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1.
Nat Commun ; 11(1): 2978, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532977

RESUMO

The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E2 (PGE2), which stimulates ß-catenin activation of GSC and M2-like TAM polarization. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE2 production. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients.

2.
Colloids Surf B Biointerfaces ; 190: 110968, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32193073

RESUMO

Owing to the excellent biocompatibility, hyperbranched polyglycerols (hbPGs) are one of the most promising polymers and widely employed in drug delivery. Presented as an excellent bioinert coating material, hbPGs can significantly improve the biosafety of biomedical nanomaterials. However, it is still unclear what specific properties of hbPGs are the key effectors to bioinertness. Here, atomic force microscopy was employed to test the Young's modulus and adhesion of hbPGs, spin-coated onto mica substrate. High Young's modulus indicated that the hbPGs cannot be further compressed and low adhesion implied that it is not easy to form hbPGs aggregators. This could owe to the intramolecular hydrogen bond. Morphology characterization of hbPGs self-assembled monolayer onto Si(100) substrate, confirmed the lower adhesion among different hbPGs and indicated their biofouling properties. Further confocal laser microscopy of cell membrane modified with alkyl chain (C18)-modified hbPGs and hbPGs-NH2, confirmed that the antifouling properties of hbPGs are determined by terminal glycerol units. Our findings demonstrated that only hbPGs with entire terminal surface can be used as perspective cell membrane modification skeleton.

3.
Nano Lett ; 20(3): 1637-1646, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32013452

RESUMO

Nanotechnology-based RNA interference (RNAi) has shown great promise in overcoming the limitations of traditional clinical treatments for glioblastoma (GBM). However, because of the complexity of brain physiology, simple blood-brain barrier (BBB) penetration or tumor-targeting strategies cannot entirely meet the demanding requirements of different therapeutic delivery stages. Herein, we developed a charge conversional biomimetic nanoplatform with a three-layer core-shell structure to programmatically overcome persistent obstacles in siRNA delivery to GBM. The resulting nanocomplex presents good biocompatibility, prolonged blood circulation, high BBB transcytosis, effective tumor accumulation, and specific uptake by tumor cells in the brain. Moreover, red blood cell membrane (RBCm) disruption and effective siRNA release can be further triggered elegantly by charge conversion from negative to positive in the endo/lysosome (pH 5.0-6.5) of tumor cells, leading to highly potent target-gene silencing with a strong anti-GBM effect. Our study provides an intelligent biomimetic nanoplatform tailored for systemically siRNA delivery to GBM, leveraging Angiopep-2 peptide-modified, immune-free RBCm and charge conversional components. Improved therapeutic efficacy, higher survival rates, and minimized systemic side effects were achieved in orthotopic U87MG-luc human glioblastoma tumor-bearing nude mice.

4.
Virus Res ; 281: 197870, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31962064

RESUMO

Soybean mosaic virus (SMV)-disease is one of the most serious and widespread diseases in soybean (Glycine max). In the present study, a DnaJ protein in soybean designated GmCPIP (SMV coat protein-interacting protein) was screened by the QIS-Seq (quantitative interactor screening with next-generation sequencing) method, and the interaction between SMV CP and GmCPIP was confirmed by the yeast two-hybrid (Y2H) system and bimolecular fluorescence complementation (BiFC) assay. Subcellular localization analysis indicated that both proteins are localized in the cytoplasm, cytomembrane and nucleus. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis showed that infection with SMV-SC4 temporarily increased the transcription of GmCPIP. Virus-induced gene silencing (VIGS) down-regulated the GmCPIP gene by 82%, and the accumulation of SMV was decreased by 88.6% in GmCPIP-silenced plants inoculated with SMV-SC4. The interaction of GmCPIP with SMV CP seems to contribute to SMV infection in soybean.

5.
Mol Cells ; 42(8): 604-616, 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31446747

RESUMO

Phosphoserine phosphatase (PSPH) is one of the key enzymes of the L-serine synthesis pathway. PSPH is reported to affect the progression and survival of several cancers in an L-serine synthesis-independent manner, but the mechanism remains elusive. We demonstrate that PSPH promotes lung cancer progression through a noncanonical L-serine-independent pathway. PSPH was significantly associated with the prognosis of lung cancer patients and regulated the invasion and colony formation of lung cancer cells. Interestingly, L-serine had no effect on the altered invasion and colony formation by PSPH. Upon measuring the phosphatase activity of PSPH on a serine-phosphorylated peptide, we found that PSPH dephosphorylated phospho-serine in peptide sequences. To identify the target proteins of PSPH, we analyzed the protein phosphorylation profile and the PSPH-interacting protein profile using proteomic analyses and found one putative target protein, IRS-1. Immunoprecipitation and immunoblot assays validated a specific interaction between PSPH and IRS1 and the dephosphorylation of phospho-IRS-1 by PSPH in lung cancer cells. We suggest that the specific interaction and dephosphorylation activity of PSPH have novel therapeutic potential for lung cancer treatment, while the metabolic activity of PSPH, as a therapeutic target, is controversial.


Assuntos
Progressão da Doença , Proteínas Substratos do Receptor de Insulina/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Monoéster Fosfórico Hidrolases/metabolismo , Serina/metabolismo , Células A549 , Animais , Humanos , Camundongos , Invasividade Neoplásica , Fosforilação , Transdução de Sinais , Análise de Sobrevida , Ensaio Tumoral de Célula-Tronco
6.
Adv Mater ; 31(37): e1903277, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31348581

RESUMO

Small interfering RNA (siRNA) holds inherent advantages and great potential for treating refractory diseases. However, lack of suitable siRNA delivery systems that demonstrate excellent circulation stability and effective at-site delivery ability is currently impeding siRNA therapeutic performance. Here, a polymeric siRNA nanomedicine (3I-NM@siRNA) stabilized by triple interactions (electrostatic, hydrogen bond, and hydrophobic) is constructed. Incorporating extra hydrogen and hydrophobic interactions significantly improves the physiological stability compared to an siRNA nanomedicine analog that solely relies on the electrostatic interaction for stability. The developed 3I-NM@siRNA nanomedicine demonstrates effective at-site siRNA release resulting from tumoral reactive oxygen species (ROS)-triggered sequential destabilization. Furthermore, the utility of 3I-NM@siRNA for treating glioblastoma (GBM) by functionalizing 3I-NM@siRNA nanomedicine with angiopep-2 peptide is enhanced. The targeted Ang-3I-NM@siRNA exhibits superb blood-brain barrier penetration and potent tumor accumulation. Moreover, by cotargeting polo-like kinase 1 and vascular endothelial growth factor receptor-2, Ang-3I-NM@siRNA shows effective suppression of tumor growth and significantly improved survival time of nude mice bearing orthotopic GBM brain tumors. New siRNA nanomedicines featuring triple-interaction stabilization together with inbuilt self-destruct delivery ability provide a robust and potent platform for targeted GBM siRNA therapy, which may have utility for RNA interference therapy of other tumors or brain diseases.


Assuntos
Terapia Genética , Glioblastoma/terapia , Nanomedicina , Interferência de RNA , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Terapia Combinada , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Camundongos
7.
AMB Express ; 9(1): 116, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31342207

RESUMO

Infectious clone vectors used widely in genetic research. While constructing soybean mosaic virus (SMV) clone vectors, we found that transformed Agrobacterium grew significantly different depending on the viral strains used. In particular, the clone vectors constructed with SMV SC15 significantly suppressed the growth of Agrobacterium. Recombinant and truncated virus vector experiments showed that the polymorphism of a P1 protein coding sequence of SC15 leads to the growth inhibition of Agrobacterium. But the lack of other protein encoding sequences, except for the sequence encoding coat protein, should reduce the ability of SC15 to suppress Agrobacterium growth. A vector (pCB301-attL-SC15P) compatible with the Gateway cloning system was constructed using this Agrobacterium inhibitory sequence. The results from the LR recombination reaction with pCB301-attL-SC15P and Agrobacterium transformation showed the valuable application potential of the Agrobacterium inhibitory sequence to serve as a negative screening factor for effective recombinant clone screening in Agrobacterium.

8.
Cancer Res ; 79(7): 1369-1382, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30683653

RESUMO

Glioblastoma (GBM) cancer stem cells (CSC) are primarily responsible for metastatic dissemination, resistance to therapy, and relapse of GBM, the most common and aggressive brain tumor. Development and maintenance of CSCs require orchestrated metabolic rewiring and metabolic adaptation to a changing microenvironment. Here, we show that cooperative interplay between the mitochondrial chaperone TRAP1 and the major mitochondria deacetylase sirtuin-3 (SIRT3) in glioma stem cells (GSC) increases mitochondrial respiratory capacity and reduces production of reactive oxygen species. This metabolic regulation endowed GSCs with metabolic plasticity, facilitated adaptation to stress (particularly reduced nutrient supply), and maintained "stemness." Inactivation of TRAP1 or SIRT3 compromised their interdependent regulatory mechanisms, leading to metabolic alterations, loss of stemness, and suppression of tumor formation by GSC in vivo. Thus, targeting the metabolic mechanisms regulating interplay between TRAP1 and SIRT3 may provide a novel therapeutic option for intractable patients with GBM. SIGNIFICANCE: Discovery and functional analysis of a TRAP1-SIRT3 complex in glioma stem cells identify potential target proteins for glioblastoma treatment.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Proteínas de Choque Térmico HSP90/metabolismo , Células-Tronco Neoplásicas/patologia , Estresse Oxidativo , Sirtuína 3/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Feminino , Glioblastoma/metabolismo , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo
9.
Small ; 14(13): e1703734, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29412512

RESUMO

The deposition of preformed nanocluster beams onto suitable supports represents a new paradigm for the precise preparation of heterogeneous catalysts. The performance of the new materials must be validated in model catalytic reactions. It is shown that gold/copper (Au/Cu) nanoalloy clusters (nanoparticles) of variable composition, created by sputtering and gas phase condensation before deposition onto magnesium oxide powders, are highly active for the catalytic reduction of 4-nitrophenol in solution at room temperature. Au/Cu bimetallic clusters offer decreased catalyst cost compared with pure Au and the prospect of beneficial synergistic effects. Energy-dispersive X-ray spectroscopy coupled with aberration-corrected scanning transmission electron microscopy imaging confirms that the Au/Cu bimetallic clusters have an alloy structure with Au and Cu atoms randomly located. Reaction rate analysis shows that catalysts with approximately equal amounts of Au and Cu are much more active than Au-rich or Cu-rich clusters. Thus, the interplay between the Au and Cu atoms at the cluster surface appears to enhance the catalytic activity substantially, consistent with model density functional theory calculations of molecular binding energies. Moreover, the physically deposited clusters with Au/Cu ratio close to 1 show a 25-fold higher activity than an Au/Cu reference sample made by chemical impregnation.

10.
Theor Appl Genet ; 131(2): 461-476, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29181547

RESUMO

KEY MESSAGE: The Mendelian gene conferring resistance to Soybean mosaic virus Strain SC20 in soybean was fine-mapped onto a 79-kb segment on Chr.13 where two closely linked candidate genes were identified and qRT-PCR verified. Soybean mosaic virus (SMV) threatens the world soybean production, particularly in China. A country-wide SMV strain system composed of 22 strains was established in China, among which SC20 is a dominant strain in five provinces in Southern China. Resistance to SC20 was evaluated in parents, F1, F2 and the F2:7 RIL (recombinant inbred line) population derived from a cross between Qihuang-1 (resistant) and NN1138-2 (susceptible). The segregation ratio of resistant to susceptible in the populations suggested a single dominant gene involved in the resistance to SC20 in Qihuang-1. A "partial genome mapping strategy" was used to map the resistance gene on Chromosome 13. Linkage analysis between 178 RILs and genetic markers showed that the SC20-resistance gene located at 3.9 and 3.8 cM to the flanking markers BARCSOYSSR_13_1099 and BARCSOYSSR_13_1185 on Chromosome 13. Subsequently, a residual heterozygote segregating population with 346 individuals was developed by selfing four plants heterozygous at markers adjacent to the tentative SC20-resistance gene; then, the candidate region was delimited to a genomic interval of approximately 79 kb flanked by the new markers gm-ssr_13-14 and gm-indel_13-3. Among the seven annotated candidate genes in this region, two genes, Glyma.13G194700 and Glyma.13G195100, encoding Toll Interleukin Receptor-nucleotide-binding-leucine-rich repeat resistance proteins were identified as candidate resistance genes by quantitative real-time polymerase chain reaction and sequence analysis. The two closely linked genes work together to cause the phenotypic segregation as a single Mendelian gene. These results will facilitate marker-assisted selection, gene cloning and breeding for the resistance to SC20.


Assuntos
Resistência à Doença/genética , Genes de Plantas , Doenças das Plantas/genética , Potyvirus , Soja/genética , Sequência de Aminoácidos , China , Mapeamento Cromossômico , Genes Dominantes , Marcadores Genéticos , Fenótipo , Doenças das Plantas/virologia , Soja/virologia
11.
Cancer Lett ; 414: 181-189, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29154973

RESUMO

Despite expressing high levels of the epidermal growth factor receptor (EGFR), a majority of oral squamous cell carcinoma (OSCC) patients show limited response to cetuximab and ultimately develop drug resistance. However, mechanism underlying cetuximab resistance in OSCC is not clearly understood. Here, using a mouse orthotopic xenograft model of OSCC, we show that bone morphogenic protein-7-phosphorylated Smad-1, -5, -8 (BMP7-p-Smad1/5/8) signaling contributes to cetuximab resistance. Tumor cells isolated from the recurrent cetuximab-resistant xenograft models exhibited low EGFR expression but extremely high levels of p-Smad1/5/8. Treatment with the bone morphogenic protein receptor type 1 (BMPRI) inhibitor, DMH1 significantly reduced cetuximab-resistant OSCC tumor growth, and combined treatment of DMH1 and cetuximab remarkably reduced relapsed tumor growth in vivo. Importantly, p-Smad1/5/8 level was elevated in cetuximab-resistant patients and this correlated with poor prognosis. Collectively, our results indicate that the BMP7-p-Smad1/5/8 signaling is a key pathway to acquired cetuximab resistance, and demonstrate that combination therapy of cetuximab and a BMP signaling inhibitor as potentially a new therapeutic strategy for overcoming acquired resistance to cetuximab in OSCC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Bucais/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/antagonistas & inibidores , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Proteínas Morfogenéticas Ósseas/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Cetuximab/administração & dosagem , Receptores ErbB/metabolismo , Humanos , Camundongos Nus , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Pirazóis/administração & dosagem , Quinolinas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo
12.
Clin Cancer Res ; 24(2): 383-394, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29208670

RESUMO

Purpose: Normal stem cells tightly control self-renewal and differentiation during development, but their neoplastic counterparts, cancer stem cells (CSCs), sustain tumorigenicity both through aberrant activation of stemness and evasion of differentiation. Although regulation of CSC stemness has been extensively studied, the molecular mechanisms suppressing differentiation remain unclear.Experimental Design: We performed in silico screening and in vitro validation studies through Western blotting, qRT-PCR for treatment of WNT and SHH signaling inhibitors, and BMP signaling inducer with control and ID1-overexpressing cells. We also performed in vivo drug treatment assays with Balb/c nude mice.Results: Inhibitor of differentiation 1 (ID1) abrogated differentiation signals from bone morphogenetic protein receptor (BMPR) signaling in glioblastoma stem cells (GSCs) to promote self-renewal. ID1 inhibited BMPR2 expression through miRNAs, miR-17 and miR-20a, which are transcriptional targets of MYC. ID1 increases MYC expression by activating WNT and SHH signaling. Combined pharmacologic blockade of WNT and SHH signaling with BMP treatment significantly suppressed GSC self-renewal and extended survival of tumor-bearing mice.Conclusions: Collectively, our results suggested that ID1 simultaneously regulates stemness through WNT and SHH signaling and differentiation through BMPR-mediated differentiation signaling in GSCs, informing a novel therapeutic strategy of combinatorial targeting of stemness and differentiation. Clin Cancer Res; 24(2); 383-94. ©2017 AACR.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Glioma/metabolismo , Proteína 1 Inibidora de Diferenciação/metabolismo , Células-Tronco Neoplásicas/metabolismo , Transdução de Sinais , Animais , Antineoplásicos/farmacologia , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Glioma/genética , Glioma/patologia , Glioma/terapia , Humanos , Proteína 1 Inibidora de Diferenciação/genética , Camundongos , Camundongos Knockout , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Tolerância a Radiação , Transdução de Sinais/efeitos dos fármacos , Transcriptoma , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Theor Appl Genet ; 130(11): 2395-2410, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28825113

RESUMO

KEY MESSAGE: Rsc15, a novel locus underlying soybean resistance to SMV, was fine mapped to a 95-kb region on chromosome 6. The Rsc15- mediated resistance is likely attributed to the gene GmPEX14 , the relative expression of which was highly correlated with the accumulation of H 2 O 2 along with the activities of POD and CAT during the early stages of SMV infection in RN-9. Soybean mosaic virus (SMV) causes severe yield losses and seed quality deterioration in soybean [Glycine max (L.) Merr.] worldwide. A series of single dominant SMV resistance genes have been identified on respective soybean chromosomes 2, 13 and 14, while one novel locus, Rsc15, underlying resistance to the virulent SMV strain SC15 from soybean cultivar RN-9 has been recently mapped to a 14.6-cM region on chromosome 6. However, candidate gene has not yet been identified within this region. In the present study, we aimed to fine map the Rsc15 region and identify candidate gene(s) for this invaluable locus. High-resolution fine-mapping revealed that the Rsc15 gene was located in a 95-kb genomic region which was flanked by the two simple sequence repeat (SSR) markers SSR_06_17 and BARCSOYSSR_06_0835. Allelic sequence comparison and expression profile analysis of candidate genes inferred that the gene Glyma.06g182600 (designated as GmPEX14) was the best candidate gene attributing for the resistance of Rsc15, and that genes encoding receptor-like kinase (RLK) (i.e., Glyma.06g175100 and Glyma.06g184400) and serine/threonine kinase (STK) (i.e., Glyma.06g182900 and Glyma.06g183500) were also potential candidates. High correlations were established between the relative expression level of GmPEX14 and the hydrogen peroxide (H2O2) concentration and activities of catalase (CAT) and peroxidase (POD) during the early stages of SMV-SC15 infection in RN-9. The results of the present study will be useful in marker-assisted breeding for SMV resistance and will lead to further understanding of the molecular mechanisms of host resistance against SMV.


Assuntos
Resistência à Doença/genética , Doenças das Plantas/genética , Potyvirus , Soja/genética , Alelos , Mapeamento Cromossômico , Genes Dominantes , Genes de Plantas , Genótipo , Repetições de Microssatélites , Doenças das Plantas/virologia , Soja/virologia
14.
Cancer Res ; 77(18): 4973-4984, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28754668

RESUMO

Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPß, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NF-κB activation and further degraded DNA damage-inducible transcript 3 (GADD153) to induce C/EBPß expression, resulting in expression of the MES transcriptome. Downregulation of TGM2 decreased sphere-forming ability, tumor size, and radioresistance and survival in a xenograft mouse model through a loss of the MES signature. A TGM2-specific inhibitor GK921 blocked MES transdifferentiation and showed significant therapeutic efficacy in mouse models of GSC. Moreover, TGM2 expression was significantly increased in recurrent MES patients and inversely correlated with patient prognosis. Collectively, our results indicate that TGM2 is a key molecular switch of necrosis-induced MES transdifferentiation and an important therapeutic target for MES GBM. Cancer Res; 77(18); 4973-84. ©2017 AACR.


Assuntos
Neoplasias Encefálicas/patologia , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteínas de Ligação ao GTP/antagonistas & inibidores , Glioma/patologia , Células-Tronco Mesenquimais/patologia , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Transglutaminases/antagonistas & inibidores , Animais , Apoptose , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proliferação de Células , Transdiferenciação Celular , Feminino , Proteínas de Ligação ao GTP/metabolismo , Glioma/genética , Glioma/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Recidiva Local de Neoplasia/metabolismo , Células-Tronco Neoplásicas/metabolismo , Transglutaminases/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Oncotarget ; 7(48): 79854-79868, 2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27821801

RESUMO

TRIM71 (tripartite motif-containing 71) belongs to the TRIM-NHL protein family, which plays a conserved role in regulating early development and differentiation. However, the molecular functions of TRIM71 have remained largely unknown. Here, we explored the role of TRIM71 together with modulation of Lin28B-let-7-HMGA2 (high-mobility group AT-hook 2) signaling in tumorigenesis. TRIM71 overexpression opposed Lin28B-induced transformation in primary cells and inhibited tumor formation in a mouse model. Specific knockdown of TRIM71 expression increased cancer cell proliferation and invasion. Conversely, overexpression of wild-type TRIM71 in non-small cell lung carcinoma (NSCLC) cells in which Lin28B-let-7-HMGA2 signaling was conserved decreased both cancer cell phenotypes. More importantly, overexpression of an ubiquitin transfer activity-deficient TRIM71 mutant in NSCLC cells had no effect on proliferation or invasion, regardless of the conservation status of Lin28B-let-7-HMGA2 signaling. The tumorigenic inhibitory action of TRIM71 was antagonized by overexpression of the TRIM71 downstream targets, Lin28B and HMGA2. Furthermore, a bioinformatics analysis revealed that TRIM71 expression was downregulated in various types of cancer tissue from patients. Taken together, these data indicate that TRIM71 acts through post-transcriptional repression of Lin28B and subsequent modulation of let-7-HMGA2 signaling during tumorigenesis to potentially function as a tumor suppressor.


Assuntos
Carcinogênese/genética , Proteína HMGA2/genética , MicroRNAs/genética , Proteínas de Ligação a RNA/genética , Proteínas com Motivo Tripartido/fisiologia , Ubiquitina-Proteína Ligases/fisiologia , Animais , Células CACO-2 , Células Cultivadas , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Células HEK293 , Proteína HMGA2/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/metabolismo , Células NIH 3T3 , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais
16.
ACS Catal ; 6(9): 6008-6017, 2016 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-27818842

RESUMO

This report focuses on a novel strategy for the preparation of transition metal-MoS2 hybrid nanoclusters based on a one-step, dual-target magnetron sputtering, and gas condensation process demonstrated for Ni-MoS2. Aberration-corrected STEM images coupled with EDX analysis confirms the presence of Ni and MoS2 in the hybrid nanoclusters (average diameter = 5.0 nm, Mo:S ratio = 1:1.8 ± 0.1). The Ni-MoS2 nanoclusters display a 100 mV shift in the hydrogen evolution reaction (HER) onset potential and an almost 3-fold increase in exchange current density compared with the undoped MoS2 nanoclusters, the latter effect in agreement with reported DFT calculations. This activity is only reached after air exposure of the Ni-MoS2 hybrid nanoclusters, suggested by XPS measurements to originate from a Ni dopant atoms oxidation state conversion from metallic to 2+ characteristic of the NiO species active to the HER. Anodic stripping voltammetry (ASV) experiments on the Ni-MoS2 hybrid nanoclusters confirm the presence of Ni-doped edge sites and reveal distinctive electrochemical features associated with both doped Mo-edge and doped S-edge sites which correlate with both their thermodynamic stability and relative abundance.

17.
Cell Rep ; 16(6): 1629-1641, 2016 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-27477274

RESUMO

Inhibitor of differentiation 1 (ID1) is highly expressed in glioblastoma stem cells (GSCs). However, the regulatory mechanism responsible for its role in GSCs is poorly understood. Here, we report that ID1 activates GSC proliferation, self-renewal, and tumorigenicity by suppressing CULLIN3 ubiquitin ligase. ID1 induces cell proliferation through increase of CYCLIN E, a target molecule of CULLIN3. ID1 overexpression or CULLIN3 knockdown confers GSC features and tumorigenicity to murine Ink4a/Arf-deficient astrocytes. Proteomics analysis revealed that CULLIN3 interacts with GLI2 and DVL2 and induces their degradation via ubiquitination. Consistent with ID1 knockdown or CULLIN3 overexpression in human GSCs, pharmacologically combined control of GLI2 and ß-CATENIN effectively diminishes GSC properties. A ID1-high/CULLIN3-low expression signature correlates with a poor patient prognosis, supporting the clinical relevance of this signaling axis. Taken together, a loss of CULLIN3 represents a common signaling node for controlling the activity of intracellular WNT and SHH signaling pathways mediated by ID1.


Assuntos
Proteínas Culina/metabolismo , Glioblastoma/metabolismo , Proteína 1 Inibidora de Diferenciação/metabolismo , Células-Tronco Neoplásicas/metabolismo , Via de Sinalização Wnt/fisiologia , Animais , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Proteínas Hedgehog/metabolismo , Humanos , Camundongos , beta Catenina/metabolismo
18.
Faraday Discuss ; 188: 39-56, 2016 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-27152749

RESUMO

The generation of beams of atomic clusters in the gas phase and their subsequent deposition (in vacuum) onto suitable catalyst supports, possibly after an intermediate mass filtering step, represents a new and attractive approach for the preparation of model catalyst particles. Compared with the colloidal route to the production of pre-formed catalytic nanoparticles, the nanocluster beam approach offers several advantages: the clusters produced in the beam have no ligands, their size can be selected to arbitrarily high precision by the mass filter, and metal particles containing challenging combinations of metals can be readily produced. However, until now the cluster approach has been held back by the extremely low rates of metal particle production, of the order of 1 microgram per hour. This is more than sufficient for surface science studies but several orders of magnitude below what is desirable even for research-level reaction studies under realistic conditions. In this paper we describe solutions to this scaling problem, specifically, the development of two new generations of cluster beam sources, which suggest that cluster beam yields of grams per hour may ultimately be feasible. Moreover, we illustrate the effectiveness of model catalysts prepared by cluster beam deposition onto agitated powders in the selective hydrogenation of 1-pentyne (a gas phase reaction) and 3-hexyn-1-ol (a liquid phase reaction). Our results for elemental Pd and binary PdSn and PdTi cluster catalysts demonstrate favourable combinations of yield and selectivity compared with reference materials synthesised by conventional methods.

20.
Brain ; 138(Pt 9): 2553-70, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26121981

RESUMO

Upregulation of microRNA-21 (miR-21) is known to be strongly associated with the proliferation, invasion, and radio-resistance of glioma cells. However, the regulatory mechanism that governs the biogenesis of miR-21 in glioma is still unclear. Here, we demonstrate that the DEAD-box RNA helicase, DDX23, promotes miR-21 biogenesis at the post-transcriptional level. The expression of DDX23 was enhanced in glioma tissues compared to normal brain, and expression level of DDX23 was highly associated with poor survival of glioma patients. Specific knockdown of DDX23 expression suppressed glioma cell proliferation and invasion in vitro and in vivo, which is similar to the function of miR-21. We found that DDX23 increased the level of miR-21 by promoting primary-to-precursor processing of miR-21 through an interaction with the Drosha microprocessor. Mutagenesis experiments critically demonstrated that the helicase activity of DDX23 was essential for the processing (cropping) of miR-21, and we further found that ivermectin, a RNA helicase inhibitor, decreased miR-21 levels by potentially inhibiting DDX23 activity and blocked invasion and cell proliferation. Moreover, treatment of ivermectin decreased glioma growth in mouse xenografts. Taken together, these results suggest that DDX23 plays an essential role in glioma progression, and might thus be a potential novel target for the therapeutic treatment of glioma.


Assuntos
Neoplasias Encefálicas/metabolismo , RNA Helicases DEAD-box/metabolismo , Glioma/metabolismo , MicroRNAs/biossíntese , Animais , Antiparasitários/farmacologia , Neoplasias Encefálicas/genética , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , RNA Helicases DEAD-box/genética , Bases de Dados Factuais/estatística & dados numéricos , Glioma/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Imunoprecipitação , Marcação In Situ das Extremidades Cortadas , Ivermectina/farmacologia , Camundongos , MicroRNAs/genética , RNA Interferente Pequeno/farmacologia , Transdução Genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto
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