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Pesquisa : E05.393.335.500 [Categoria DeCS]
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  1 / 19946 MEDLINE  
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[PMID]:29351307
[Au] Autor:Merentie M; Rissanen R; Lottonen-Raikaslehto L; Huusko J; Gurzeler E; Turunen MP; Holappa L; Mäkinen P; Ylä-Herttuala S
[Ad] Endereço:A. I. Virtanen Institute for Molecular Sciences, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
[Ti] Título:Doxycycline modulates VEGF-A expression: Failure of doxycycline-inducible lentivirus shRNA vector to knockdown VEGF-A expression in transgenic mice.
[So] Source:PLoS One;13(1):e0190981, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Vascular endothelial growth factor-A (VEGF-A) is the master regulator of angiogenesis, vascular permeability and growth. However, its role in mature blood vessels is still not well understood. To better understand the role of VEGF-A in the adult vasculature, we generated a VEGF-A knockdown mouse model carrying a doxycycline (dox)-regulatable short hairpin RNA (shRNA) transgene, which silences VEGF-A. The aim was to find the critical level of VEGF-A reduction for vascular well-being in vivo. In vitro, the dox-inducible lentiviral shRNA vector decreased VEGF-A expression efficiently and dose-dependently in mouse endothelial cells and cardiomyocytes. In the generated transgenic mice plasma VEGF-A levels decreased shortly after the dox treatment but returned back to normal after two weeks. VEGF-A expression decreased shortly after the dox treatment only in some tissues. Surprisingly, increasing the dox exposure time and dose led to elevated VEGF-A expression in some tissues of both wildtype and knockdown mice, suggesting that dox itself has an effect on VEGF-A expression. When the effect of dox on VEGF-A levels was further tested in naïve/non-transduced cells, the dox administration led to a decreased VEGF-A expression in endothelial cells but to an increased expression in cardiomyocytes. In conclusion, the VEGF-A knockdown was achieved in a dox-regulatable fashion with a VEGF-A shRNA vector in vitro, but not in the knockdown mouse model in vivo. Dox itself was found to regulate VEGF-A expression explaining the unexpected results in mice. The effect of dox on VEGF-A levels might at least partly explain its previously reported beneficial effects on myocardial and brain ischemia. Also, this effect on VEGF-A should be taken into account in all studies using dox-regulated vectors.
[Mh] Termos MeSH primário: Doxiciclina/farmacologia
Regulação da Expressão Gênica/efeitos dos fármacos
Técnicas de Silenciamento de Genes
Lentivirus/genética
RNA Interferente Pequeno/genética
Fator A de Crescimento do Endotélio Vascular/genética
[Mh] Termos MeSH secundário: Animais
Vetores Genéticos
Camundongos
Camundongos Transgênicos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (RNA, Small Interfering); 0 (Vascular Endothelial Growth Factor A); N12000U13O (Doxycycline)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180120
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190981


  2 / 19946 MEDLINE  
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[PMID]:29214789
[Au] Autor:Kim CW; Han JH; Wu L; Choi JY
[Ad] Endereço:Department of Otorhinolaryngology, Hallym University College of Medicine, Seoul, Korea.
[Ti] Título:microRNA-183 is Essential for Hair Cell Regeneration after Neomycin Injury in Zebrafish.
[So] Source:Yonsei Med J;59(1):141-147, 2018 Jan.
[Is] ISSN:1976-2437
[Cp] País de publicação:Korea (South)
[La] Idioma:eng
[Ab] Resumo:PURPOSE: microRNAs (miRNAs) are non-coding RNAs composed of 20 to 22 nucleotides that regulate development and differentiation in various organs by silencing specific RNAs and regulating gene expression. In the present study, we show that the microRNA (miR)-183 cluster is upregulated during hair cell regeneration and that its inhibition reduces hair cell regeneration following neomycin-induced ototoxicity in zebrafish. MATERIALS AND METHODS: miRNA expression patterns after neomycin exposure were analyzed using microarray chips. Quantitative polymerase chain reaction was performed to validate miR-183 cluster expression patterns following neomycin exposure (500 µM for 2 h). After injection of an antisense morpholino (MO) to miR-183 (MO-183) immediately after fertilization, hair cell regeneration after neomycin exposure in neuromast cells was evaluated by fluorescent staining (YO-PRO1). The MO-183 effect also was assessed in transgenic zebrafish larvae expressing green fluorescent protein (GFP) in inner ear hair cells. RESULTS: Microarray analysis clearly showed that the miR-183 cluster (miR-96, miR-182, and miR-183) was upregulated after neomycin treatment. We also confirmed upregulated expression of the miR-183 cluster during hair cell regeneration after neomycin-induced ototoxicity. miR-183 inhibition using MO-183 reduced hair cell regeneration in both wild-type and GFP transgenic zebrafish larvae. CONCLUSION: Our work demonstrates that the miR-183 cluster is essential for the regeneration of hair cells following ototoxic injury in zebrafish larvae. Therefore, regulation of the miR-183 cluster can be a novel target for stimulation of hair cell regeneration.
[Mh] Termos MeSH primário: Células Ciliadas Auditivas/fisiologia
MicroRNAs/metabolismo
Regeneração/genética
Peixe-Zebra/genética
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Contagem de Células
Perfilação da Expressão Gênica
Regulação da Expressão Gênica/efeitos dos fármacos
Técnicas de Silenciamento de Genes
Proteínas de Fluorescência Verde/metabolismo
Células Ciliadas Auditivas/efeitos dos fármacos
Larva/efeitos dos fármacos
Larva/genética
MicroRNAs/genética
Morfolinos/farmacologia
Neomicina/toxicidade
Regeneração/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MIRN183 microRNA, zebrafish); 0 (MicroRNAs); 0 (Morpholinos); 1404-04-2 (Neomycin); 147336-22-9 (Green Fluorescent Proteins)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171208
[St] Status:MEDLINE
[do] DOI:10.3349/ymj.2018.59.1.141


  3 / 19946 MEDLINE  
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[PMID]:29441965
[Au] Autor:Cai Z; Liu J; Bian H; Cai J; Guo X
[Ti] Título:MiR-455 enhances adipogenic differentiation of 3T3-L1 cells through targeting uncoupling protein-1.
[So] Source:Pharmazie;71(11):625-628, 2016 Nov 02.
[Is] ISSN:0031-7144
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Accumulating evidence suggests that microRNAs (miRNAs) play an important role in regulating the pathways in adipose tissue that control processes such as adipogenesis, insulin resistance, and inflammation. Adipogenic differentiation of preadipocytes is a complex process regulated by various factors including miRNAs and cytokines. MiR-455 is a well-known miRNA that enhances adipogenesis. Uncoupling protein-1 (UCP-1), a heparinbinding growth factor, plays a negative role in adipogenesis. In this investigation, we demonstrate that UCP-1 is a target gene of miR-455 during adipogenic differentiation in 3T3-L1 preadipocytes. MiR-455 downregulates UCP-1 expression through interaction with a target site of miR-455 in the coding region of mouse UCP-1. The rare codons upstream of the target site regulate miR-455-induced translational knockdown of UCP-1, which provides more insight into the mechanism of adipogenic differentiation. Thus, these results suggest that the acceerative adipogenic effect of miR-455 in 3T3-L1 cells is due, at least in part, to suppression of UCP-1.
[Mh] Termos MeSH primário: Adipogenia/efeitos dos fármacos
Diferenciação Celular/efeitos dos fármacos
MicroRNAs/farmacologia
Proteína Desacopladora 1/efeitos dos fármacos
[Mh] Termos MeSH secundário: Células 3T3-L1
Tecido Adiposo/citologia
Tecido Adiposo/efeitos dos fármacos
Animais
Códon
Regulação para Baixo/efeitos dos fármacos
Técnicas de Silenciamento de Genes
Genes Reporter/genética
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Proteína Desacopladora 1/biossíntese
Proteína Desacopladora 1/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Codon); 0 (MIRN455 microRNA, mouse); 0 (MicroRNAs); 0 (Ucp1 protein, mouse); 0 (Uncoupling Protein 1)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180215
[St] Status:MEDLINE
[do] DOI:10.1691/ph.2016.6734


  4 / 19946 MEDLINE  
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[PMID]:29270670
[Au] Autor:Lv C; Wang H; Tong Y; Yin H; Wang D; Yan Z; Liang Y; Wu D; Su Q
[Ad] Endereço:Department of General Surgery, Shengjing Hospital Affiliated to China Medical University, Shenyang City, Liaoning Province, 110004, People's Republic of China.
[Ti] Título:The function of BTG3 in colorectal cancer cells and its possible signaling pathway.
[So] Source:J Cancer Res Clin Oncol;144(2):295-308, 2018 Feb.
[Is] ISSN:1432-1335
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: B-cell translocation gene 3 (BTG3) has been identified as a candidate driver gene for various cancers, but its specific role in colorectal cancer (CRC) is poorly understood. We aimed to investigate the relationship between expression of BTG3 and clinicopathological features and prognosis, as well as to explore the effects and the role of a possible BTG3 molecular mechanism on aggressive colorectal cancer behavior. METHODS: BTG3 expression was assessed by immunohistochemistry (IHC) on specimens from 140 patients with CRC. The association of BTG3 expression with clinicopathological features was examined. To confirm the biological role of BTG3 in CRC, two CRC cell lines expressing BTG3 were used and BTG3 expression was knocked down by shRNA. CCK-8, cell cycle, apoptosis, migration, and invasion assays were performed. The influence of BTG3 knockdown was further investigated by genomic microarray to uncover the potential molecular mechanisms underlying BTG3-mediated CRC development and progression. RESULTS: BTG3 was downregulated in colorectal cancer tissues and positively correlated with pathological classification (p = 0.037), depth of invasion (p = 0.016), distant metastasis (p = 0.024), TNM stage (p = 0.007), and overall survival (OS) and disease-free survival (DFS). BTG3 knockdown promoted cell proliferation, migration, invasion, relieved G2 arrest, and inhibited apoptosis in HCT116 and LoVo cells. A genomic microarray analysis showed that numerous tumor-associated signaling pathways and oncogenes were altered by BTG3 knockdown. At the mRNA level, nine genes referred to the extracellular-regulated kinase/mitogen-activated protein kinase pathway were differentially expressed. Western blotting revealed that BTG3 knockdown upregulated PAK2, RPS6KA5, YWHAB, and signal transducer and activator of transcription (STAT)3 protein levels, but downregulated RAP1A, DUSP6, and STAT1 protein expression, which was consistent with the genomic microarray data. CONCLUSIONS: BTG3 expression might contribute to CRC carcinogenesis. BTG3 knockdown might strengthen the aggressive colorectal cancer behavior.
[Mh] Termos MeSH primário: Neoplasias Colorretais/metabolismo
Proteínas/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Movimento Celular/fisiologia
Proliferação Celular/fisiologia
Neoplasias Colorretais/genética
Neoplasias Colorretais/patologia
Regulação para Baixo
Feminino
Técnicas de Silenciamento de Genes
Células HCT116
Células HT29
Seres Humanos
Imuno-Histoquímica
Masculino
Meia-Idade
Inclusão em Parafina
Proteínas/genética
Transdução de Sinais
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BTG3 protein, human); 0 (Proteins)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171223
[St] Status:MEDLINE
[do] DOI:10.1007/s00432-017-2561-9


  5 / 19946 MEDLINE  
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[PMID]:28471021
[Au] Autor:Spessott WA; Sanmillan ML; Kulkarni VV; McCormick ME; Giraudo CG
[Ad] Endereço:Department of Pathology and Laboratory Medicine, University of Pennsylvania - The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
[Ti] Título:Syntaxin 4 mediates endosome recycling for lytic granule exocytosis in cytotoxic T-lymphocytes.
[So] Source:Traffic;18(7):442-452, 2017 Jul.
[Is] ISSN:1600-0854
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Adaptive and innate immunity utilize the perforin-killing pathway to eliminate virus-infected or cancer cells. Cytotoxic T-lymphocytes (CTLs) and natural killer cells mediate this process by releasing toxic proteins at the contact area with target cells known as immunological synapse (IS). Formation of a stable IS and exocytosis of toxic proteins requires persistent fusion of Rab11a recycling endosomes with the plasma membrane (PM) that may assure the delivery of key effector proteins. Despite the importance of the recycling endosomal compartment, the membrane fusion proteins that control this process at the IS remain elusive. Here, by performing knockdown experiments we found that syntaxin 4 (STX4) is necessary for cytotoxic activity and CD107a degranulation against target cells in a similar fashion to syntaxin 11, which is involved in lytic granule (LG) exocytosis and immunodeficiency when it is mutated. Using total internal reflection fluorescent microscopy we identified that STX4 mediates fusion of EGFP-Rab11a vesicles at the IS. Immunoprecipitation experiments in lysates of activated CTLs indicate that endogenous STX4 may drive this fusion step by interacting with cognate proteins: Munc18-3/SNAP23/VAMP7 and/or VAMP8. These results reveal the role of STX4 in mediating fusion of Rab11a endosomes upstream of lytic granules (LGs) exocytosis and further demonstrate the importance of this pathway in controlling CTL-mediated cytotoxicity.
[Mh] Termos MeSH primário: Grânulos Citoplasmáticos/metabolismo
Endossomos/metabolismo
Exocitose/imunologia
Proteínas Qa-SNARE/metabolismo
Linfócitos T Citotóxicos/metabolismo
[Mh] Termos MeSH secundário: Degranulação Celular
Linhagem Celular
Grânulos Citoplasmáticos/imunologia
Citotoxicidade Imunológica
Técnicas de Silenciamento de Genes
Seres Humanos
Proteína 1 de Membrana Associada ao Lisossomo/metabolismo
Transporte Proteico
Proteínas Qa-SNARE/genética
Linfócitos T Citotóxicos/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lysosomal-Associated Membrane Protein 1); 0 (Qa-SNARE Proteins)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1111/tra.12490


  6 / 19946 MEDLINE  
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[PMID]:28455144
[Au] Autor:Zhang F; Lu YX; Chen Q; Zou HM; Zhang JM; Hu YH; Li XM; Zhang WJ; Zhang W; Lin C; Li XN
[Ad] Endereço:Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: zfan1985@yeah.net.
[Ti] Título:Identification of NCK1 as a novel downstream effector of STAT3 in colorectal cancer metastasis and angiogenesis.
[So] Source:Cell Signal;36:67-78, 2017 Aug.
[Is] ISSN:1873-3913
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Signal transducer and activator of transcription 3 (STAT3) is known to activate targets associated with invasion, proliferation, and angiogenesis in a wide variety of cancers. The adaptor protein NCK1 is involved in cytoskeletal movement and was identified as a STAT3-associated target in human tumors. However, the underlying molecular mechanism associated with colorectal cancer (CRC) metastasis is not yet completely understood. In this study, we report a novel STAT3 to NCK1 signaling pathway in colorectal cancer (CRC). We investigated the expression of NCK1 and its potential clinical and biological significance in CRC. NCK1 was noticeably up-regulated in human CRC tissues. NCK1 was also significantly associated with serosal invasion, lymph metastasis, and tumor-node-metastasis classification but was inversely correlated with differentiation. Gain-of-function and loss-of-function studies have shown that ectopic expression of NCK1 enhanced metastasis and angiogenesis in CRC cells. By gene expression analyses, we revealed a high co-overexpression of STAT3 and NCK1 in CRC tissues. Ectopic overexpression of STAT3 in CRC cells induced the expression of NCK1, whereas STAT3 knockdown decreased the expression of NCK1. Promoter activation and binding analyses demonstrated that STAT3 promoted the expression of NCK1 via direct action on the NCK1 promoter. The knock down of NCK1 partially reduced the CRC cell metastasis and angiogenesis promoted by STAT3. Additionally, by co-immunoprecipitation assays, we verified that NCK1 interacted with PAK1, which resulted in the activation of the PAK1/ERK pathway. STAT3 induced the transcription of NCK1 and triggered a PAK1/ERK cascade in CRC. These findings suggest a novel STAT3 to NCK1 to PAK1/ERK signaling mechanism that is potentially critical for CRC metastasis and angiogenesis.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Neoplasias Colorretais/irrigação sanguínea
Neoplasias Colorretais/patologia
Metástase Linfática/patologia
Neovascularização Patológica/metabolismo
Proteínas Oncogênicas/metabolismo
Fator de Transcrição STAT3/metabolismo
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/genética
Animais
Movimento Celular
Galinhas
Neoplasias Colorretais/genética
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Feminino
Quinase 2 de Adesão Focal/metabolismo
Regulação Neoplásica da Expressão Gênica
Técnicas de Silenciamento de Genes
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Masculino
Camundongos Nus
Meia-Idade
Proteínas Oncogênicas/genética
Transcrição Genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Nck protein); 0 (Oncogene Proteins); 0 (STAT3 Transcription Factor); EC 2.7.10.2 (Focal Adhesion Kinase 2); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE


  7 / 19946 MEDLINE  
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[PMID]:29311544
[Au] Autor:Bernardes de Jesus B; Marinho SP; Barros S; Sousa-Franco A; Alves-Vale C; Carvalho T; Carmo-Fonseca M
[Ad] Endereço:Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028, Lisboa, Portugal. bruno.jesus@medicina.ulisboa.pt.
[Ti] Título:Silencing of the lncRNA Zeb2-NAT facilitates reprogramming of aged fibroblasts and safeguards stem cell pluripotency.
[So] Source:Nat Commun;9(1):94, 2018 01 08.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Aging imposes a barrier to somatic cell reprogramming through poorly understood mechanisms. Here, we report that fibroblasts from old mice express higher levels of Zeb2, a transcription factor that activates epithelial-to-mesenchymal transition. Synthesis of Zeb2 protein is controlled by a natural antisense transcript named Zeb2-NAT. We show that transfection of adult fibroblasts with specific LNA Gapmers induces a robust downregulation of Zeb2-NAT transcripts and Zeb2 protein and enhances the reprogramming of old fibroblasts into pluripotent cells. We further demonstrate that Zeb2-NAT expression is precociously activated by differentiation stimuli in embryonic stem (ES) cells. By knocking down Zeb2-NAT, we were able to maintain ES cells challenged with commitment signals in the ground state of pluripotency. In conclusion, our study identifies a long noncoding RNA that is overlapping and antisense to the Zeb2 locus as a target for rejuvenation strategies.
[Mh] Termos MeSH primário: Reprogramação Celular/genética
Senescência Celular/genética
Fibroblastos/citologia
RNA Longo não Codificante/fisiologia
Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo
[Mh] Termos MeSH secundário: Animais
Fibroblastos/metabolismo
Regulação da Expressão Gênica
Técnicas de Silenciamento de Genes
Inativação Gênica
Camundongos
Células-Tronco Pluripotentes
RNA Antissenso/fisiologia
Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética
Homeobox 2 de Ligação a E-box com Dedos de Zinco/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (RNA, Antisense); 0 (RNA, Long Noncoding); 0 (ZEB2 protein, mouse); 0 (Zinc Finger E-box Binding Homeobox 2)
[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:180110
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-01921-6


  8 / 19946 MEDLINE  
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[PMID]:28460457
[Au] Autor:Trivedi T; Zheng Y; Fournier PGJ; Murthy S; John S; Schillo S; Dunstan CR; Mohammad KS; Zhou H; Seibel MJ; Guise TA
[Ad] Endereço:Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia.
[Ti] Título:The vitamin D receptor is involved in the regulation of human breast cancer cell growth via a ligand-independent function in cytoplasm.
[So] Source:Oncotarget;8(16):26687-26701, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Vitamin D has pleiotropic effects on multiple tissues, including malignant tumors. Vitamin D inhibits breast cancer growth through activation of the vitamin D receptor (VDR) and via classical nuclear signaling pathways. Here, we demonstrate that the VDR can also function in the absence of its ligand to control behaviour of human breast cancer cells both outside and within the bone microenvironment. Stable shRNA expression was used to knock down VDR expression in MCF-7 cells, generating two VDR knockdown clonal lines. In ligand-free culture, knockdown of VDR in MCF-7 cells significantly reduced proliferation and increased apoptosis, suggesting that the VDR plays a ligand-independent role in cancer cell growth. Implantation of these VDR knockdown cells into the mammary fat pad of nude mice resulted in reduced tumor growth in vivo compared with controls. In the intra-tibial xenograft model, VDR knockdown greatly reduced the ability of the cells to form tumors in the bone microenvironment. The in vitro growth of VDR knockdown cells was rescued by the expression of a mutant form of VDR which is unable to translocate to the nucleus and hence accumulates in the cytoplasm. Thus, our data indicate that in the absence of ligand, the VDR promotes breast cancer growth both in vitro and in vivo and that cytoplasmic accumulation of VDR is sufficient to produce this effect in vitro. This new mechanism of VDR action in breast cancer cells contrasts the known anti-proliferative nuclear actions of the VDR-vitamin D ligand complex.
[Mh] Termos MeSH primário: Neoplasias da Mama/metabolismo
Receptores de Calcitriol/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose/genética
Neoplasias Ósseas/genética
Neoplasias Ósseas/metabolismo
Neoplasias Ósseas/patologia
Neoplasias da Mama/genética
Linhagem Celular Tumoral
Proliferação Celular
Citoplasma/metabolismo
Modelos Animais de Doenças
Feminino
Expressão Gênica
Técnicas de Silenciamento de Genes
Xenoenxertos
Seres Humanos
Ligantes
Camundongos
Mutação
Osteosclerose/genética
Osteosclerose/metabolismo
Transporte Proteico
Receptores de Calcitriol/genética
Vitamina D/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); 0 (Receptors, Calcitriol); 0 (VDR protein, human); 1406-16-2 (Vitamin D)
[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:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15803


  9 / 19946 MEDLINE  
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[PMID]:28460442
[Au] Autor:Bhinge K; Yang L; Terra S; Nasir A; Muppa P; Aubry MC; Yi J; Janaki N; Kovtun IV; Murphy SJ; Halling G; Rahi H; Mansfield A; de Andrade M; Yang P; Vasmatzis G; Peikert T; Kosari F
[Ad] Endereço:Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
[Ti] Título:EGFR mediates activation of RET in lung adenocarcinoma with neuroendocrine differentiation characterized by ASCL1 expression.
[So] Source:Oncotarget;8(16):27155-27165, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Achaete-scute homolog 1 (ASCL1) is a neuroendocrine transcription factor specifically expressed in 10-20% of lung adenocarcinomas (AD) with neuroendocrine (NE) differentiation (NED). ASCL1 functions as an upstream regulator of the RET oncogene in AD with high ASCL1 expression (A+AD). RET is a receptor tyrosine kinase with two main human isoforms; RET9 (short) and RET51 (long). We found that elevated expression of RET51 associated mRNA was highly predictive of poor survival in stage-1 A+AD (p=0.0057). Functional studies highlighted the role of RET in promoting invasive properties of A+AD cells. Further, A+AD cells demonstrated close to 10 fold more sensitivity to epidermal growth factor receptor (EGFR) inhibitors, including gefitinib, than AD cells with low ASCL1 expression. Treatment with EGF robustly induced phosphorylation of RET at Tyr-905 in A+AD cells with wild type EGFR. This phosphorylation was blocked by gefitinib and by siRNA-EGFR. Immunoprecipitation experiments found EGFR in a complex with RET in the presence of EGF and suggested that RET51 was the predominant RET isoform in the complex. In the microarray datasets of stage-1 and all stages of A+AD, high levels of EGFR and RET RNA were significantly associated with poor overall survival (p < 0.01 in both analyses). These results implicate EGFR as a key regulator of RET activation in A+AD and suggest that EGFR inhibitors may be therapeutic in patients with A+AD tumors even in the absence of an EGFR or RET mutation.
[Mh] Termos MeSH primário: Adenocarcinoma/genética
Adenocarcinoma/metabolismo
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética
Carcinoma Neuroendócrino/genética
Carcinoma Neuroendócrino/metabolismo
Regulação Neoplásica da Expressão Gênica
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/metabolismo
Proteínas Proto-Oncogênicas c-ret/genética
Receptor do Fator de Crescimento Epidérmico/metabolismo
[Mh] Termos MeSH secundário: Adenocarcinoma/mortalidade
Adenocarcinoma/patologia
Processamento Alternativo
Carcinoma Neuroendócrino/mortalidade
Carcinoma Neuroendócrino/patologia
Ciclo Celular/genética
Linhagem Celular Tumoral
Movimento Celular/genética
Proliferação Celular
Técnicas de Silenciamento de Genes
Inativação Gênica
Seres Humanos
Neoplasias Pulmonares/mortalidade
Neoplasias Pulmonares/patologia
Gradação de Tumores
Fosforilação
Prognóstico
Ligação Proteica
Inibidores de Proteínas Quinases/farmacologia
RNA Mensageiro/genética
RNA Interferente Pequeno/genética
Receptor do Fator de Crescimento Epidérmico/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ASCL1 protein, human); 0 (Basic Helix-Loop-Helix Transcription Factors); 0 (Protein Kinase Inhibitors); 0 (RNA, Messenger); 0 (RNA, Small Interfering); EC 2.7.10.1 (Proto-Oncogene Proteins c-ret); EC 2.7.10.1 (Receptor, Epidermal Growth Factor)
[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:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15676


  10 / 19946 MEDLINE  
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[PMID]:28460435
[Au] Autor:Li ZW; Zhu YR; Zhou XZ; Zhuo BB; Wang XD
[Ad] Endereço:The Center of Diagnosis and Treatment for Children's Bone Diseases, The Children's Hospital Affiliated to Soochow University, Suzhou, China.
[Ti] Título:microRNA-135b expression silences Ppm1e to provoke AMPK activation and inhibit osteoblastoma cell proliferation.
[So] Source:Oncotarget;8(16):26424-26433, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Forced-activation of AMP-activated protein kinase (AMPK) can possibly inhibit osteoblastoma cells. Here, we aim to provoke AMPK activation via microRNA silencing its phosphatase Ppm1e (protein phosphatase Mg2+/Mn2+-dependent 1e). We showed that microRNA-135b-5p ("miR-135b-5p"), the anti-Ppm1e microRNA, was significantly downregulated in human osteoblastoma tissues. It was correlated with Ppm1e upregulation and AMPKα1 de-phosphorylation. Forced-expression of miR-135b-5p in human osteoblastoma cells (MG-63 and U2OS lines) silenced Ppm1e, and induced a profound AMPKα1 phosphorylation (at Thr-172). Osteoblastoma cell proliferation was inhibited after miR-135b-5p expression. Intriguingly, Ppm1e shRNA knockdown similarly induced AMPKα1 phosphorylation, causing osteoblastoma cell proliferation. Reversely, AMPKα1 shRNA knockdown or dominant negative mutation almost abolished miR-135b-5p's actions in osteoblastoma cells. Further in vivo studies demonstrated that U2OS tumor growth in mice was dramatically inhibited after expressing miR-135b-5p or Ppm1e shRNA. Together, our results suggest that miR-135b-induced Ppm1e silence induces AMPK activation to inhibit osteoblastoma cell proliferation.
[Mh] Termos MeSH primário: Proteínas Quinases Ativadas por AMP/metabolismo
Neoplasias Ósseas/genética
Neoplasias Ósseas/metabolismo
Inativação Gênica
MicroRNAs/genética
Osteoblastoma/genética
Osteoblastoma/metabolismo
Proteína Fosfatase 2C/genética
[Mh] Termos MeSH secundário: Animais
Neoplasias Ósseas/patologia
Linhagem Celular Tumoral
Proliferação Celular
Modelos Animais de Doenças
Ativação Enzimática
Regulação Neoplásica da Expressão Gênica
Técnicas de Silenciamento de Genes
Seres Humanos
Camundongos
Mutação
Osteoblastoma/patologia
Fosforilação
RNA Interferente Pequeno/genética
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MIRN135 microRNA, human); 0 (MicroRNAs); 0 (RNA, Small Interfering); EC 2.7.11.31 (AMP-Activated Protein Kinases); EC 3.1.3.16 (PPM1E protein, human); EC 3.1.3.16 (Protein Phosphatase 2C)
[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:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15477



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