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1.
Nucleic Acids Res ; 47(15): 7753-7766, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31340025

RESUMO

MicroRNAs (miRNAs) are short, noncoding RNAs that regulate gene expression by suppressing mRNA translation and reducing mRNA stability. A miRNA can potentially bind many mRNAs, thereby affecting the expression of oncogenes and tumor suppressor genes as well as the activity of whole pathways. The promise of miRNA therapeutics in cancer is to harness this evolutionarily conserved mechanism for the coordinated regulation of gene expression, and thus restoring a normal cell phenotype. However, the promiscuous binding of miRNAs can provoke unwanted off-target effects, which are usually caused by high-dose single-miRNA treatments. Thus, it is desirable to develop miRNA therapeutics with increased specificity and efficacy. To achieve that, we propose the concept of miRNA cooperativity in order to exert synergistic repression on target genes, thus lowering the required total amount of miRNAs. We first review miRNA therapies in clinical application. Next, we summarize the knowledge on the molecular mechanism and biological function of miRNA cooperativity and discuss its application in cancer therapies. We then propose and discuss a systems biology approach to investigate miRNA cooperativity for the clinical setting. Altogether, we point out the potential of miRNA cooperativity to reduce off-target effects and to complement conventional, targeted, or immune-based therapies for cancer.


Assuntos
Antineoplásicos/uso terapêutico , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias/terapia , RNA Neoplásico/genética , Biologia de Sistemas/métodos , Antagomirs/genética , Antagomirs/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Quimioterapia Adjuvante/métodos , Redes Reguladoras de Genes , Humanos , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/agonistas , RNA Neoplásico/antagonistas & inibidores , RNA Neoplásico/metabolismo , Bibliotecas de Moléculas Pequenas/uso terapêutico , Proteínas Supressoras de Tumor/agonistas , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
2.
J Biosci ; 44(2)2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31180057

RESUMO

Cervical cancer (CC) is one of the most common female malignancies in the world. Although paclitaxel (PTX) is a critical chemotherapy agent for the treatment of CC, its treatment outcome is limited by the development of drug resistance. The present study aims to define the role of long non-coding RNA (lncRNA) LINC00511 in the progression of CC with the involvement of cell proliferation, apoptosis and resistance to PTX in Hela/PTX cells. CC and adjacent normal tissue samples were collected from 84 patients with CC, and used to determine LINC0051 expression. PTX-resistant Hela/PTX cell line was constructed, in which LINC0051 was overexpressed or silenced to further investigate the effect of LINC00511 on PTX-resistant Hela/PTX cell viability, proliferation, migration, invasion, cell cycle, apoptosis and resistance of CC cells to PTX. The expression of Bcl-2, Bax, cleaved-caspase-3, matrix metalloproteinase (MMP)-2, MMP-9, multidrug resistance protein 1 (MRP1) and P-glycoprotein (P-GP) was also assessed. High-expression of LINC00511 was found in CC with its close association with the tumor stage, tumor size and lymph node metastasis. After silencing LINC00511 expression, the expression of MRP1, P-GP, Bcl-2, MMP-2 and MMP-9 was decreased, while Bax and cleaved-caspase-3 increased with more CC cells arrested at G1 phase. Furthermore, silencing of LINC00511 could suppress cell resistance to PTX, cell viability, cell proliferation, migration and invasion yet promoted cell apoptosis in PTX-resistant Hela/PTX cells. Collectively, our findings demonstrate that silencing of LINC00511 could inhibit CC cell resistance to PTX, cell proliferation, migration and invasion, and promote cell apoptosis in CC. Silencing of LINC00511 provides a novel therapeutic target for CC.


Assuntos
Adenocarcinoma/genética , Carcinoma de Células Escamosas/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/genética , Neoplasias do Colo do Útero/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Adulto , Idoso , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/cirurgia , Caspase 3/genética , Caspase 3/metabolismo , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Estadiamento de Neoplasias , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Paclitaxel/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/cirurgia , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
3.
RNA ; 25(8): 948-962, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31076459

RESUMO

CRISPR-Cas systems are a class of adaptive immune systems in prokaryotes that use small CRISPR RNAs (crRNAs) in conjunction with CRISPR-associated (Cas) nucleases to recognize and degrade foreign nucleic acids. Recent studies have revealed that Type III CRISPR-Cas systems synthesize second messenger molecules previously unknown to exist in prokaryotes, cyclic oligoadenylates (cOA). These molecules activate the Csm6 nuclease to promote RNA degradation and may also coordinate additional cellular responses to foreign nucleic acids. Although cOA production has been reconstituted and characterized for a few bacterial and archaeal Type III systems, cOA generation and its regulation have not been explored for the Staphylococcus epidermidis Type III-A CRISPR-Cas system, a longstanding model for CRISPR-Cas function. Here, we demonstrate that this system performs Mg2+-dependent synthesis of 3-6 nt cOA. We show that activation of cOA synthesis is perturbed by single nucleotide mismatches between the crRNA and target RNA at discrete positions, and that synthesis is antagonized by Csm3-mediated target RNA cleavage. Altogether, our results establish the requirements for cOA production in a model Type III CRISPR-Cas system and suggest a natural mechanism to dampen immunity once the foreign RNA is destroyed.


Assuntos
Nucleotídeos de Adenina/metabolismo , Proteínas Associadas a CRISPR/metabolismo , Oligorribonucleotídeos/metabolismo , RNA Bacteriano/metabolismo , Staphylococcus epidermidis/metabolismo , Nucleotídeos de Adenina/biossíntese , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Proteínas Associadas a CRISPR/química , Sistemas CRISPR-Cas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Magnésio/metabolismo , Modelos Moleculares , Oligorribonucleotídeos/biossíntese , Polimorfismo de Nucleotídeo Único , Sistemas do Segundo Mensageiro
4.
Mol Cancer ; 18(1): 82, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30953511

RESUMO

BACKGROUND: Gallbladder cancer is the most common biliary tract malignancy and not sensitive to chemotherapy. Autophagy is an important factor prolonging the survival of cancer cells under chemotherapeutic stress. We aimed to investigate the role of long non-coding RNAs (lncRNAs) in autophagy and chemoresistance of gallbladder cancer cells. METHODS: We established doxorubicin (Dox)-resistant gallbladder cancer cells and used microarray analysis to compare the expression profiles of lncRNAs in Dox-resistant gallbladder cancer cells and their parental cells. Knockdown or exogenous expression of lncRNA combined with in vitro and in vivo assays were performed to prove the functional significance of lncRNA. The effects of lncRNA on autophagy were assessed by stubRFP-sensGFP-LC3 and western blot. We used RNA pull-down and mass spectrometry analysis to identify the target proteins of lncRNA. RESULTS: The drug-resistant property of gallbladder cancer cells is related to their enhanced autophagic activity. And we found a lncRNA ENST00000425894 termed gallbladder cancer drug resistance-associated lncRNA1 (GBCDRlnc1) that serves as a critical regulator in gallbladder cancer chemoresistance. Furthermore, we discovered that GBCDRlnc1 is upregulated in gallbladder cancer tissues. Knockdown of GBCDRlnc1, via inhibiting autophagy at initial stage, enhanced the sensitivity of Dox-resistant gallbladder cancer cells to Dox in vitro and in vivo. Mechanically, we identified that GBCDRlnc1 interacts with phosphoglycerate kinase 1 and inhibits its ubiquitination in Dox-resistant gallbladder cancer cells, which leads to the down-regulation of autophagy initiator ATG5-ATG12 conjugate. CONCLUSIONS: Our findings established that the chemoresistant driver GBCDRlnc1 might be a candidate therapeutic target for the treatment of advanced gallbladder cancer.


Assuntos
Autofagia/genética , Neoplasias da Vesícula Biliar/genética , Regulação Neoplásica da Expressão Gênica , Fosfoglicerato Quinase/genética , RNA Longo não Codificante/genética , Idoso , Animais , Antibióticos Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Proteína 12 Relacionada à Autofagia/genética , Proteína 12 Relacionada à Autofagia/metabolismo , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/patologia , Humanos , Masculino , Camundongos , Camundongos Nus , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Fosfoglicerato Quinase/metabolismo , RNA Longo não Codificante/agonistas , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Ubiquitinação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Mol Cancer ; 18(1): 84, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30961617

RESUMO

BACKGROUND: Long noncoding RNAs (lncRNAs), defined as the transcripts longer than 200 nt without protein-coding capacity, have been found to be aberrantly expressed in diverse human diseases including cancer. A reciprocal translocation between chromosome 9 and 22 generates the chimeric Bcr-Abl oncogene, which is associated with several hematological malignancies. However, the functional relevance between aberrantly expressed lncRNAs and Bcr-Abl-mediated leukemia remains obscure. METHODS: LncRNA cDNA microarray was used to identify novel lncRNAs involved in Bcr-Abl-mediated cellular transformation. To study the functional relevance of novel imatinib-upregulated lncRNA (IUR) family in Abl-induced tumorigenesis, Abl-transformed cell survival and xenografted tumor growth in mice was evaluated. Primary bone marrow transformation and in vivo leukemia transplant using lncRNA-IUR knockdown (KD) transgenic mice were further conducted to corroborate the role of lncRNA-IUR in Abl-induced tumorigenesis. Transcriptome RNA-seq, Western blot, RNA pull down and RNA Immunoprecipitation (RIP) were employed to determine the mechanisms by which lncRNA-IUR-5 regulates Bcr-Abl-mediated tumorigenesis. RESULTS: We identified a conserved lncRNA-IUR family as a key negative regulator of Bcr-Abl-induced tumorigenesis. Increased expression of lncRNA-IUR was detected in both human and mouse Abl-transformed cells upon imatinib treatment. In contrast, reduced expression of lncRNA-IUR was observed in the peripheral blood lymphocytes derived from Bcr-Abl-positive acute lymphoblastic leukemia (ALL) patients compared to normal subjects. Knockdown of lncRNA-IUR remarkably promoted Abl-transformed leukemic cell survival and xenografted tumor growth in mice, whereas overexpression of lncRNA-IUR had opposite effects. Also, silencing murine lncRNA-IUR promoted Bcr-Abl-mediated primary bone marrow transformation and Abl-transformed leukemia cell survival in vivo. Besides, knockdown of murine lncRNA-IUR in transgenic mice provided a favorable microenvironment for development of Abl-mediated leukemia. Finally, we demonstrated that lncRNA-IUR-5 suppressed Bcr-Abl-mediated tumorigenesis by negatively regulating STAT5-mediated expression of CD71. CONCLUSIONS: The results suggest that lncRNA-IUR may act as a critical tumor suppressor in Bcr-Abl-mediated tumorigenesis by suppressing the STAT5-CD71 pathway. This study provides new insights into functional involvement of lncRNAs in leukemogenesis.


Assuntos
Antígenos CD/genética , Proteínas de Fusão bcr-abl/genética , Regulação Neoplásica da Expressão Gênica , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , RNA Longo não Codificante/genética , Receptores da Transferrina/genética , Fator de Transcrição STAT5/genética , Adolescente , Adulto , Animais , Antígenos CD/metabolismo , Antineoplásicos/farmacologia , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Pré-Escolar , Feminino , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Camundongos , Camundongos Nus , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , RNA Longo não Codificante/agonistas , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores da Transferrina/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Kaohsiung J Med Sci ; 35(5): 277-283, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30897301

RESUMO

MicroRNA-26a (miR-26a) has been reported to be involved in the tumorigenesis of several tumors, but its biological function and molecular mechanism in multiple myeloma (MM) are still unknown. In this study, we found that overexpression of miR-26a obviously inhibited MM cell growth, and delayed tumor growth in xenografts. Further studies showed that overexpression of miR-26a induced cell cycle arrest at G0/G1 phase in MM cells. MiR-26a mimic down-regulated the expression levels of CDK6 and E2F1, but up-regulated p53 and p21 expression. In contrast, overexpression of CDK6 decreased the effect of miR-26a mimic on MM cell survival. Moreover, miR-26a targeted CDK6 mRNA and thus suppressed CDK6 protein expression. Overexpression of miR-26a also enhanced the cytotoxic action of doxorubicin against MM. These results demonstrated that miR-26a was involved in the development of MM through regulating CDK6 signaling pathway, and indicated that miR-26a could be as a novel target for anti-tumor therapy in clinic as a single strategy or in combination with other anti-tumor drugs in MM.


Assuntos
Carcinogênese/genética , Quinase 6 Dependente de Ciclina/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Mieloma Múltiplo/genética , RNA Mensageiro/genética , Animais , Antibióticos Antineoplásicos/farmacologia , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Doxorrubicina/farmacologia , Fator de Transcrição E2F1/antagonistas & inibidores , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Feminino , Humanos , Camundongos , Camundongos Nus , MicroRNAs/agonistas , MicroRNAs/metabolismo , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/metabolismo , Fase de Repouso do Ciclo Celular/genética , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Bioengineered ; 10(1): 1-12, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30836864

RESUMO

This study is aimed to elucidate the mechanisms underlying the role of miR-485-5p in small cell lung cancer (SCLC). The expression of miR-485-5p were quantified with real time quantitative PCR and it was found that the level of miR-485-5p was lower in SCLC tissues than normal tissues. In cultured SCLC cell lines, overexpression of miR-485-5p reduced cell proliferation, migration, and invasion in vitro, whereas knockdown of miR-485-5p performed contrary. FLOT2 expression was obviously upregulated and negatively correlated with miR-485-5p expression level in SCLC tissues. Overexpression of miR-485-5p significantly inhibited the protein expression of flotillin-2 (FLOT2) in cultured SCLC cells. Luciferase reporter assay confirmed that FLOT2 was a direct target of miR-485-5p in SCLC cells. It is concluded that miR-485-5p, as a tumor suppressor, inhibits the growth and metastasis in SCLC by targeting FLOT2. Upregulation of miR-485-5p expression may be an attractive strategy for SCLC therapy.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Proteínas de Membrana/genética , MicroRNAs/genética , Carcinoma de Pequenas Células do Pulmão/genética , Regiões 3' não Traduzidas , Antagomirs/genética , Antagomirs/metabolismo , Apoptose/genética , Sequência de Bases , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Genes Reporter , Humanos , Luciferases/genética , Luciferases/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metástase Linfática , Proteínas de Membrana/metabolismo , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Mimetismo Molecular , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Transdução de Sinais , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia
8.
RNA ; 25(6): 737-746, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30926754

RESUMO

Human RNA exoribonuclease 2 (Rexo2) is an evolutionarily conserved 3'-to-5' DEDDh-family exonuclease located primarily in mitochondria. Rexo2 degrades small RNA oligonucleotides of <5 nucleotides (nanoRNA) in a way similar to Escherichia coli Oligoribonuclease (ORN), suggesting that it plays a role in RNA turnover in mitochondria. However, how Rexo2 preferentially binds and degrades nanoRNA remains elusive. Here, we show that Rexo2 binds small RNA and DNA oligonucleotides with the highest affinity, and it is most robust in degrading small nanoRNA into mononucleotides in the presence of magnesium ions. We further determined three crystal structures of Rexo2 in complex with single-stranded RNA or DNA at resolutions of 1.8-2.2 Å. Rexo2 forms a homodimer and interacts mainly with the last two 3'-end nucleobases of substrates by hydrophobic and π-π stacking interactions via Leu53, Trp96, and Tyr164, signifying its preference in binding and degrading short oligonucleotides without sequence specificity. Crystal structure of Rexo2 is highly similar to that of the RNA-degrading enzyme ORN, revealing a two-magnesium-ion-dependent hydrolysis mechanism. This study thus provides the molecular basis for human Rexo2, showing how it binds and degrades nanoRNA into nucleoside monophosphates and plays a crucial role in RNA salvage pathways in mammalian mitochondria.


Assuntos
Proteínas 14-3-3/química , Biomarcadores Tumorais/química , DNA de Cadeia Simples/química , Exorribonucleases/química , Magnésio/química , Proteínas Mitocondriais/química , Oligorribonucleotídeos/química , RNA/química , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Sítios de Ligação , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Cátions Bivalentes , Clonagem Molecular , Cristalografia por Raios X , DNA de Cadeia Simples/genética , DNA de Cadeia Simples/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Exorribonucleases/genética , Exorribonucleases/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Hidrólise , Interações Hidrofóbicas e Hidrofílicas , Magnésio/metabolismo , Mitocôndrias/química , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Modelos Moleculares , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , RNA/genética , RNA/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
9.
Mol Cancer ; 18(1): 30, 2019 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-30813931

RESUMO

Ectopic Viral Integration site 1 (EVI1) upregulation is implicated in 10-25% of pediatric acute myeloid leukemia (AML) and has an inferior outcome with current chemotherapy regimens. Here we report that EVI1 upregulation is associated with methylation of the miR-9 promoter and correlated with downregulation of miR-9 in human AML cell lines and bone marrow (BM) cells from pediatric patients. Reactivation of miR-9 by hypomethylating agents and forced expression of miR-9 in EVI1high leukemia cell lines and primary leukemia cells results in apoptosis and decreased proliferation of EVI1high leukemia cells. Furthermore, re-expression of miR-9 delays disease progression in EVI1high leukemia-xenograft mice. Our results suggest that EVI1-induced hypermethylation and downregulation of the miR-9 plays an important role in leukemogenesis in EVI-1high pediatric AML, indicating that hypomethylating agents may be a potential therapeutic strategy for EVI1high pediatric AML.


Assuntos
Epigênese Genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/genética , Proteína do Locus do Complexo MDS1 e EVI1/genética , MicroRNAs/genética , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células , Criança , Metilação de DNA/efeitos dos fármacos , Decitabina/farmacologia , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Proteína do Locus do Complexo MDS1 e EVI1/metabolismo , Camundongos , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Transdução de Sinais , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Cell Host Microbe ; 25(2): 336-343.e4, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30713099

RESUMO

Immune responses counteract infections but also cause collateral damage to hosts. Oligoadenylate synthetase 1 (OAS1) binds double-stranded RNA from invading viruses and produces 2'-5' linked oligoadenylate (2-5A) to activate ribonuclease L (RNase L), which cleaves RNA to inhibit virus replication. OAS1 can also undergo autoactivation by host RNAs, a potential trade-off to antiviral activity. We investigated functional variation in primate OAS1 as a model for how immune pathways evolve to mitigate costs and observed a surprising frequency of loss-of-function variation. In gorillas, we identified a polymorphism that severely decreases catalytic function, mirroring a common variant in humans that impairs 2-5A synthesis through alternative splicing. OAS1 loss-of-function variation is also common in monkeys, including complete loss of 2-5A synthesis in tamarins. The frequency of loss-of-function alleles suggests that costs associated with OAS1 activation can be so detrimental to host fitness that pathogen-protective effects are repeatedly forfeited.


Assuntos
2',5'-Oligoadenilato Sintetase/genética , 2',5'-Oligoadenilato Sintetase/farmacologia , Antivirais/farmacologia , Mutação , Primatas/imunologia , 2',5'-Oligoadenilato Sintetase/metabolismo , Nucleotídeos de Adenina/metabolismo , Sequência de Aminoácidos , Animais , Endorribonucleases/metabolismo , Evolução Molecular , Variação Genética , Haplorrinos , Humanos , Modelos Moleculares , Oligorribonucleotídeos/metabolismo , Conformação Proteica , RNA de Cadeia Dupla/metabolismo , Análise de Sequência de Proteína , Replicação Viral/efeitos dos fármacos , Vírus/efeitos dos fármacos
11.
Mol Cancer ; 18(1): 22, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30736860

RESUMO

BACKGROUND: Though esophageal cancer is three to four times more common among males than females worldwide, this type of cancer still ranks in the top incidence among women, even more than the female specific cancer types. The occurrence is currently attributed to extrinsic factors, including tobacco use and alcohol consumption. However, limited attention has been given to gender-specific intrinsic genetic factors, especially in female. METHODS: We re-annotated a large cohort of microarrays on 179 ESCC patients and identified female-specific differently expressed lncRNAs. The associations between FMR1-AS1 and the risk and prognosis of ESCC were examined in 206 diagnosed patients from eastern China and validated in 188 additional patients from southern China. The effects of FMR1-AS1 on the malignant phenotypes on female ESCC cells were detected in vitro and in vivo. ChIRP-MS, reporter gene assays and EMSA were conducted to identify the interaction and regulation among FMR1-AS1, TLR7 and NFκB. RESULTS: We found FMR1-AS1 expression is exclusively altered and closely associated with the level of sXCI in female ESCC patients, and its overexpression may correlate to poor clinical outcome. ChIRP-MS data indicate that FMR1-AS1 could be packaged into exosomes and released into tumor microenvironment. Functional studies demonstrated that FMR1-AS1 could bind to endosomal toll-like receptor 7 (TLR7) and activate downstream TLR7-NFκB signaling, promoting the c-Myc expression, thus inducing ESCC cell proliferation, anti-apoptosis and invasion ability. Exosome incubation and co-xenograft assay indicate that FMR1-AS1 exosomes may secreted from ESCC CSCs, transferring stemness phenotypes to recipient non-CSCs in tumor microenvironment. Furthermore, we also found a correlation between the serum levels of FMR1-AS1 and the overall survival (OS) of the female ESCC patients. CONCLUSIONS: Our results highlighted exosomal FMR1-AS1 in maintaining CSC dynamic interconversion state through the mechanism of activating TLR7-NFκB signaling, upregulating c-Myc level in recipient cells, which may be taken as an attractive target approach for advancing current precision cancer therapeutics in female patients.


Assuntos
Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Regulação Neoplásica da Expressão Gênica , NF-kappa B/genética , Proteínas Proto-Oncogênicas c-myc/genética , RNA Longo não Codificante/genética , Receptor 7 Toll-Like/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/patologia , Exossomos/metabolismo , Exossomos/patologia , Feminino , Humanos , Camundongos Nus , NF-kappa B/metabolismo , Células-Tronco Neoplásicas , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Longo não Codificante/agonistas , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Análise de Sobrevida , Receptor 7 Toll-Like/metabolismo , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Methods Enzymol ; 616: 191-218, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30691643

RESUMO

Type III CRISPR effector complexes utilize a bound CRISPR RNA (crRNA) to detect the presence of RNA from invading mobile genetic elements in the cell. This RNA binding results in the activation of two enzymatic domains of the Cas10 subunit-the HD nuclease domain, which degrades DNA, and PALM/cyclase domain. The latter synthesizes cyclic oligoadenylate (cOA) molecules by polymerizing ATP, and cOA acts as a second messenger in the cell, switching on the antiviral response by activating host ribonucleases and other proteins. In this chapter, we focus on the methods required to study the biochemistry of this recently discovered cOA signaling pathway. We cover protein expression and purification, synthesis of cOA and its linear analogues, kinetic analysis of cOA synthesis and cOA-stimulated ribonuclease activity, and small molecule detection and identification with thin-layer chromatography and mass spectrometry. The methods described are based on our recent studies of the type III CRISPR system in Sulfolobus solfataricus, but are widely applicable to other type III systems.


Assuntos
Nucleotídeos de Adenina/metabolismo , Proteínas Arqueais/metabolismo , Proteínas Associadas a CRISPR/metabolismo , Sistemas CRISPR-Cas , Oligorribonucleotídeos/metabolismo , Sulfolobus solfataricus/metabolismo , Nucleotídeos de Adenina/genética , Proteínas Arqueais/genética , Proteínas Associadas a CRISPR/genética , Clonagem Molecular/métodos , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Escherichia coli/genética , Cinética , Oligorribonucleotídeos/genética , Sistemas do Segundo Mensageiro , Transdução de Sinais , Sulfolobus solfataricus/genética
13.
Mol Med Rep ; 19(2): 1110-1116, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30569090

RESUMO

The present study investigated the effect of microRNA (miR)­15a­3p on the proliferation, migration and apoptosis of lens epithelial cells and its potential mechanism, in order to further elucidate the pathogenesis of age­related cataracts (ARCs). The HLE­B3 human lens epithelial cell line was transfected with miR­15a­3p mimic. Expression of the miR­15a­3p mimic was measured by fluorescence­based reverse transcription­quantitative polymerase chain reaction analysis. Cell proliferation, apoptosis, invasion and migration were investigated using MTT and plate clone formation assays, terminal deoxynucleotidyl transferase dUTP nick end labeling and flow cytometry, and a wound healing assay and Transwell assay, respectively. The protein expression levels of B­cell lymphoma 2 (BCL2) and myeloid cell leukemia sequence 1 (MCL1) were also compared between transfected and wild­type HLE­B3 cells by western blot analysis. The results showed that transfection with the miR­15a­3p mimic significantly suppressed the proliferation of HLE­B3 cells, induced cell apoptosis and increased the proportion of early apoptotic cells. The migration of HLE­B3 cells was significantly inhibited following transfection with miR­15a­3p mimic (P<0.01), whereas cell invasion was unaffected (P>0.05). In addition, reduced protein levels of BCL2 and MCL1 were observed in the miR­15a­3p mimic­transfected HLE­B3 cells (P<0.01). In conclusion, miR­15a­3p may suppress cell proliferation and migration, and induce cell apoptosis in lens epithelial cells through inhibiting the expression of BCL2 and MCL1, which contributes to the onset of ARCs.


Assuntos
Apoptose/genética , Regulação Neoplásica da Expressão Gênica , Cristalino/metabolismo , MicroRNAs/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Idoso , Antagomirs/genética , Antagomirs/metabolismo , Catarata/genética , Catarata/metabolismo , Catarata/patologia , Linhagem Celular Transformada , Movimento Celular , Proliferação de Células , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Cristalino/patologia , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Modelos Biológicos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Transfecção
14.
J Biosci ; 43(5): 985-1000, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30541958

RESUMO

Retinal injury plays a leading role in the onset of visual impairment. Current forms of treatment are not able to ameliorate scarring, cell death and tissue and axon regeneration. Recently, microRNA-216a (miR-216a) has been reported to regulate snx5, a novel notch signalling pathway component during retinal development. This study aims to elucidate the role of miR-216a in yttrium aluminium garnet (YAG) laser-induced retinal injury by targeting glial cell line-derived neurotrophic factor (GDNF) via GDNF/GDNF family neurotrophic factor receptor α1 (GFRα1)/rearranged during transfection (RET) signalling pathway. Wistar male rats were first randomly assigned into control and model groups. Immunohistochemistry was performed to detect the GDNF positive expression rate and terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) staining for apoptotic index (AI) of retinal tissue. Retinal neurons were divided into normal, blank, negative control (NC), miR-216a mimic, miR-216a inhibitor, siRNA-GDNF and miR-216a inhibitor?siRNA-GDNF groups. Dual luciferase reporter assay was conducted in order to identify the targeting relationship between GDNF and miR-216a. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot were used for the analysis of mRNA and protein levels of miR-216a and related genes. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine cell proliferation and flow cytometry was used to observe cell cycle and apoptosis. Results show that the model group had an increased GDNF positive rate, AI of retinal tissue and mRNA and protein levels of cellular oncogene fos (c-fos), vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), GDNF, GFRα1 and bcl-2-associated X protein (bax), declined miR-216a level and mRNA and protein levels of RET and bcl-2 compared with the control group. GDNF was verified as the target gene for miR-216a. Compared with the blank and NC groups, the miR-216a mimic and siRNA-GDNF groups had higher mRNA and protein levels of c-fos, VEGF and bax, cell number in the G1 phase and increased cell apoptosis but reduced BDNF, GDNF, GFRα1, RET and bcl-2 expression, cell proliferation and cell numbers in the S phase, while the opposite trend was observed in the miR-216a inhibitor group. Taken together, our findings demonstrate that elevated GDNF levels can reduce the retinal injury, whereby down-regulated miR-216a aggravates the YAG laser-induced retinal injury by targeting the GDNF level through the GDNF/ GFRα1/RET signalling pathway.


Assuntos
Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Lasers de Estado Sólido/efeitos adversos , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-ret/genética , Retina/metabolismo , Degeneração Retiniana/genética , Animais , Antagomirs/genética , Antagomirs/metabolismo , Apoptose , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ciclo Celular/genética , Proliferação de Células , Células Ependimogliais/metabolismo , Células Ependimogliais/patologia , Regulação da Expressão Gênica , Fator Neurotrófico Derivado de Linhagem de Célula Glial/antagonistas & inibidores , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Masculino , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Wistar , Retina/lesões , Degeneração Retiniana/etiologia , Degeneração Retiniana/metabolismo , Degeneração Retiniana/patologia , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
15.
Mol Med Rep ; 18(2): 1524-1530, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29845275

RESUMO

Autophagy, part of the innate immune defense mechanisms, is activated during the initial phase of septic insult. Previous studies indicated that micro (mi)RNAs are additionally involved in the host response to sepsis; however, the association between miRNAs and autophagy during this process is not fully understood. To study the role of miRNA (miR)­23a in autophagy initiated by sepsis, macrophages treated with lipopolysaccharides, in addition to blood samples from patients, were evaluated for miR­23a expression levels. Cell viability, inflammatory mediators and autophagic markers were investigated following overexpression or inhibition of miR­23a. The results suggested that miR­23a was suppressed subsequent to septic insult, promoting autophagy and suppressing a hyper inflammatory response, leading to enhanced cell viability. A luciferase assay and western blot analysis confirmed ubiquitin­like protein ATG12 to be the target of miR­23a. The present study revealed that the downregulation of miR­23a regulates an inflammatory response during septic insult via autophagy promotion.


Assuntos
Proteína 12 Relacionada à Autofagia/genética , Autofagia/genética , MicroRNAs/genética , Sepse/genética , Idoso , Animais , Antagomirs/genética , Antagomirs/metabolismo , Proteína 12 Relacionada à Autofagia/imunologia , Sequência de Bases , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica , Genes Reporter , Humanos , Lipopolissacarídeos/farmacologia , Luciferases/genética , Luciferases/metabolismo , Masculino , Camundongos , MicroRNAs/antagonistas & inibidores , MicroRNAs/imunologia , Pessoa de Meia-Idade , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Células RAW 264.7 , Sepse/imunologia , Sepse/patologia , Transdução de Sinais
16.
Biochem Biophys Res Commun ; 500(4): 966-972, 2018 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-29715460

RESUMO

BACKGROUND: Long non-coding RNAs (lncRNAs) have been demonstrated to be intensively involved in the development of various carcinomas, including glioblastoma multiforme (GBM). However, only a few of them have been well characterized. LncRNA CASP5 have been found to be up-regulated in GBM tissues compared with normal tissues in a microarray-based lncRNA profiling study. In the present study, we further explored the biological role of lncRNA CASP5 in GBM. METHODS: We examined the expression level of lncRNA CASP5 in GBM tissues as well as GBM cell lines. CCK-8 assay, flow cytometric analysis, western blotting, orthotopic GBM model as well as transwell assay were performed to investigate the biological role of CASP5. RESULTS: We observed that lncRNA CASP5 was highly expressed in GBM tissues and cell lines. Knockdown of CASP5 greatly inhibited GBM proliferation and resulted in G1 cell cycle arrest along with higher apoptosis ratios in vitro and in vivo, while overexpression led to the opposite phenomenon. Furthermore, the migration and invasion ability of GBM cells were significantly decreased after CASP5 down-regulation, while increased migration and invasion can be observed after CASP5 up-regulation. CONCLUSION: We demonstrate for the first time the potential oncogenic role of lncRNA CASP5 which may be helpful for identifying novel therapeutic targets in GBM.


Assuntos
Neoplasias Encefálicas/genética , Caspases/genética , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , RNA Longo não Codificante/genética , Animais , Antagomirs/genética , Antagomirs/metabolismo , Apoptose/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Caspases/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Genes Reporter , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Luciferases/genética , Luciferases/metabolismo , Masculino , Camundongos , Camundongos Nus , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Plasmídeos/química , Plasmídeos/metabolismo , RNA Longo não Codificante/agonistas , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Técnicas Estereotáxicas , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto
17.
PLoS Pathog ; 14(4): e1006989, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29652922

RESUMO

The OAS/RNase L pathway is one of the best-characterized effector pathways of the IFN antiviral response. It inhibits the replication of many viruses and ultimately promotes apoptosis of infected cells, contributing to the control of virus spread. However, viruses have evolved a range of escape strategies that act against different steps in the pathway. Here we unraveled a novel escape strategy involving Theiler's murine encephalomyelitis virus (TMEV) L* protein. Previously we found that L* was the first viral protein binding directly RNase L. Our current data show that L* binds the ankyrin repeats R1 and R2 of RNase L and inhibits 2'-5' oligoadenylates (2-5A) binding to RNase L. Thereby, L* prevents dimerization and oligomerization of RNase L in response to 2-5A. Using chimeric mouse hepatitis virus (MHV) expressing TMEV L*, we showed that L* efficiently inhibits RNase L in vivo. Interestingly, those data show that L* can functionally substitute for the MHV-encoded phosphodiesterase ns2, which acts upstream of L* in the OAS/RNase L pathway, by degrading 2-5A.


Assuntos
2',5'-Oligoadenilato Sintetase/metabolismo , Nucleotídeos de Adenina/metabolismo , Endorribonucleases/antagonistas & inibidores , Vírus da Hepatite Murina/fisiologia , Oligorribonucleotídeos/metabolismo , Theilovirus/metabolismo , Proteínas Virais/metabolismo , Animais , Antivirais/metabolismo , Endorribonucleases/fisiologia , Células HeLa , Hepatite Viral Animal/metabolismo , Hepatite Viral Animal/virologia , Interações Hospedeiro-Patógeno , Humanos , Camundongos
18.
Biochem Biophys Res Commun ; 500(4): 930-936, 2018 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-29705696

RESUMO

MicroRNAs (miRNAs) are a class of small non-coding RNAs that are widely involved in a variety of biological processes. Different skeletal muscle fiber type composition exhibits characteristic differences in functional properties and energy metabolism of skeletal muscle. However, the molecular mechanism by which miRNAs control the different type of muscle fiber formation is still not fully understood. In the present study, we characterized the role of microRNA-139-5p (miR-139-5p) in the regulation of myosin heavy chain (MyHC) isoform expression and its underlying mechanisms. Here we found that the expression of miR-139-5p was significantly higher in mouse slow-twitch muscle than in fast-twitch muscle. Overexpression of miR-139-5p downregulated the expression of MyHC I and MyHC IIa, whereas inhibition of miR-139-5p upregulated them. We also found that the levels of calcineurin (CaN), NFATc1, MEF2C and MCIP1.4, which are the components of CaN/NFAT signaling pathway that has shown to positively regulate slow fiber-selective gene expression, were notably inhibited by miR-139-5p overexpression. Furthermore, treatment of phenylephrine (PE), a α1-adrenoceptor agonist, abolished the inhibitory effect of miR-139-5p on MyHC I and MyHC IIa expression. Together, our findings indicated that the role of miR-139-5p in regulating the MyHC isoforms, especially MyHC I and MyHC IIa, may be achieved through inhibiting CaN/NFAT signaling pathway.


Assuntos
Calcineurina/genética , MicroRNAs/genética , Fibras Musculares de Contração Rápida/metabolismo , Fibras Musculares de Contração Lenta/metabolismo , Cadeias Pesadas de Miosina/genética , Fatores de Transcrição NFATC/genética , Animais , Antagomirs/genética , Antagomirs/metabolismo , Calcineurina/metabolismo , Linhagem Celular Transformada , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Fibras Musculares de Contração Rápida/citologia , Fibras Musculares de Contração Rápida/efeitos dos fármacos , Fibras Musculares de Contração Lenta/citologia , Fibras Musculares de Contração Lenta/efeitos dos fármacos , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Mioblastos/citologia , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Fatores de Transcrição NFATC/metabolismo , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Fenilefrina/farmacologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transdução de Sinais
19.
Int J Mol Sci ; 19(2)2018 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-29401684

RESUMO

Acute myeloid leukemias (AML) are clonal disorders of hematopoietic progenitor cells which are characterized by relevant heterogeneity in terms of phenotypic, genotypic, and clinical features. Among the genetic aberrations that control disease development there are microRNAs (miRNAs). miRNAs are small non-coding RNAs that regulate, at post-transcriptional level, translation and stability of mRNAs. It is now established that deregulated miRNA expression is a prominent feature in AML. Functional studies have shown that miRNAs play an important role in AML pathogenesis and miRNA expression signatures are associated with chemotherapy response and clinical outcome. In this review we summarized miRNA signature in AML with different cytogenetic, molecular and clinical characteristics. Moreover, we reviewed the miRNA regulatory network in AML pathogenesis and we discussed the potential use of cellular and circulating miRNAs as biomarkers for diagnosis and prognosis and as therapeutic targets.


Assuntos
Biomarcadores Tumorais/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/terapia , MicroRNAs/genética , Proteínas de Fusão Oncogênica/genética , Animais , Antagomirs/genética , Antagomirs/metabolismo , Antagomirs/uso terapêutico , Biomarcadores Tumorais/agonistas , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Aberrações Cromossômicas , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patologia , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Camundongos , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Terapia de Alvo Molecular , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Oligorribonucleotídeos/uso terapêutico , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/metabolismo , Prognóstico , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Mol Med Rep ; 17(3): 4181-4186, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29328381

RESUMO

MicroRNA (miR)-150 has been demonstrated to protect the heart from ischemic injury. However, the protective effect of miR­150 in hypoxia­injured cardiomyocytes remains unclear. The present study aimed to investigate the target gene of miR­150 and the underlying molecular mechanisms of miR­150 in hypoxia­induced cardiomyocyte apoptosis. Using the hypoxia model of human cardiomyocytes (HCMs) in vitro, it was demonstrated that miR­150 was markedly inhibited in HCMs after hypoxia treatment. Overexpressing miR­150 significantly decreased hypoxia­induced HCM death and apoptosis. In addition, GRP94 was revealed to be a direct target of miR­150. Additionally, GRP94 was demonstrated to be involved in hypoxia­induced HCM apoptosis, and the protein expression levels of GRP94 were increased in HCMs in the presence of hypoxia. These findings demonstrated that miR­150 is involved in hypoxia­mediated gene regulation and apoptosis in HCMs. Furthermore, GRP94 knockout increased the cell viability of hypoxia­impaired HCMs with miR­150 mimic or miR­150 inhibitor transfection. In conclusion, miR­150 may serve a protective role in cardiomyocyte hypoxia injury, and the underlying mechanism was mediated, at least partially, by inhibiting GRP94 expression. These findings may provide a novel insight for the therapy of hypoxia-induced myocardial I/R injury.


Assuntos
Apoptose/efeitos dos fármacos , Glicoproteínas de Membrana/genética , MicroRNAs/genética , Miócitos Cardíacos/efeitos dos fármacos , Oxigênio/farmacologia , Regiões 3' não Traduzidas , Antagomirs/genética , Antagomirs/metabolismo , Apoptose/genética , Sequência de Bases , Sítios de Ligação , Hipóxia Celular , Linhagem Celular , Regulação da Expressão Gênica , Genes Reporter , Humanos , Luciferases/genética , Luciferases/metabolismo , Glicoproteínas de Membrana/metabolismo , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Transdução de Sinais
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