critical TCR preferences in the bronchoalveolar lavage fluid (BALF) of COVID-19 patients at various disease stages. Indeed, monitoring the dynamics of immune repertoire changes in COVID-19 patients could serve as a crucial biomarker for predicting disease progression and recovery. Furthermore, the study explored TCR bias in both peripheral blood mononuclear cells (PBMCs) and BALF. The most common αß VJ pair observed in BALF was TRAV12-3-J18-TRBV7-6-J2-7. In addition, a comparative analysis with the VDJdb database indicated that the HLA-A*02:01 allele exhibited the widest distribution and highest frequency in COVID-19 patients across different periods. This comprehensive examination provided a global characterization of the TCR immune repertoire in COVID-19 patients, contributing significantly to our understanding of TCR bias induced by SARS-CoV-2.


Assuntos
COVID-19 , Receptores de Antígenos de Linfócitos T alfa-beta , SARS-CoV-2 , Humanos , COVID-19/imunologia , SARS-CoV-2/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Adulto , Líquido da Lavagem Broncoalveolar/imunologia , Idoso , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Imunidade Adaptativa/imunologia , Índice de Gravidade de Doença
3.
Cancer Cell Int ; 24(1): 60, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38326861

RESUMO

BACKGROUND: Glioblastoma (GBM) characterized by immune escape is the most malignant primary brain tumors, which has strong immunosuppressive effect. Programmed death ligand-1 (PD-L1) is a recognized immunosuppressive member on the surface of tumor cells, and plays a crucial role in immune evasion of tumors. Actually, little is known about the regulation of PD-L1 expression in GBM. Insulin-like growth factor binding protein 3 (IGFBP3) is upregulated in GBM and is related to poor patient prognosis. However, it remains unclear whether IGFBP3 plays a role in the regulation of PD-L1 expression in GBM. METHODS: The role of IGFBP3 in the glioma immune microenvironment was investigated using the CIBERSORT algorithm. The correlation between IGFBP3 and PD-L1 expression was analyzed using TCGA and CGGA databases. QRT-PCR, immunoblotting and RNA-seq were used to examine the regulatory effect of IGFBP3 on PD-L1 expression. Co-culture assay, cell counting kit (CCK-8), qRT-PCR, ELISA and flow cytometry were performed to explore the function of IGFBP3 in inducing immunosuppression. The biological role of IGFBP3 was verified using immunohistochemical, immunofluorescence and mice orthotopic tumor model. RESULTS: In this study, we analyzed immune cells infiltration in gliomas and found that IGFBP3 may be associated with an immunosuppressive microenvironment. Then, by analyzing TCGA and CGGA databases, our results showed that IGFBP3 and PD-L1 expression were positively correlated in GBM patients, but not in LGG patients. In vitro experiments conducted on different GBM cell lines revealed that the overexpression of IGFBP3 led to an increase in PD-L1 expression, which was reversible upon knockdown IGFBP3. Mechanistically, IGFBP3 activated the JAK2/STAT3 signaling pathway, leading to an increase in PD-L1 expression. Additionally, co-culture experiments results showed IGFBP3 overexpression induced upregulation of PD-L1 expression promoted apoptosis in Jurkat cells, and this effect was blocked by IGFBP3 antibody and PDL-1 inhibitors. Importantly, in vivo experiments targeting IGFBP3 suppressed tumor growth and significantly prolonged the survival of mice. CONCLUSIONS: This research demonstrated IGFBP3 is a novel regulator for PD-L1 expression in GBM, and identified a new mechanism by which IGFBP3 regulates immune evasion through PD-L1, suggesting that IGFBP3 may be a potential novel target for GBM therapy.

4.
Cell Death Discov ; 9(1): 279, 2023 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-37528096

RESUMO

To date, there is no effective therapy for pathological cardiac hypertrophy, which can ultimately lead to heart failure. Bellidifolin (BEL) is an active xanthone component of Gentianella acuta (G. acuta) with a protective function for the heart. However, the role and mechanism of BEL action in cardiac hypertrophy remain unknown. In this study, the mouse model of cardiac hypertrophy was established by isoprenaline (ISO) induction with or without BEL treatment. The results showed that BEL alleviated cardiac dysfunction and pathological changes induced by ISO in the mice. The expression of cardiac hypertrophy marker genes, including ANP, BNP, and ß-MHC, were inhibited by BEL both in mice and in H9C2 cells. Furthermore, BEL repressed the epigenetic regulator bromodomain-containing protein 4 (BRD4) to reduce the ISO-induced acetylation of H3K122 and phosphorylation of RNA Pol II. The Nox4/ROS/ADAM17 signalling pathway was also inhibited by BEL in a BRD4 dependent manner. Thus, BEL alleviated cardiac hypertrophy and cardiac dysfunction via the BRD4/Nox4/ROS axes during ISO-induced cardiac hypertrophy. These findings clarify the function and molecular mechanism of BEL action in the therapeutic intervention of cardiac hypertrophy.

5.
iScience ; 26(5): 106639, 2023 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-37192967

RESUMO

Dual or multi-targets therapy targeting epidermal growth factor receptor variant III (EGFRvIII) and other molecular may relax the constraint for glioblastoma (GBM), putting forward the urgent requirement of finding candidate molecules. Here, the insulin-like growth factor binding protein-3 (IGFBP3) was considered a candidate, whereas the mechanisms of IGFBP3 production remain unclear. We treated GBM cells with exogenous transforming growth factor ß (TGF-ß) to simulate the microenvironment. We found that TGF-ß and EGFRvIII transactivation induced the activation of transcription factor c-Jun, which specifically bound to the promoter region of IGFBP3 through Smad2/3 and ERK1/2 pathways and promoted the production and secretion of IGFBP3. IGFBP3 knockdown inhibited the activation of TGF-ß and EGFRvIII signals and the malignant behaviors triggered by them in vitro and in vivo. Collectively, our results indicated a positive feedback loop of p-EGFRvIII/IGFBP3 under administration of TGF-ß, blocking IGFBP3 may be an additional target in EGFRvIII-expressing GBM-selective therapeutic strategy.

6.
Front Oncol ; 13: 1143664, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37139163

RESUMO

5-Demethylnobiletin is the active ingredient in citrus polymethoxyflavones that could inhibit the proliferation of several tumor cells. However, the anti-tumor effect of 5-Demethylnobiletin on glioblastoma and the underlying molecular mechanisms are remains unknown. In our study, 5-Demethylnobiletin markedly inhibited the viability, migration and invasion of glioblastoma U87-MG, A172 and U251 cells. Further research revealed that 5-Demethylnobiletin induces cell cycle arrest at the G0/G1 phase in glioblastoma cells by downregulating Cyclin D1 and CDK6 expression levels. Furthermore, 5-Demethylnobiletin significantly induced glioblastoma cells apoptosis by upregulating the protein levels of Bax and downregulating the protein level of Bcl-2, subsequently increasing the expression of cleaved caspase-3 and cleaved caspase-9. Mechanically, 5-Demethylnobiletin trigged G0/G1 phase arrest and apoptosis by inhibiting the ERK1/2, AKT and STAT3 signaling pathway. Furthermore, 5-Demethylnobiletin inhibition of U87-MG cell growth was reproducible in vivo model. Therefore, 5-Demethylnobiletin is a promising bioactive agent that might be used as glioblastoma treatment drug.

7.
Front Immunol ; 13: 1003651, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36466873

RESUMO

Glioblastoma multiforme (GBM) is the most malignant intracranial tumor in adults, characterized by extensive infiltrative growth, high vascularization, and resistance to multiple therapeutic approaches. Among the many factors affecting the therapeutic effect, the immunosuppressive GBM microenvironment that is created by cells and associated molecules via complex mechanisms plays a particularly important role in facilitating evasion of the tumor from the immune response. Accumulating evidence is also revealing a close association of the gut microbiota with the challenges in the treatment of GBM. The gut microbiota establishes a connection with the central nervous system through bidirectional signals of the gut-brain axis, thus affecting the occurrence and development of GBM. In this review, we discuss the key immunosuppressive components in the tumor microenvironment, along with the regulatory mechanism of the gut microbiota involved in immunity and metabolism in the GBM microenvironment. Lastly, we concentrate on the immunotherapeutic strategies currently under investigation, which hold promise to overcome the hurdles of the immunosuppressive tumor microenvironment and improve the therapeutic outcome for patients with GBM.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Adulto , Humanos , Glioblastoma/terapia , Fatores Imunológicos , Imunoterapia , Imunossupressores , Neoplasias Encefálicas/terapia , Microambiente Tumoral
8.
Mol Biol Rep ; 49(11): 11133-11148, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36151399

RESUMO

The sequence assembly algorithms have rapidly evolved with the vigorous growth of genome sequencing technology over the past two decades. Assembly mainly uses the iterative expansion of overlap relationships between sequences to construct the target genome. The assembly algorithms can be typically classified into several categories, such as the Greedy strategy, Overlap-Layout-Consensus (OLC) strategy, and de Bruijn graph (DBG) strategy. In particular, due to the rapid development of third-generation sequencing (TGS) technology, some prevalent assembly algorithms have been proposed to generate high-quality chromosome-level assemblies. However, due to the genome complexity, the length of short reads, and the high error rate of long reads, contigs produced by assembly may contain misassemblies adversely affecting downstream data analysis. Therefore, several read-based and reference-based methods for misassembly identification have been developed to improve assembly quality. This work primarily reviewed the development of DNA sequencing technologies and summarized sequencing data simulation methods, sequencing error correction methods, various mainstream sequence assembly algorithms, and misassembly identification methods. A large amount of computation makes the sequence assembly problem more challenging, and therefore, it is necessary to develop more efficient and accurate assembly algorithms and alternative algorithms.


Assuntos
Algoritmos , Genoma , Análise de Sequência de DNA/métodos , Sequência de Bases , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Software
9.
Comput Biol Med ; 145: 105534, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35585730

RESUMO

Structural variation (SV) is a vital part of biological genetic diversity. The simulation and identification with high efficiency and accuracy are considered to be very important. With the continuous development and wide application of various technologies, computer simulation of genomic data has attracted wide attention due to its intuitive and convenient advantages. Meanwhile, there are several high-quality methods used for structural variation identification based on second-generation (short-read) and third-generation (long-read) data. These methods utilize various strategies and compatible aligners and exhibit specific characteristics. In addition, genomic visualization tools use graphical interfaces to visualize the data, which are convenient for data observation, validation, and even for the manual curation of several questionable data. The present study summarized the methods of simulation, identification, and visualization tools for structural variation in the context of sequencing technology development. Overall, this review aimed to offer a more comprehensive understanding of the impact of SV.


Assuntos
Variação Estrutural do Genoma , Genômica , Simulação por Computador , Variação Genética , Genoma Humano , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Análise de Sequência de DNA/métodos
10.
Biochem Biophys Res Commun ; 496(4): 1040-1046, 2018 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-29366782

RESUMO

The impact of DNA mismatch repair (MMR) on resistance to temozolomide (TMZ) therapy in patients with glioblastoma (GBM) is recently reported but the mechanisms are not understood. We aim to analyze the correlation between MMR function and the acquired TMZ resistance in GBM using both relevant clinical samples and TMZ resistant cells. First we found increased expression of MSH6, one of key components of MMR, in recurrent GBM patients' samples who underwent TMZ chemotherapy, comparing with those matched samples collected at the time of diagnosis. Using the cellular models of acquired resistance to TMZ, we further confirmed the up-regulation of MSH6 in TMZ resistant cells. Moreover, a TCGA dataset contains a large cohort of GBM clinical samples with or without TMZ treatment reinforced the increased expression of MSH6 and other MMR genes after long-term TMZ chemotherapy, which may resulted in MMR dysfunction and acquired TMZ resistance. Our results suggest that increased expression of MSH6, or other MMR, may be a new mechanism contributing to the acquired resistance during TMZ therapy; and may serve as an indicator to the resistance in GBM.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Dacarbazina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Adulto , Antineoplásicos Alquilantes/administração & dosagem , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Dacarbazina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Temozolomida , Resultado do Tratamento , Células Tumorais Cultivadas , Regulação para Cima
11.
Int J Mol Med ; 39(3): 725-733, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28204824

RESUMO

The methylation-mediated silencing of tumor suppressors, including key apoptosis-related genes plays an important role in the pathogenesis and therapeutic resistance in human cancer. In this study, we aimed to elucidate the role and mechanisms of resistance to apoptosis with caspase-8 gene downregulation in human malignant glioma. Reverse transcription-polymerase chain reaction (RT-PCR) and methylation-specific PCR (MSP) were used to examine caspase-8 expressoin at the mRNA level and gene methylation status in normal brain tissue, glioma tissue and cancer cell lines. Caspase-8 protein kinase activity was measured by caspase-8 colorimetric assays; cell apoptosis was examined by Annexin V/propidium iodide (PI) staining; the rates of tumor cell apoptosis were detected by flow cytometry. Our results revealed that caspase-8 gene silencing may result from the methylation of its gene promoter in human glioma tissues. The expression of caspase-8 at the mRNA level was significantly associated with the grade of human glioma. In certain human cancer cell lines, the expression at the mRNA level, protein kinase activity and tumor cell anti-apoptotic activity and resistance were related to the methylation status of the caspase-8 gene promoter. Thus, the caspase-8 gene methylation status may be used as an indicator for the early diagnosis of human malignant glioma. Combination therapy with demethylation reagents may overcome therapeutic resistance in the same malignancy.


Assuntos
Apoptose/genética , Caspase 8/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/patologia , Adulto , Anexina A5/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Caspase 8/metabolismo , Linhagem Celular Tumoral , Ilhas de CpG , Ativação Enzimática , Feminino , Inativação Gênica , Glioma/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Regiões Promotoras Genéticas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Carga Tumoral , Adulto Jovem
12.
Biochem Biophys Res Commun ; 470(2): 466-472, 2016 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-26742423

RESUMO

Glioblastoma (GBM) is the most aggressive type of primary brain tumor. Its interaction with the tumor microenvironment promotes tumor progression. Furthermore, GBM bearing expression of EGFRvIII displays more adaptation to tumor microenvironment related stress. But the mechanisms were poorly understood. Here, we presented evidence that in the human U87MG glioblastoma tumor model, EGFRvIII overexpression led aberrant kinase activation and nuclear translocation of EGFRvIII/ERK1/2 under hypoxia, which induced growth advantage by resisting apoptosis. Additionally, EGFRvIII defective in nuclear entry impaired this capacity in hypoxia adaptation, and partially interrupted ERK1/2 nuclear translocation. Pharmacology or genetic interference ERK1/2 decreased hypoxia resistance triggered by EGFRvIII expression, but not EGFRvIII nuclear translocation. In summary, this study identified a novel role for EGFRvIII in hypoxia tolerance, supporting an important link between hypoxia and subcellular localization alterations of the receptor.


Assuntos
Núcleo Celular/metabolismo , Receptores ErbB/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Transporte Ativo do Núcleo Celular/fisiologia , Apoptose , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células , Microambiente Celular , Regulação da Expressão Gênica/fisiologia , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Oxigênio/metabolismo
13.
Oncotarget ; 7(4): 4680-94, 2016 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-26717039

RESUMO

Glioblastoma (GBM) is one of the most lethal brain tumors with a short survival time. EGFR amplification and mutation is the most significant genetic signature in GBM. About half of the GBMs with EGFR amplification express a constitutively autophosphorylated variant of EGFR, known as EGFRvIII. Our in vitro data demonstrated further enhanced EGFRvIII activity and tumor cell invasion in the tumor microenvironment of hypoxia plus extracellular matrix (ECM) vitronectin, in which EGFRvIII and integrin ß3 tended to form complexes. The treatment with ITGB3 siRNA or the integrin antagonist cilengetide preferentially interrupted the EGFRvIII/integrin ß3 complex, effectively reduced tumor cell invasion and activation of downstream signaling effectors. Cilengitide is recently failed in Phase III CENTRIC trial in unselected patients with GBM. However, we found that cilengitide demonstrated efficacious tumor regression via inhibition of tumor growth and angiogenesis in EGFRvIII orthotopic xenografts. Bioinformatics analysis emphasized key roles of integrin ß3, hypoxia and vitronectin and their strong correlations with EGFRvIII expression in malignant glioma patient samples in vivo. In conclusion, we demonstrate that EGFRvIII/integrin ß3 complexes promote GBM progression and metastasis in the environment of hypoxia and vitronectin-enrichment, and cilengitide may serve as a promising therapeutics for EGFRvIII-positive GBMs.


Assuntos
Neoplasias Encefálicas/secundário , Receptores ErbB/metabolismo , Glioblastoma/patologia , Hipóxia/patologia , Integrina beta3/metabolismo , Microambiente Tumoral , Vitronectina/metabolismo , Animais , Apoptose , Western Blotting , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Movimento Celular , Proliferação de Células , Progressão da Doença , Receptores ErbB/genética , Feminino , Imunofluorescência , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Hipóxia/genética , Hipóxia/metabolismo , Técnicas Imunoenzimáticas , Imunoprecipitação , Integrina beta3/genética , Camundongos , Camundongos Nus , Microscopia de Fluorescência , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Células Tumorais Cultivadas , Vitronectina/genética , Ensaios Antitumorais Modelo de Xenoenxerto
14.
BMC Bioinformatics ; 16: 386, 2015 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-26573684

RESUMO

BACKGROUND: Because of the short read length of high throughput sequencing data, assembly errors are introduced in genome assembly, which may have adverse impact to the downstream data analysis. Several tools have been developed to eliminate these errors by either 1) comparing the assembled sequences with some similar reference genome, or 2) analyzing paired-end reads aligned to the assembled sequences and determining inconsistent features alone mis-assembled sequences. However, the former approach cannot distinguish real structural variations between the target genome and the reference genome while the latter approach could have many false positive detections (correctly assembled sequence being considered as mis-assembled sequence). RESULTS: We present misFinder, a tool that aims to identify the assembly errors with high accuracy in an unbiased way and correct these errors at their mis-assembled positions to improve the assembly accuracy for downstream analysis. It combines the information of reference (or close related reference) genome and aligned paired-end reads to the assembled sequence. Assembly errors and correct assemblies corresponding to structural variations can be detected by comparing the genome reference and assembled sequence. Different types of assembly errors can then be distinguished from the mis-assembled sequence by analyzing the aligned paired-end reads using multiple features derived from coverage and consistence of insert distance to obtain high confident error calls. CONCLUSIONS: We tested the performance of misFinder on both simulated and real paired-end reads data, and misFinder gave accurate error calls with only very few miscalls. And, we further compared misFinder with QUAST and REAPR. misFinder outperformed QUAST and REAPR by 1) identified more true positive mis-assemblies with very few false positives and false negatives, and 2) distinguished the correct assemblies corresponding to structural variations from mis-assembled sequence. misFinder can be freely downloaded from https://github.com/hitbio/misFinder.


Assuntos
Escherichia coli/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Schizosaccharomyces/genética , Análise de Sequência de DNA/métodos , Software , Simulação por Computador
16.
PLoS One ; 9(8): e104404, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25116327

RESUMO

Human uveitis is a type of T cell-mediated autoimmune disease that often shows relapse-remitting courses affecting multiple biological processes. As a cytoplasmic process, autophagy has been seen as an adaptive response to cell death and survival, yet the link between autophagy and T cell-mediated autoimmunity is not certain. In this study, based on the differentially expressed genes (GSE19652) between the recurrent versus monophasic T cell lines, whose adoptive transfer to susceptible animals may result in respective recurrent or monophasic uveitis, we proposed grouping annotations on a subcellular layered interactome framework to analyze the specific bioprocesses that are linked to the recurrence of T cell autoimmunity. That is, the subcellular layered interactome was established by the Cytoscape and Cerebral plugin based on differential expression, global interactome, and subcellular localization information. Then, the layered interactomes were grouping annotated by the ClueGO plugin based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. The analysis showed that significant bioprocesses with autophagy were orchestrated in the cytoplasmic layered interactome and that mTOR may have a regulatory role in it. Furthermore, by setting up recurrent and monophasic uveitis in Lewis rats, we confirmed by transmission electron microscopy that, in comparison to the monophasic disease, recurrent uveitis in vivo showed significantly increased autophagy activity and extended lymphocyte infiltration to the affected retina. In summary, our framework methodology is a useful tool to disclose specific bioprocesses and molecular targets that can be attributed to a certain disease. Our results indicated that targeted inhibition of autophagy pathways may perturb the recurrence of uveitis.


Assuntos
Doenças Autoimunes/genética , Autofagia/genética , Redes Reguladoras de Genes , Anotação de Sequência Molecular , Linfócitos T/metabolismo , Uveíte/genética , Animais , Doenças Autoimunes/imunologia , Biologia Computacional , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Espaço Intracelular/genética , Espaço Intracelular/metabolismo , Ratos , Linfócitos T/imunologia , Linfócitos T/ultraestrutura , Uveíte/imunologia
17.
Neuro Oncol ; 16(9): 1229-43, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24861878

RESUMO

BACKGROUND: As a commonly mutated form of the epidermal growth factor receptor, EGFRvIII strongly promotes glioblastoma (GBM) tumor invasion and progression, but the mechanisms underlying this promotion are not fully understood. METHODS: Through gene manipulation, we established EGFRvIII-, wild-type EGFR-, and vector-expressing GBM cells. We used cDNA microarrays, bioinformatics analysis, target-blocking migration and invasion assays, Western blotting, and an orthotopic U87MG GBM model to examine the phenotypic shifts and treatment effects of EGFRvIII expression in vitro and in vivo. Confocal imaging, co-immunoprecipitation, and siRNA assays detected the focal adhesion-associated complex and their relationships to the EGFRvIII/JAK2/STAT3 axis in GBM cells. RESULTS: The activation of JAK2/STAT3 signaling is vital for promoting migration and invasion in EGFRvIII-GBM cells. AG490 or WP1066, the JAK2/STAT3 inhibitors, specifically destroyed EGFRvIII/JAK2/STAT3-related focal adhesions and depleted the activation of EGFR/Akt/FAK and JAK2/STAT3 signaling, thereby abolishing the ability of EGFRvIII-expressing GBM cells to migrate and invade. Furthermore, the RNAi silencing of JAK2 in EGFRvIII-expressing GBM cells significantly attenuated their ability to migrate and invade; however, as a result of a potential EGFRvIII-JAK2-STAT3 activation loop, neither EGFR nor STAT3 knockdown yielded the same effects. Moreover, AG490 or JAK2 gene knockdown greatly suppressed tumor invasion and progression in the U87MG-EGFRvIII orthotopic models. CONCLUSION: Taken together, our data demonstrate that JAK2/STAT3 signaling is essential for EGFRvIII-driven migration and invasion by promoting focal adhesion and stabilizing the EGFRvIII/JAK2/STAT3 axis. Targeting JAK2/STAT3 therapy, such as AG490, may have potential clinical implications for the tailored treatment of GBM patients bearing EGFRvIII-positive tumors.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Receptores ErbB/metabolismo , Glioblastoma/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Tirfostinas/administração & dosagem , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Inibidores Enzimáticos/administração & dosagem , Adesões Focais/efeitos dos fármacos , Adesões Focais/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Janus Quinase 2/metabolismo , Camundongos , Camundongos Nus , Invasividade Neoplásica , Fator de Transcrição STAT3/metabolismo
18.
Clin Exp Pharmacol Physiol ; 40(1): 13-21, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23110505

RESUMO

The aim of the present study was to analyse the antiproliferative effects and mechanisms of action of protein kinase inhibitors (PKIs) in human glioblastoma multiforme (GBM) cells with different epidermal growth factor receptor (EGFR) and phosphatase and tensin homologue (PTEN) status. The GBM cell models were established by transfection of plasmids carrying wild-type EGFR, mutated EGFRvIII or PTEN and clonal selection in U87MG cells. Phosphatidylinositol 3-kinase (PI3-K)/AKT pathway-focused gene profiles were examined by real-time polymerase chain reaction-based assays, protein expression was evaluated by western blotting and the antiproliferative effects of PKI treatment were determined by the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay in GBM cells. The cell model with intact PTEN and low EGFR levels was the most sensitive to treatment with the EGFR inhibitor erlotinib, whereas the model with EGFRvIII was the most resistant to treatment with the mitogen-activated protein kinase kinase inhibitor U0126. The dual PI3-K and mammalian target of rapamycin (mTOR) inhibitor PI103 had the most potent antiproliferative effects against all GBM cells tested. Following simultaneous stimulation of AKT and extracellular signal-regulated kinase, rapamycin concentrations > 0.5 nmol/L failed to exhibit a further growth inhibitory effect. Concurrent inhibition of mTOR and ribosomal protein s6 activity may underlie the inhibition of GBM proliferation by PKI. In conclusion, overexpression of EGFR or EGFRvIII, accompanied by a loss of PTEN, contributed to the activation of multiple intracellular signalling pathways in GBM cells. Rigorous examination of biomarkers in tumour tissues before and after treatment may be necessary to determine the efficacy of PKI therapy in patients with GBM.


Assuntos
Receptores ErbB/genética , Glioblastoma/tratamento farmacológico , PTEN Fosfo-Hidrolase/genética , Inibidores de Proteínas Quinases/farmacologia , Butadienos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/biossíntese , Receptores ErbB/metabolismo , Cloridrato de Erlotinib , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Furanos/farmacologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Nitrilas/farmacologia , PTEN Fosfo-Hidrolase/biossíntese , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/farmacologia , Pirimidinas/farmacologia , Quinazolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
19.
Mol Cell Biochem ; 370(1-2): 89-102, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22829019

RESUMO

Glioblastoma multiforme (GBM) was shown to harbor therapy-resistant cancer stem cells that were major causes of recurrence. PDGFR (platelet-derived growth factor receptor) and c-Kit (stem cell factor receptor) signaling play important roles in initiation and maintenance of malignant glioma. This study demonstrated that long-term culture with imatinib mesylate, the tyrosine kinase inhibitor against PDGFR and c-Kit resulted in reduced cancer stem cell ability in glioblastoma cells through cell differentiation. Derived from RG glioblastoma cells co-cultured with imatinib for 3 months, RG-IM cells showed distinct properties of cell cycle distribution and morphology in addition to significantly decreased ability to form aggregates and colonies in vitro and tumorigenicity in vivo. Increased expression of GFAP (astrocyte marker) and class III ß-tubulin isotype (Tuj1, neuron marker) were detected with morphology like neurons or astrocytes in RG-IM cells. Furthermore, decreased expression of stem cell markers, i.e., CD133, Oct-3/4, nestin, and Bmi1, and increased terminal neural cell markers, GFAP, Tuj1, etc., were identified in RG-IM at the mRNA level. All these markers were changed in RG cells when PDGFRB and c-Kit expression were double knocked down by siRNA. Cell differentiation agent, all-trans retinoic acid (ATRA) caused similar effect as that with imatinib in RG cells, while adding PDGF-B and SCF in RG-IM resulted in cell dedifferentiation to some extent. Moreover, differentiation in RG cells treated by imatinib or ATRA was mainly driven by MAPK signaling pathways. In summary, continuous inhibition on PDGFR and c-Kit signaling disturbed glioma stem cells biology in subsets of GBM cells and may have potentials in clinical applications.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Glioblastoma/enzimologia , Glioblastoma/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Animais , Benzamidas , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/patologia , Ativação Enzimática/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Humanos , Mesilato de Imatinib , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Fatores de Tempo
20.
Nucleic Acids Res ; 40(16): 7653-65, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22705797

RESUMO

Accumulating evidence indicates that microRNAs (miRNAs) can function as oncogenes or tumor suppressor genes by controlling few key targets, which in turn contribute to the pathogenesis of cancer. The identification of cancer-related key miRNA-target interactions remains a challenge. We performed a systematic analysis of known cancer-related key interactions manually curated from published papers based on different aspects including sequence, expression and function. Known cancer-related key interactions show more miRNA binding sites (especially for 8mer binding sites), more reliable binding of miRNA to the target region, higher expression associations and broader functional coverage when compared to non-disease-related interactions. Through integrating these sequence, expression and function features, we proposed a bioinformatics approach termed PCmtI to prioritize cancer-related key interactions. Ten-fold cross-validation of our approach revealed that it can achieve an area under the receiver operating characteristic curve of 93.9%. Subsequent leave-one-miRNA-out cross-validation also demonstrated the performance of our approach. Using miR-155 as a case, we found that the top ranked interactions can account for most functions of miR-155. In addition, we further demonstrated the power of our approach by 23 recently identified cancer-related key interactions. The approach described here offers a new way for the discovery of novel cancer-related key miRNA-target interactions.


Assuntos
Genômica/métodos , MicroRNAs/metabolismo , Neoplasias/genética , RNA Mensageiro/metabolismo , Regiões 3' não Traduzidas , Sítios de Ligação , Linhagem Celular Tumoral , Humanos , MicroRNAs/química , Mapeamento de Interação de Proteínas , Software
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