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  1 / 1917 MEDLINE  
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[PMID]:29295981
[Au] Autor:Kimura K; Hohjoh H; Fukuoka M; Sato W; Oki S; Tomi C; Yamaguchi H; Kondo T; Takahashi R; Yamamura T
[Ad] Endereço:Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan.
[Ti] Título:Circulating exosomes suppress the induction of regulatory T cells via let-7i in multiple sclerosis.
[So] Source:Nat Commun;9(1):17, 2018 01 02.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system. Foxp3 regulatory T (Treg) cells are reduced in frequency and dysfunctional in patients with MS, but the underlying mechanisms of this deficiency are unclear. Here, we show that induction of human IFN-γ IL-17A Foxp3 CD4 T cells is inhibited in the presence of circulating exosomes from patients with MS. The exosomal miRNA profile of patients with MS differs from that of healthy controls, and let-7i, which is markedly increased in patients with MS, suppresses induction of Treg cells by targeting insulin like growth factor 1 receptor (IGF1R) and transforming growth factor beta receptor 1 (TGFBR1). Consistently, the expression of IGF1R and TGFBR1 on circulating naive CD4 T cells is reduced in patients with MS. Thus, our study shows that exosomal let-7i regulates MS pathogenesis by blocking the IGF1R/TGFBR1 pathway.
[Mh] Termos MeSH primário: Exossomos/imunologia
MicroRNAs/imunologia
Esclerose Múltipla/imunologia
Linfócitos T Reguladores/imunologia
[Mh] Termos MeSH secundário: Adulto
Linfócitos T CD4-Positivos/imunologia
Linfócitos T CD4-Positivos/metabolismo
Exossomos/genética
Exossomos/metabolismo
Feminino
Fatores de Transcrição Forkhead/genética
Fatores de Transcrição Forkhead/imunologia
Fatores de Transcrição Forkhead/metabolismo
Seres Humanos
Interleucina-17/genética
Interleucina-17/imunologia
Interleucina-17/metabolismo
Masculino
MicroRNAs/genética
Meia-Idade
Esclerose Múltipla/sangue
Esclerose Múltipla/genética
Proteínas Serina-Treonina Quinases/genética
Proteínas Serina-Treonina Quinases/imunologia
Proteínas Serina-Treonina Quinases/metabolismo
Receptores de Somatomedina/genética
Receptores de Somatomedina/imunologia
Receptores de Somatomedina/metabolismo
Receptores de Fatores de Crescimento Transformadores beta/genética
Receptores de Fatores de Crescimento Transformadores beta/imunologia
Receptores de Fatores de Crescimento Transformadores beta/metabolismo
Linfócitos T Reguladores/metabolismo
Transcriptoma/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (FOXP3 protein, human); 0 (Forkhead Transcription Factors); 0 (IGF1R protein, human); 0 (IL17A protein, human); 0 (Interleukin-17); 0 (MicroRNAs); 0 (Receptors, Somatomedin); 0 (Receptors, Transforming Growth Factor beta); 0 (mirnlet7 microRNA, human); EC 2.7.1.11 (TGF-beta type I receptor); EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180104
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02406-2


  2 / 1917 MEDLINE  
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[PMID]:27779100
[Au] Autor:Xie B; Cao K; Li J; Chen J; Tang J; Chen X; Xia K; Zhou X; Cheng Y; Zhou J; Xie H
[Ad] Endereço:Deptment of Plastic Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
[Ti] Título:Hmgb1 inhibits Klotho expression and malignant phenotype in melanoma cells by activating NF-κB.
[So] Source:Oncotarget;7(49):80765-80782, 2016 Dec 06.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The molecular and cellular mechanisms behind the involvement of inflammation in melanoma have not been fully elucidated. In this study, knockdown of Hmgb1 expression increased apoptosis, reduced invasion and p-NF-κB expression, but increased Klotho protein level in melanoma tumor cells. The effect of Hmgb1 knockdown was overcome by LPS. Introduction of exogenous Hmgb1 significantly decreased apoptosis, increased invasion, elevated p-NF-κB, but lowered Klotho protein level in melanoma cells. The effect of exogenous Hmgb1 was agonized by NF-κB inhibitor CAPE. Hmgb1 knockdown activated, but exogenous Hmgb1 inactivated, p-IGF1R/p-PI3K p-85/p-Akt/p-mTOR signaling. Knockdown of Klotho gene expression significantly decreased apoptosis, increased invasion in melanoma cells, and inhibited xenograft A375 tumor growth. A significantly high percentage of cells stained positive for p-NF-κB, but negative for Klotho, in melanoma tissues compared to normal and benign skin tissues. The positive p-NF-κB and negative Klotho protein expression correlated with poor prognosis in melanoma patients. Multivariate analysis revealed an independent association between p-NF-κB / Klotho protein level and overall survival. In conclusion, Hmgb1 can inhibit Klotho gene expression and malignant phenotype in melanoma cells through activation of NF-κB signaling.
[Mh] Termos MeSH primário: Glucuronidase/metabolismo
Proteína HMGB1/metabolismo
Melanoma/metabolismo
NF-kappa B/metabolismo
Neoplasias Cutâneas/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Animais
Apoptose
Pontos de Checagem do Ciclo Celular
Linhagem Celular Tumoral
Movimento Celular
Proliferação Celular
Distribuição de Qui-Quadrado
Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo
Feminino
Regulação Neoplásica da Expressão Gênica
Glucuronidase/genética
Proteína HMGB1/genética
Seres Humanos
Estimativa de Kaplan-Meier
Masculino
Melanoma/genética
Melanoma/patologia
Camundongos Endogâmicos BALB C
Camundongos Nus
Meia-Idade
Análise Multivariada
Invasividade Neoplásica
Fosforilação
Modelos de Riscos Proporcionais
Proteínas Proto-Oncogênicas c-akt/metabolismo
Interferência de RNA
Receptores de Somatomedina/metabolismo
Transdução de Sinais
Neoplasias Cutâneas/genética
Neoplasias Cutâneas/patologia
Serina-Treonina Quinases TOR/metabolismo
Fatores de Tempo
Transfecção
Carga Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HMGB1 Protein); 0 (HMGB1 protein, human); 0 (IGF1R protein, human); 0 (NF-kappa B); 0 (Receptors, Somatomedin); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.137 (Class Ia Phosphatidylinositol 3-Kinase); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.2.1.31 (Glucuronidase); EC 3.2.1.31 (klotho protein)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.12623


  3 / 1917 MEDLINE  
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[PMID]:29278769
[Au] Autor:Liu MD; Wu H; Wang S; Pang P; Jin S; Sun CF; Liu FY
[Ad] Endereço:Department of Oromaxillofacial-Head and Neck, Oral Maxillofacial Surgery, School of Stomatology, China Medical University, Shenyang, Liaoning 110002, PR China.
[Ti] Título:MiR-1275 promotes cell migration, invasion and proliferation in squamous cell carcinoma of head and neck via up-regulating IGF-1R and CCR7.
[So] Source:Gene;646:1-7, 2018 Mar 10.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:PURPOSE: miRNAs can play vital role in migration, invasion and proliferation in Squamous cell carcinoma of head and neck (SCCHN). In our study, we attempted to validate the expression and function of miR-1275 in SCCHN, and we also identified the mechanism by which miR-1275 affects migration, invasion and proliferation of SCCHN. METHODS: Real-time polymerase chain reaction (RT-PCR) was employed to evaluate the expression of miR-1275 in both SCCHN tissues and cell lines. The role of miR-1275 in SCCHN cells was verified by cell function experiments upon transfection with miR-1275 mimics and inhibitor. Western blot analysis was employed to test the target gene expression of miR-1275. Survival analysis was made with the information of SCCHN patients expressed miR-1275 from The Cancer Genome Atlas (TCGA) database. RESULTS: miR-1275 expression was up-regulated in SCCHN tissues and advanced metastatic SCCHN cells. Increasing miR-1275 expression in SCCHN could promote cell migration, invasion and proliferation probably by upregulating Insulin-like growth factor 1 receptor (IGF-1R) and C-C chemokine receptor type 7(CCR7) protein levels, whereas inhibition of miR-1275 could lead the opposite effects, although others have already demonstrated that IGF-1R is a direct target of miR-1275. Survival analysis suggested that patients with lower miR-1275 expression may have a better outcome. CONCLUSIONS: Herein we report for the first time that miR-1275 could act as a tumor-promoter in SCCHN possibly by regulating its target gene via novel miRNA mechanisms. MiR-1275 plays an important role in promoting SCCHN progression. The miR-1275 may be a potential therapeutic target for SCCHN treatment in the future.
[Mh] Termos MeSH primário: Carcinoma de Células Escamosas/genética
Neoplasias de Cabeça e Pescoço/genética
MicroRNAs/genética
Receptores CCR7/metabolismo
Receptores de Somatomedina/metabolismo
Regulação para Cima
[Mh] Termos MeSH secundário: Regiões 3' não Traduzidas
Idoso
Linhagem Celular Tumoral
Movimento Celular
Proliferação Celular
Feminino
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Masculino
Meia-Idade
Invasividade Neoplásica
Prognóstico
Receptores de Somatomedina/genética
Análise de Sobrevida
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3' Untranslated Regions); 0 (CCR7 protein, human); 0 (IGF1R protein, human); 0 (MIRN1275 microRNA, human); 0 (MicroRNAs); 0 (Receptors, CCR7); 0 (Receptors, Somatomedin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180202
[Lr] Data última revisão:
180202
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171227
[St] Status:MEDLINE


  4 / 1917 MEDLINE  
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[PMID]:28954282
[Au] Autor:Andersson MK; Afshari MK; Andrén Y; Wick MJ; Stenman G
[Ad] Endereço:Sahlgrenska Cancer Center, Department of Pathology and Genetics, University of Gothenburg, Gothenburg, Sweden; Preclinical Research, South Texas Accelerated Research Therapeutics, San Antonio, TX.
[Ti] Título:Targeting the Oncogenic Transcriptional Regulator MYB in Adenoid Cystic Carcinoma by Inhibition of IGF1R/AKT Signaling.
[So] Source:J Natl Cancer Inst;109(9), 2017 Sep 01.
[Is] ISSN:1460-2105
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: Adenoid cystic carcinoma (ACC) is an aggressive cancer with no curative treatment for patients with recurrent/metastatic disease. The MYB-NFIB gene fusion is the main genomic hallmark and a potential therapeutic target. Methods: Oncogenic signaling pathways were studied in cultured cells and/or tumors from 15 ACC patients. Phospho-receptor tyrosine kinase (RTK) arrays were used to study the activity of RTKs. Effects of RTK inhibition on cell proliferation were analyzed with AlamarBlue, sphere assays, and two ACC xenograft models (n = 4-9 mice per group). The molecular effects of MYB-NFIB knockdown and IGF1R inhibition were studied with quantitative polymerase chain reaction, immunoblot, and gene expression microarrays. All statistical tests were two-sided. Results: The MYB-NFIB fusion drives proliferation of ACC cells and is crucial for spherogenesis. Intriguingly, the fusion is regulated through AKT-dependent signaling induced by IGF1R overexpression and is downregulated upon IGF1R-inhibition (% expression of control ± SD = 27.2 ± 1.3, P < .001). MYB-NFIB regulates genes involved in cell cycle control, DNA replication/repair, and RNA processing. The transcriptional program induced by MYB-NFIB affects critical oncogenic mediators normally controlled by MYC and is reversed by pharmacological inhibition of IGF1R. Co-activation of epidermal growth factor receptor (EGFR) and MET promoted proliferation of ACC cells, and combined targeting of IGFR1/EGFR/MET induced differentiation and synergistically inhibited the growth of patient-derived xenografted ACCs (ACCX5M1, % growth of control ± SD = 34.9 ± 20.3, P = .006; ACCX6, % growth of control ± SD = 24.1 ± 17.5, P = .04). Conclusions: MYB-NFIB is an oncogenic driver and a key therapeutic target in ACC that is regulated by AKT-dependent IGF1R signaling. Our studies uncover a new strategy to target an oncogenic transcriptional master regulator and provide new important insights into the biology and treatment of ACC.
[Mh] Termos MeSH primário: Carcinoma Adenoide Cístico/genética
Carcinoma Adenoide Cístico/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Proteínas Proto-Oncogênicas c-myb/metabolismo
Receptores de Somatomedina/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Animais
Apoptose
Biomarcadores Tumorais
Carcinoma Adenoide Cístico/tratamento farmacológico
Carcinoma Adenoide Cístico/patologia
Ciclo Celular
Proliferação Celular/genética
Análise por Conglomerados
Modelos Animais de Doenças
Feminino
Perfilação da Expressão Gênica
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Fator de Crescimento Insulin-Like II/farmacologia
Masculino
Meia-Idade
Gradação de Tumores
Proteínas de Fusão Oncogênicas/genética
Proteínas de Fusão Oncogênicas/metabolismo
Fosforilação
Inibidores de Proteínas Quinases/farmacologia
Proteínas Proto-Oncogênicas c-myb/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-myb/genética
Transdução de Sinais/efeitos dos fármacos
Transcrição Genética
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (IGF1R protein, human); 0 (MYB-NFIB fusion protein, human); 0 (Oncogene Proteins, Fusion); 0 (Protein Kinase Inhibitors); 0 (Proto-Oncogene Proteins c-myb); 0 (Receptors, Somatomedin); 67763-97-7 (Insulin-Like Growth Factor II); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170928
[St] Status:MEDLINE
[do] DOI:10.1093/jnci/djx017


  5 / 1917 MEDLINE  
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[PMID]:28945762
[Au] Autor:Solomon-Zemler R; Sarfstein R; Werner H
[Ad] Endereço:Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
[Ti] Título:Nuclear insulin-like growth factor-1 receptor (IGF1R) displays proliferative and regulatory activities in non-malignant cells.
[So] Source:PLoS One;12(9):e0185164, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The insulin-like growth factor-1 receptor (IGF1R) mediates the biological actions of IGF1 and IGF2. The IGF1R is involved in both physiological and pathological activities and is usually overexpressed in most types of cancer. In addition to its classical mechanism of action, recent evidence has shown a nuclear presence of IGF1R, associated with novel genomic/transcriptional types of activities. The present study was aimed at evaluating the hypothesis that nuclear IGF1R localization is not restricted to cancer cells and might constitute a novel physiologically relevant regulatory mechanism. Our data shows that nuclear translocation takes place in a wide array of cells, including normal diploid fibroblasts. In addition, we provide evidence for a synergistic effect of a nuclear translocation blocker along with selective IGF1R inhibitors in terms of decreasing cell proliferation. Given the important role of the IGF1R in mitogenesis, the present results may be of translational relevance in cancer research. In conclusion, results are consistent with the concept that nuclear IGF1R fulfills important physiological and pathological roles.
[Mh] Termos MeSH primário: Proliferação Celular/fisiologia
Receptores de Somatomedina/fisiologia
[Mh] Termos MeSH secundário: Transporte Ativo do Núcleo Celular/efeitos dos fármacos
Cadaverina/análogos & derivados
Cadaverina/farmacologia
Linhagem Celular
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Movimento Celular/fisiologia
Núcleo Celular/fisiologia
Proliferação Celular/efeitos dos fármacos
Transformação Celular Neoplásica
Células Cultivadas
Fibroblastos/metabolismo
Técnicas de Silenciamento de Genes
Seres Humanos
Células MCF-7
Microscopia Confocal
Receptores de Somatomedina/antagonistas & inibidores
Receptores de Somatomedina/genética
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (IGF1R protein, human); 0 (Receptors, Somatomedin); I9N81SC5HD (monodansylcadaverine); L90BEN6OLL (Cadaverine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170926
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185164


  6 / 1917 MEDLINE  
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[PMID]:28932920
[Au] Autor:Liu YC; Park YR; Kim SL; Lee ST; Kim SW
[Ad] Endereço:Department of Physiology, Chonbuk National University Medical School, Jeonju, Republic of Korea.
[Ti] Título:MicroRNA-30a Inhibits Colorectal Cancer Metastasis Through Down-Regulation of Type I Insulin-Like Growth Factor Receptor.
[So] Source:Dig Dis Sci;62(11):3040-3049, 2017 Nov.
[Is] ISSN:1573-2568
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: miR-30a expression is down-regulated and regulates tumor suppressors in various cancers. AIM: We investigated the mechanisms underlying the biological role of miR-30a in CRC. METHODS: MicroRNA, mRNA, and protein expression were analyzed by quantitative real-time PCR and Western blot. The migration and invasion abilities of CRC were determined by wound healing assay, and trans-well migration and invasion. A luciferase reporter assay was used to confirm the targets of miR-30a. RESULTS: miR-30a expression was significantly down-regulated in CRC tissues and in CRC tissue with lymph node metastasis compared to CRC tissue without metastasis. Overexpression of miR-30a suppressed migration and invasion through insulin-like growth factor 1 receptor (IGF1R) in CRC cells. miR-30a suppresses IGF1R protein expression and inhibits ß-catenin or p-AKT and increases E-cadherin expression. The IGF1R expression level is also up-regulated in CRC tumors and inversely correlated with miR-30a in CRC specimens. CONCLUSIONS: miR-30a functions as a tumor-suppressive miRNA, which may provide a therapeutic strategy for metastasis of CRC.
[Mh] Termos MeSH primário: Movimento Celular
Neoplasias Colorretais/metabolismo
MicroRNAs/metabolismo
Receptores de Somatomedina/metabolismo
[Mh] Termos MeSH secundário: Regiões 3' não Traduzidas
Idoso
Sítios de Ligação
Caderinas/metabolismo
Linhagem Celular Tumoral
Neoplasias Colorretais/genética
Neoplasias Colorretais/patologia
Regulação para Baixo
Feminino
Regulação Neoplásica da Expressão Gênica
Células HEK293
Seres Humanos
Masculino
MicroRNAs/genética
Meia-Idade
Metástase Neoplásica
Fosforilação
Proteínas Proto-Oncogênicas c-akt/metabolismo
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Receptores de Somatomedina/genética
Transdução de Sinais
Transfecção
beta Catenina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3' Untranslated Regions); 0 (CDH1 protein, human); 0 (CTNNB1 protein, human); 0 (Cadherins); 0 (IGF1R protein, human); 0 (MIRN30 microRNA, human); 0 (MicroRNAs); 0 (RNA, Messenger); 0 (Receptors, Somatomedin); 0 (beta Catenin); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1007/s10620-017-4763-z


  7 / 1917 MEDLINE  
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[PMID]:28898232
[Au] Autor:Wang X; Zhu Q; Lin Y; Wu L; Wu X; Wang K; He Q; Xu C; Wan X; Wang X
[Ad] Endereço:Department of Gynecology and Obstetrics, XinHua Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200092, China.
[Ti] Título:Crosstalk between TEMs and endothelial cells modulates angiogenesis and metastasis via IGF1-IGF1R signalling in epithelial ovarian cancer.
[So] Source:Br J Cancer;117(9):1371-1382, 2017 Oct 24.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Epithelial ovarian cancer (EOC) is the leading cause of death from gynaecologic malignancies and has a poor prognosis due to metastasis. Drugs targeting the angiogenesis pathway significantly improve patient outcome. However, the key factors linking angiogenesis and metastasis have not been elucidated. In this study, we found Tie2 expressing monocytes (CD14 Tie2 , TEMs) as key contributors to angiogenesis and metastasis of EOC. METHODS: Tissue slides were evaluated by immunofluorescence for the presence of total tissue macrophages and TEMs. The correlation between microvascular density (MVD) values and the TEMs number or ratio was calculated in both ovarian cancer tissues and peritoneum. The rate of TEMs in monocytes was evaluated in the peripheral blood of female healthy donors, benign cysts patients, and EOC patients using flow cytometry. The TEMs rate in ascites from EOC patients was also evaluated by flow cytometry. The concentration of Ang2, as the ligand of Tie2, was examined by ELISA in serum samples of EOC patients, benign cysts patients, and ascites samples of EOC patients. The effects of Ang2 on the migration and the cytokine expression of TEMs were further examined. The pro- angiogenesis activity of TEMs via IGF1 was performed in both in vivo and in vitro. And the IGF1 blocking test was performed using neutralising antibody. RESULTS: TEMs were significantly higher in tumour foci, peripheral blood and ascites in EOC patients. The proportion of TEMs among total tissue macrophages was positively correlated with tumour MVD. In vivo animal results showed that TEMs promoted EOC angiogenesis and metastasis. Further functional and mechanisms studies revealed that concentration of angiopoietin 2 (Ang2), a ligand of Tie2, was elevated in EOC ascites which further recruit TEMs in a dose-dependent manner as a powerful chemokine to TEMs. Recruited TEMs promoted endothelial cell function through IGF1-activated downstream signalling. Blocking secreted IGF1 using inhibiting antibody reduced TEMs mediated angiogenesis and metastasis. CONCLUSIONS: TEMs significantly increased in EOC patients and were recruited to tumour loci by the increased Ang2. The increased TEMs have diagnostic value in ovarian cancer and were positively correlated with the MVD in ovarian cancer tissue. Furthermore, TEMs promote angiogenesis via IGF1 in both in vivo and in vitro experimental systems after stimulation by Ang2. Altogether, this study paves the way to develop novel therapy targets as the axis of Ang2-TEMs-IGF1 in EOC.
[Mh] Termos MeSH primário: Endotélio Vascular/metabolismo
Fator de Crescimento Insulin-Like I/metabolismo
Monócitos/patologia
Neoplasias Epiteliais e Glandulares/irrigação sanguínea
Neoplasias Epiteliais e Glandulares/secundário
Neovascularização Patológica/patologia
Neoplasias Ovarianas/irrigação sanguínea
Neoplasias Ovarianas/secundário
Receptor TIE-2/metabolismo
Receptores de Somatomedina/metabolismo
[Mh] Termos MeSH secundário: Angiopoietina-2/metabolismo
Animais
Biomarcadores Tumorais/metabolismo
Movimento Celular
Células Cultivadas
Endotélio Vascular/citologia
Feminino
Seres Humanos
Camundongos
Camundongos Nus
Monócitos/metabolismo
Estadiamento de Neoplasias
Neoplasias Epiteliais e Glandulares/metabolismo
Neovascularização Patológica/metabolismo
Neoplasias Ovarianas/metabolismo
Prognóstico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiopoietin-2); 0 (Biomarkers, Tumor); 0 (IGF1R protein, human); 0 (Receptors, Somatomedin); 67763-96-6 (Insulin-Like Growth Factor I); EC 2.7.10.1 (Receptor, TIE-2)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170913
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2017.297


  8 / 1917 MEDLINE  
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[PMID]:28870985
[Au] Autor:Shapiro L; Chatterjee S; Ramadan DG; Davies KM; Savage MO; Metherell LA; Storr HL
[Ad] Endereço:Centre for EndocrinologyWilliam Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
[Ti] Título:Whole-exome sequencing gives additional benefits compared to candidate gene sequencing in the molecular diagnosis of children with growth hormone or IGF-1 insensitivity.
[So] Source:Eur J Endocrinol;177(6):485-501, 2017 Dec.
[Is] ISSN:1479-683X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: GH insensitivity (GHI) is characterised by short stature, IGF-1 deficiency and normal/elevated serum GH. IGF-1 insensitivity results in pre- and post-natal growth failure with normal/high IGF-1 levels. The prevalence of genetic defects is unknown. OBJECTIVE: To identify the underlying genetic diagnoses in a paediatric cohort with GH or IGF-1 insensitivity using candidate gene (CGS) and whole-exome sequencing (WES) and assess factors associated with the discovery of a genetic defect. METHODS: We undertook a prospective study of 132 patients with short stature and suspected GH or IGF-1 insensitivity referred to our centre for genetic analysis. 107 (96 GHI, 88 probands; 11 IGF-1 insensitivity, 9 probands) underwent CGS. WES was performed in those with no defined genetic aetiology following CGS. RESULTS: A genetic diagnosis was discovered 38/107 (36%) patients (32% probands) by CGS. WES revealed 11 patients with genetic variants in genes known to cause short stature. A further 2 patients had hypomethylation in the H19/IGF2 region or mUPD7 consistent with Silver-Russell Syndrome (total with genetic diagnosis 51/107, 48% or 41/97, 42% probands). WES also identified homozygous putative variants in and in 2 patients. Low height SDS and consanguinity were highly predictive for identifying a genetic defect. CONCLUSIONS: Comprehensive genetic testing confirms the genetic heterogeneity of GH/IGF-1 insensitivity and successfully identified the genetic aetiology in a significant proportion of cases. WES is rapid and may isolate genetic variants that have been missed by traditional clinically driven genetic testing. This emphasises the benefits of specialist diagnostic centres.
[Mh] Termos MeSH primário: Nanismo/genética
Transtornos do Crescimento/genética
Hipotonia Muscular/genética
Síndrome de Silver-Russell/genética
Coluna Vertebral/anormalidades
[Mh] Termos MeSH secundário: Adolescente
Proteínas de Transporte/genética
Criança
Pré-Escolar
Proteínas Culina/genética
Proteínas do Citoesqueleto/genética
Metilação de DNA
Nanismo/diagnóstico
Nanismo/metabolismo
Exoma/genética
Proteína do Grupo de Complementação A da Anemia de Fanconi/genética
Feminino
Glicoproteínas/genética
Transtornos do Crescimento/diagnóstico
Transtornos do Crescimento/metabolismo
Hormônio do Crescimento Humano/metabolismo
Seres Humanos
Lactente
Fator de Crescimento Insulin-Like I/metabolismo
Fator de Crescimento Insulin-Like II/genética
Masculino
Técnicas de Diagnóstico Molecular
Hipotonia Muscular/diagnóstico
Hipotonia Muscular/metabolismo
Receptores de Somatomedina/genética
Análise de Sequência de DNA
Síndrome de Silver-Russell/diagnóstico
Síndrome de Silver-Russell/metabolismo
Coluna Vertebral/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CUL7 protein, human); 0 (Carrier Proteins); 0 (Cullin Proteins); 0 (Cytoskeletal Proteins); 0 (FANCA protein, human); 0 (Fanconi Anemia Complementation Group A Protein); 0 (Glycoproteins); 0 (IGF1R protein, human); 0 (IGF2 protein, human); 0 (OBSL1 protein, human); 0 (Receptors, Somatomedin); 0 (insulin-like growth factor binding protein, acid labile subunit); 0 (somatotropin-binding protein); 12629-01-5 (Human Growth Hormone); 67763-96-6 (Insulin-Like Growth Factor I); 67763-97-7 (Insulin-Like Growth Factor II)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE
[do] DOI:10.1530/EJE-17-0453


  9 / 1917 MEDLINE  
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[PMID]:28821609
[Au] Autor:Lyons A; Coleman M; Riis S; Favre C; O'Flanagan CH; Zhdanov AV; Papkovsky DB; Hursting SD; O'Connor R
[Ad] Endereço:From the Cell Biology Laboratory and.
[Ti] Título:Insulin-like growth factor 1 signaling is essential for mitochondrial biogenesis and mitophagy in cancer cells.
[So] Source:J Biol Chem;292(41):16983-16998, 2017 Oct 13.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mitochondrial activity and metabolic reprogramming influence the phenotype of cancer cells and resistance to targeted therapy. We previously established that an insulin-like growth factor 1 (IGF-1)-inducible mitochondrial UTP carrier (PNC1/SLC25A33) promotes cell growth. This prompted us to investigate whether IGF signaling is essential for mitochondrial maintenance in cancer cells and whether this contributes to therapy resistance. Here we show that IGF-1 stimulates mitochondrial biogenesis in a range of cell lines. In MCF-7 and ZR75.1 breast cancer cells, IGF-1 induces peroxisome proliferator-activated receptor γ coactivator 1ß (PGC-1ß) and PGC-1α-related coactivator (PRC). Suppression of PGC-1ß and PRC with siRNA reverses the effects of IGF-1 and disrupts mitochondrial morphology and membrane potential. IGF-1 also induced expression of the redox regulator nuclear factor-erythroid-derived 2-like 2 (NFE2L2 alias NRF-2). Of note, MCF-7 cells with acquired resistance to an IGF-1 receptor (IGF-1R) tyrosine kinase inhibitor exhibited reduced expression of PGC-1ß, PRC, and mitochondrial biogenesis. Interestingly, these cells exhibited mitochondrial dysfunction, indicated by reactive oxygen species expression, reduced expression of the mitophagy mediators BNIP3 and BNIP3L, and impaired mitophagy. In agreement with this, IGF-1 robustly induced BNIP3 accumulation in mitochondria. Other active receptor tyrosine kinases could not compensate for reduced IGF-1R activity in mitochondrial protection, and MCF-7 cells with suppressed IGF-1R activity became highly dependent on glycolysis for survival. We conclude that IGF-1 signaling is essential for sustaining cancer cell viability by stimulating both mitochondrial biogenesis and turnover through BNIP3 induction. This core mitochondrial protective signal is likely to strongly influence responses to therapy and the phenotypic evolution of cancer.
[Mh] Termos MeSH primário: Fator de Crescimento Insulin-Like I/metabolismo
Mitocôndrias/metabolismo
Degradação Mitocondrial
Dinâmica Mitocondrial
Proteínas de Neoplasias/metabolismo
Neoplasias/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Proteínas de Transporte/genética
Proteínas de Transporte/metabolismo
Sobrevivência Celular/genética
Seres Humanos
Fator de Crescimento Insulin-Like I/genética
Células MCF-7
Proteínas de Membrana/genética
Proteínas de Membrana/metabolismo
Mitocôndrias/genética
Fator 2 Relacionado a NF-E2/genética
Fator 2 Relacionado a NF-E2/metabolismo
Proteínas de Neoplasias/genética
Neoplasias/genética
Neoplasias/patologia
Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética
Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo
Proteínas Proto-Oncogênicas/genética
Proteínas Proto-Oncogênicas/metabolismo
Receptores de Somatomedina/genética
Receptores de Somatomedina/metabolismo
Proteínas Supressoras de Tumor/genética
Proteínas Supressoras de Tumor/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BNIP3 protein, human); 0 (BNIP3L protein, human); 0 (Carrier Proteins); 0 (IGF1R protein, human); 0 (Membrane Proteins); 0 (NF-E2-Related Factor 2); 0 (NFE2L2 protein, human); 0 (Neoplasm Proteins); 0 (PPARGC1A protein, human); 0 (PPARGC1B protein, human); 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha); 0 (Proto-Oncogene Proteins); 0 (Receptors, Somatomedin); 0 (Tumor Suppressor Proteins); 67763-96-6 (Insulin-Like Growth Factor I)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170820
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.792838


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[PMID]:28772281
[Au] Autor:Ciuleanu TE; Ahmed S; Kim JH; Mezger J; Park K; Thomas M; Chen J; Poondru S; VanTornout JM; Whitcomb D; Blackhall F
[Ad] Endereço:Oncological Institute I Chiricuta and UMF Iuliu Hatieganu, Cluj-Napoca, Romania.
[Ti] Título:Randomised Phase 2 study of maintenance linsitinib (OSI-906) in combination with erlotinib compared with placebo plus erlotinib after platinum-based chemotherapy in patients with advanced non-small cell lung cancer.
[So] Source:Br J Cancer;117(6):757-766, 2017 Sep 05.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Maintenance therapy is important in advanced/metastatic non-small cell lung cancer (NSCLC). Erlotinib as switch maintenance following platinum-based chemotherapy increases survival. Cross-talk between the epidermal growth factor receptor and insulin-like growth factor receptor (IGFR) pathways mediate resistance to individual receptor blockade. This study compared maintenance linsitinib plus erlotinib vs erlotinib plus placebo in patients with NSCLC. METHODS: In this Phase II randomised trial, patients without progression following four cycles of first-line platinum-based chemotherapy (N=205) received continuous schedule maintenance oral linsitinib 150 mg or placebo BID combined with erlotinib 150 mg QD for 21-day cycles. The primary endpoint was progression-free survival (PFS). RESULTS: The study was unblinded early due to linsitinib non-superiority. No difference was found between the two treatment groups in median PFS of 125 days linsitinib vs 129 days placebo (P=0.601); no difference in overall survival (OS) was observed. Tolerability was similar, although in the linsitinib group, treatment-related adverse events and discontinuations were more frequent. No drug-drug interaction was implicated. CONCLUSIONS: Linsitinib maintenance therapy added to erlotinib did not improve PFS or OS in non-progressing NSCLC patients. This highlights the need for robust biomarkers of response for combinations that incorporate IGFR-targeted therapies in maintenance or other therapeutic settings.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
Cloridrato de Erlotinib/uso terapêutico
Imidazóis/uso terapêutico
Neoplasias Pulmonares/tratamento farmacológico
Quimioterapia de Manutenção
Pirazinas/uso terapêutico
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
Carcinoma Pulmonar de Células não Pequenas/patologia
Cloridrato de Erlotinib/efeitos adversos
Feminino
Seres Humanos
Imidazóis/efeitos adversos
Estimativa de Kaplan-Meier
Neoplasias Pulmonares/patologia
Masculino
Meia-Idade
Placebos/uso terapêutico
Compostos de Platina/uso terapêutico
Pirazinas/efeitos adversos
Receptores de Somatomedina/antagonistas & inibidores
Receptores de Somatomedina/genética
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol); 0 (Imidazoles); 0 (Placebos); 0 (Platinum Compounds); 0 (Pyrazines); 0 (Receptors, Somatomedin); DA87705X9K (Erlotinib Hydrochloride)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170914
[Lr] Data última revisão:
170914
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170804
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2017.226



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