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2.
Mol Cancer ; 20(1): 98, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34325714

RESUMO

BACKGROUND: Breast cancer (BC) has a marked tendency to spread to the bone, resulting in significant skeletal complications and mortality. Recently, circular RNAs (circRNAs) have been reported to contribute to cancer initiation and progression. However, the function and mechanism of circRNAs in BC bone metastasis (BC-BM) remain largely unknown. METHODS: Bone-metastatic circRNAs were screened using circRNAs deep sequencing and validated using in situ hybridization in BC tissues with or without bone metastasis. The role of circIKBKB in inducing bone pre-metastatic niche formation and bone metastasis was determined using osteoclastogenesis, immunofluorescence and bone resorption pit assays. The mechanism underlying circIKBKB-mediated activation of NF-κB/bone remodeling factors signaling and EIF4A3-induced circIKBKB were investigated using RNA pull-down, luciferase reporter, chromatin isolation by RNA purification and enzyme-linked immunosorbent assays. RESULTS: We identified that a novel circRNA, circIKBKB, was upregulated significantly in bone-metastatic BC tissues. Overexpressing circIKBKB enhanced the capability of BC cells to induce formation of bone pre-metastatic niche dramatically by promoting osteoclastogenesis in vivo and in vitro. Mechanically, circIKBKB activated NF-κB pathway via promoting IKKß-mediated IκBα phosphorylation, inhibiting IκBα feedback loop and facilitating NF-κB to the promoters of multiple bone remodeling factors. Moreover, EIF4A3, acted acting as a pre-mRNA splicing factor, promoted cyclization of circIKBKB by directly binding to the circIKBKB flanking region. Importantly, treatment with inhibitor eIF4A3-IN-2 reduced circIKBKB expression and inhibited breast cancer bone metastasis effectively. CONCLUSION: We revealed a plausible mechanism for circIKBKB-mediated NF-κB hyperactivation in bone-metastatic BC, which might represent a potential strategy to treat breast cancer bone metastasis.

3.
Cancer Res ; 81(14): 3835-3848, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34049973

RESUMO

Mitochondrial dynamics play vital roles in the tumorigenicity and malignancy of various types of cancers by promoting the tumor-initiating potential of cancer cells, suggesting that targeting crucial factors that drive mitochondrial dynamics may lead to promising anticancer therapies. In the current study, we report that overexpression of mitochondrial fission factor (MFF), which is upregulated significantly in liver cancer-initiating cells (LCIC), promotes mitochondrial fission and enhances stemness and tumor-initiating capability in non-LCICs. MFF-induced mitochondrial fission evoked mitophagy and asymmetric stem cell division and promoted a metabolic shift from oxidative phosphorylation to glycolysis that decreased mitochondrial reactive oxygen species (ROS) production, which prevented ROS-mediated degradation of the pluripotency transcription factor OCT4. CRISPR affinity purification in situ of regulatory elements showed that T-box transcription factor 19 (TBX19), which is overexpressed uniquely in LCICs compared with non-LCICs and liver progenitor cells, forms a complex with PRMT1 on the MFF promoter in LCICs, eliciting epigenetic histone H4R3me2a/H3K9ac-mediated transactivation of MFF. Targeting PRMT1 using furamidine, a selective pharmacologic inhibitor, suppressed TBX19-induced mitochondrial fission, leading to a profound loss of self-renewal potential and tumor-initiating capacity of LCICs. These findings unveil a novel mechanism underlying mitochondrial fission-mediated cancer stemness and suggest that regulation of mitochondrial fission via inhibition of PRMT1 may be an attractive therapeutic option for liver cancer treatment. SIGNIFICANCE: These findings show that TBX19/PRMT1 complex-mediated upregulation of MFF promotes mitochondrial fission and tumor-initiating capacity in liver cancer cells, identifying PRMT1 as a viable therapeutic target in liver cancer.

4.
Adv Sci (Weinh) ; 8(4): 2001961, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33643786

RESUMO

The incidence of bone metastases in hepatocellular carcinoma (HCC) has increased prominently over the past decade owing to the prolonged overall survival of HCC patients. However, the mechanisms underlying HCC bone-metastasis remain largely unknown. In the current study, HCC-secreted lectin galactoside-binding soluble 3 (LGALS3) is found to be significantly upregulated and correlates with shorter bone-metastasis-free survival of HCC patients. Overexpression of LGALS3 enhances the metastatic capability of HCC cells to bone and induces skeletal-related events by forming a bone pre-metastatic niche via promoting osteoclast fusion and podosome formation. Mechanically, ubiquitin ligaseRNF219-meidated α-catenin degradation prompts YAP1/ß-catenin complex-dependent epigenetic modifications of LGALS3 promoter, resulting in LGALS3 upregulation and metastatic bone diseases. Importantly, treatment with verteporfin, a clinical drug for macular degeneration, decreases LGALS3 expression and effectively inhibits skeletal complications of HCC. These findings unveil a plausible role for HCC-secreted LGALS3 in pre-metastatic niche and can suggest a promising strategy for clinical intervention in HCC bone-metastasis.

5.
Nat Commun ; 11(1): 5127, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046716

RESUMO

Despite the importance of AKT overactivation in tumor progression, results from clinical trials of various AKT inhibitors remain suboptimal, suggesting that AKT-driven tumor metastasis needs to be further understood. Herein, based on long non-coding RNA (lncRNA) profiling induced by active AKT, we identify that VAL (Vimentin associated lncRNA, LINC01546), which is directly induced by AKT/STAT3 signaling, functions as a potent pro-metastatic molecule and is essential for active AKT-induced tumor invasion, metastasis and anoikis resistance in lung adenocarcinoma (LAD). Impressively, chemosynthetic siRNAs against VAL shows great therapeutic potential in AKT overactivation-driven metastasis. Interestingly, similar to activated AKT in LAD cells, although unable to induce epithelial-mesenchymal transition (EMT), VAL exerts potent pro-invasive and pro-metastatic effects through directly binding to Vimentin and competitively abrogating Trim16-depedent Vimentin polyubiquitination and degradation. Taken together, our study provides an interesting demonstration of a lncRNA-mediated mechanism for active AKT-driven EMT-independent LAD metastasis and indicates the great potential of targeting VAL or Vimentin stability as a therapeutic approach.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Transição Epitelial-Mesenquimal , Neoplasias Pulmonares/metabolismo , RNA Longo não Codificante/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Vimentina/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/fisiopatologia , Animais , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/fisiopatologia , Camundongos , Metástase Neoplásica , Proteólise , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , Vimentina/genética
6.
Cancer Res ; 80(4): 675-688, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31948940

RESUMO

Suppression of gluconeogenesis elevates glycolysis and is commonly observed in tumors derived from gluconeogenic tissues including liver and kidney, yet the definitive regulatory mechanism remains elusive. Here, we screened an array of transcription regulators and identified the enhancer of zeste homolog 2 (EZH2) as a key factor that inhibits gluconeogenesis in cancer cells. Specifically, EZH2 repressed the expression of a rate-limiting gluconeogenic enzyme fructose-1, 6-bisphosphatase 1 (FBP1) and promoted tumor growth primarily through FBP1 suppression. Furthermore, EZH2 was upregulated by genotoxins that commonly induce hepatic and renal tumorigenesis. Genotoxin treatments augmented EZH2 acetylation, leading to reduced association between EZH2 and its E3 ubiquitin ligase SMURF2. Consequently, EZH2 became less ubiquitinated and more stabilized, promoting FBP1 attenuation and tumor formation. Intriguingly, FBP1 physically interacted with EZH2, competed for EZH2 binding, and dissembled the polycomb complex. Therefore, FBP1 suppresses polycomb-initiated transcriptional responses and constitutes a double-negative feedback loop indispensable for EZH2-promoted tumorigenesis. Finally, EZH2 and FBP1 levels were inversely correlated in tumor tissues and accurately predicted patient survival. This work reveals an unexpected cross-talk between epigenetic and metabolic events, and identifies a new feedback circuitry that highlights EZH2 inhibitors as liver and kidney cancer therapeutics. SIGNIFICANCE: A novel feedback loop involving EZH2 and suppression of the gluconeogenesis enzyme FBP1 promotes hepatocellular cancer growth.See related commentary by Leithner, p. 657.


Assuntos
Gluconeogênese , Neoplasias Renais/genética , Carcinogênese , Linhagem Celular Tumoral , Proteína Potenciadora do Homólogo 2 de Zeste , Epigênese Genética , Frutose , Regulação Neoplásica da Expressão Gênica , Humanos
7.
Cancer Res ; 79(22): 5785-5798, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31530567

RESUMO

The N6-methyladenosine (m6A) modification influences various mRNA metabolic events and tumorigenesis, however, its functions in nonsense-mediated mRNA decay (NMD) and whether NMD detects induced carcinogenesis pathways remain undefined. Here, we showed that the m6A methyltransferase METTL3 sustained its oncogenic role by modulating NMD of splicing factors and alternative splicing isoform switches in glioblastoma (GBM). Methylated RNA immunoprecipitation-seq (MeRIP-seq) analyses showed that m6A modification peaks were enriched at metabolic pathway-related transcripts in glioma stem cells (GSC) compared with neural progenitor cells. In addition, the clinical aggressiveness of malignant gliomas was associated with elevated expression of METTL3. Furthermore, silencing METTL3 or overexpressing dominant-negative mutant METTL3 suppressed the growth and self-renewal of GSCs. Integrated transcriptome and MeRIP-seq analyses revealed that downregulating the expression of METTL3 decreased m6A modification levels of serine- and arginine-rich splicing factors (SRSF), which led to YTHDC1-dependent NMD of SRSF transcripts and decreased SRSF protein expression. Reduced expression of SRSFs led to larger changes in alternative splicing isoform switches. Importantly, the phenotypes mediated by METTL3 deficiency could be rescued by downregulating BCL-X or NCOR2 isoforms. Overall, these results establish a novel function of m6A in modulating NMD and uncover the mechanism by which METTL3 promotes GBM tumor growth and progression. SIGNIFICANCE: These findings establish the oncogenic role of m6A writer METTL3 in glioblastoma stem cells.


Assuntos
Adenosina/análogos & derivados , Glioblastoma/metabolismo , Degradação do RNAm Mediada por Códon sem Sentido/fisiologia , RNA Mensageiro/metabolismo , Adenosina/metabolismo , Processamento Alternativo/fisiologia , Animais , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Glioma/metabolismo , Humanos , Metiltransferases/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células-Tronco Neurais/metabolismo , Transcriptoma/fisiologia
8.
Nat Commun ; 10(1): 3761, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434880

RESUMO

The mechanisms underlying how cells subjected to genotoxic stress reestablish reduction-oxidation (redox) homeostasis to scavenge genotoxic stress-induced reactive oxygen species (ROS), which maintains the physiological function of cellular processes and cell survival, remain unclear. Herein, we report that, via a TCF-independent mechanism, genotoxic stress induces the enrichment of ß-catenin in chromatin, where it forms a complex with ATM phosphorylated-JDP2 and PRMT5. This elicits histone H3R2me1/H3R2me2s-induced transcriptional activation by the recruitment of the WDR5/MLL methyltransferase complexes and concomitant H3K4 methylation at the promoters of multiple genes in GSH-metabolic cascade. Treatment with OICR-9429, a small-molecule antagonist of the WDR5-MLL interaction, inhibits the ß-catenin/JDP2/PRMT5 complex-reestablished GSH metabolism, leading to a lethal increase in the already-elevated levels of ROS in the genotoxic-agent treated cancer cells. Therefore, our results unveil a plausible role for ß-catenin in reestablishing redox homeostasis upon genotoxic stress and shed light on the mechanisms of inducible chemotherapy resistance in cancer.


Assuntos
Dano ao DNA/fisiologia , Glutationa/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Repressoras/metabolismo , beta Catenina/metabolismo , Células A549 , Animais , Compostos de Bifenilo/farmacologia , Linhagem Celular Tumoral , Cromatina , Di-Hidropiridinas/farmacologia , Feminino , Glutationa/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Homeostase , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteína de Leucina Linfoide-Mieloide/metabolismo , Neoplasias/metabolismo , Regiões Promotoras Genéticas , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Ativação Transcricional
9.
Clin Infect Dis ; 67(suppl_2): S217-S224, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30423047

RESUMO

Objectives: mcr-1-mediated colistin resistance in bacteria is concerning, as colistin is used in treating multidrug-resistant bacterial infections. And mcr-1-producing bacteria have been identified in multiple sources. Up to 248 million people use public transportation daily in China, however; public transportation hasn't been studied as a potential source of community-based transmission of mcr-1. Herein we investigated mcr-1-producing isolates from public transportation and explored the genomic characteristics of them. Methods: Surface samples were collected from public transportation in Guangzhou, China, from October 2016 to April 2017. Polymerase chain reaction was performed to detect mcr-1 gene, plasmid replicon type and phylogenetic group. Minimum inhibitory concentrations (MICs) were determined by microdilution method. S1-nuclease digestion and pulsed-field gel electrophoresis (S1-PFGE) and Southern blotting were performed with mcr-1-harboring plasmids. Whole-genome sequencing was performed with mcr-1-producing isolates. Results: Of the 737 samples with bacterial growth, 26 isolates were positive for mcr-1, including 23 Escherichia coli and 3 Klebsiella pneumoniae isolates. The E. coli isolates belonged to phylogroups A and B1. Most mcr-1-producing isolates were resistant to ampicillin (25), cefotaxime (21), fosfomycin (16), and gentamicin (15). S1-PFGE, Southern blotting and replicon typing showed that mcr-1 was mainly located on ~33.3 kb to ~220 kb IncX4, IncI2 and IncHI2 plasmids in E. coli, while located on ~33.3 kb untyped plasmid in K. pneumoniae. Several sequence types (ST), including ST2253, ST101, ST10 complex and ST37, were revealed. Between 53 and 66 (mean = 61.8) resistance genes were identified among mcr-1-producing isolates. Conclusions: Public transportation may serve as a source of mcr-1-producing bacteria.


Assuntos
Antibacterianos/farmacologia , Infecções por Enterobacteriaceae/transmissão , Enterobacteriaceae/efeitos dos fármacos , Transportes , China/epidemiologia , Colistina/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Enterobacteriaceae/genética , Infecções por Enterobacteriaceae/epidemiologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/genética , Testes de Sensibilidade Microbiana , Veículos Automotores , Plasmídeos/genética , Reação em Cadeia da Polimerase , Saúde Pública , Ferrovias , Sequenciamento Completo do Genoma
10.
Stem Cell Reports ; 10(4): 1324-1339, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29503092

RESUMO

Yin Yang 1 (YY1) regulates early embryogenesis and adult tissue formation. However, the role of YY1 in stem cell regulation remains unclear. YY1 has a Polycomb group (PcG) protein-dependent role in mammalian cells. The PcG-independent functions of YY1 are also reported, although their underlying mechanism is still undefined. This paper reports the role of YY1 and BAF complex in the OCT4-mediated pluripotency network in mouse embryonic stem cells (mESCs). The interaction between YY1 and BAF complex promotes mESC proliferation and pluripotency. Knockdown of Yy1 or Smarca4, the core component of the BAF complex, downregulates pluripotency markers and upregulates several differentiation markers. Moreover, YY1 enriches at both promoter and super-enhancer regions to stimulate transcription. Thus, this study elucidates the role of YY1 in regulating pluripotency through its interaction with OCT4 and the BAF complex and the role of BAF complex in integrating YY1 into the core pluripotency network.


Assuntos
Elementos Facilitadores Genéticos/genética , Células-Tronco Embrionárias Murinas/metabolismo , Complexos Multiproteicos/metabolismo , Regiões Promotoras Genéticas , Transcrição Genética , Fator de Transcrição YY1/metabolismo , Animais , Linhagem Celular , Linhagem da Célula , Proliferação de Células , Redes e Vias Metabólicas , Camundongos , Modelos Biológicos , Fator 3 de Transcrição de Octâmero/metabolismo , Ligação Proteica , Mapas de Interação de Proteínas
11.
Nucleic Acids Res ; 45(15): 8647-8660, 2017 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-28911119

RESUMO

mRNA 3' end processing is an essential step in gene expression. It is well established that canonical eukaryotic pre-mRNA 3' processing is carried out within a macromolecular machinery consisting of dozens of trans-acting proteins. However, it is unknown whether RNAs play any role in this process. Unexpectedly, we found that a subset of small nucleolar RNAs (snoRNAs) are associated with the mammalian mRNA 3' processing complex. These snoRNAs primarily interact with Fip1, a component of cleavage and polyadenylation specificity factor (CPSF). We have functionally characterized one of these snoRNAs and our results demonstrated that the U/A-rich SNORD50A inhibits mRNA 3' processing by blocking the Fip1-poly(A) site (PAS) interaction. Consistently, SNORD50A depletion altered the Fip1-RNA interaction landscape and changed the alternative polyadenylation (APA) profiles and/or transcript levels of a subset of genes. Taken together, our data revealed a novel function for snoRNAs and provided the first evidence that non-coding RNAs may play an important role in regulating mRNA 3' processing.


Assuntos
Processamento de Terminações 3' de RNA/genética , RNA Mensageiro/metabolismo , RNA Nucleolar Pequeno/fisiologia , Fator de Especificidade de Clivagem e Poliadenilação/metabolismo , Regulação da Expressão Gênica , Células HeLa , Humanos , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Poli A/metabolismo , Ligação Proteica , RNA Nucleolar Pequeno/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo
12.
Neural Regen Res ; 8(12): 1122-31, 2013 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-25206406

RESUMO

The astrocyte is a critical regulator of neuronal survival after ischemic brain injury. Electroacupuncture may be an effective therapy for cerebral ischemia, as electroacupuncture frequency can affect the structural integrity of astrocytes. In this study, a rat model of middle cerebral artery occlusion established using the modified thread embolism method was treated with electroacupuncture of the bilateral Quchi (LI11) and Zusanli (ST36) at 15, 30, and 100 Hz frequencies. Behavioral testing, immunohistochemistry and electron microscopy were used to explore the effect of these electroacupuncture frequencies used on maintaining the structural integrity of ischemic brain tissue. Compared with the model and 100 Hz electroacupuncture groups, the 15 and 30 Hz electroacupuncture groups displayed decreased neurological deficit scores, as evaluated by the "Longa" method, significantly increased glial fibrillary acidic protein expression, and alleviated ultrastructural damage of astrocytes at the edge of the infarct. Our experimental findings indicate that 15 and 30 Hz electroacupuncture intervention can favorably maintain the structural integrity of astrocytes and play a protective role in cerebral ischemic injury. Astrocyte structural integrity may be the mechanism underlying acupuncture production of ischemic tolerance.

13.
Zhongguo Zhen Jiu ; 31(1): 55-9, 2011 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-21355160

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture on the neural plasticity in rats with cerebral infarction and investigate its mechanism. METHODS: Sixty rats were randomly divided into a sham operation group, an acupuncture group and a non-acupuncture group, and each group was randomly divided into a 1-day subgroup, a 7-day subgroup and a 14-day subgroup. Cerebral infarction model was induced by the thread embolism method. The rats in the acupuncture group were treated by electroacupuncture at "Zusanli" (ST 36) and "Neiguan" (PC 6) for 20 minutes, once each day, while the rats in the sham operation group and the non-acupuncture group were just bound and fixed at the same time without acupuncture treatment. Neurological defects were assessed by Neurological Severity Score (NSS) and the changes of the expression of growth associated protein 43 (GAP-43) in peripheral nerve around cerebral infarction area were detected by immunohistochemistry technique. RESULTS: The expression of the positive cells of GAP-43 around cerebral infarction area showed no significant distinction among the three groups at 1st day (P > 0.05), while the GAP-43 expression level of around cerebral infarction area in the acupuncture group (IOD:8. 990 1 +/- 0.098 7, 5.816 1 +/- 0.204 6) were significant higher than those in the sham operation group (IOD: 1.300 2 +/- 0.093 3, 1.362 6 +/- 0.216 6) and in the non-acupuncture group (IOD: 2.753 4 +/- 0.0875, 1.616 5 +/- 0.186 8) at 7th day and 14th day, respectively (all P < 0.01). CONCLUSION: Electroacupuncture at "Zusanli" (ST 36) and "Neiguan" (PC 6) can improve the neural function and promote its remodeling in rats with cerebral infarction and the relevant mechanisms may be involved in enhancement of GAP-43 expressions around ischemic region.


Assuntos
Pontos de Acupuntura , Infarto Cerebral/genética , Infarto Cerebral/terapia , Eletroacupuntura , Proteína GAP-43/genética , Animais , Infarto Cerebral/metabolismo , Modelos Animais de Doenças , Proteína GAP-43/metabolismo , Humanos , Masculino , Distribuição Aleatória , Ratos
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