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1.
Cell Mol Life Sci ; 76(21): 4203-4219, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31300868

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, with a high mortality rate. Its dismal prognosis is attributed to late diagnosis, high risk of recurrence and drug resistance. To improve the survival of patients with HCC, new approaches are required for early diagnosis, real-time monitoring and effective treatment. Exosomes are small membranous vesicles released by most cells that contain biological molecules and play a great role in intercellular communication under physiological or pathological conditions. In cancer, exosomes from tumor cells or non-tumor cells can be taken up by neighboring or distant target cells, and the cargoes in exosomes are functional to modulate the behaviors of tumors or reshape tumor microenvironment (TME). As essential components, non-coding RNAs (ncRNAs) are selectively enriched in exosomes, and exosomal ncRNAs participate in regulating specific aspects of tumor development, including tumorigenesis, tumor metastasis, angiogenesis, immunomodulation and drug resistance. Besides, dysregulated exosomal ncRNAs have emerged as potential biomarkers, and exosomes can serve as natural vehicles to deliver tumor-suppressed ncRNAs for treatment. In this review, we briefly summarize the biology of exosomes, the functions of exosomal ncRNAs in HCC development and their potential clinical applications, including as biomarkers and therapeutic tools.


Assuntos
Carcinoma Hepatocelular/genética , Exossomos/genética , Neoplasias Hepáticas/genética , RNA Neoplásico/fisiologia , RNA não Traduzido/fisiologia , Animais , Biomarcadores Tumorais/fisiologia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Sistemas de Liberação de Medicamentos , Exossomos/metabolismo , Regulação Neoplásica da Expressão Gênica , Terapia Genética/métodos , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Terapia de Alvo Molecular/métodos , RNA Neoplásico/metabolismo , RNA não Traduzido/metabolismo
2.
Hematol Oncol ; 37(4): 474-482, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31325181

RESUMO

LncRNAs play critical roles in various pathophysiological and biological processes, such as protein translation, RNA splicing, and epigenetic modification. Indeed, abundant evidences demonstrated that lncRNA act as competing endogenous RNAs (ceRNAs) to participate in tumorigenesis. However, little is known about the underlying function of lncRNA in nonhomologous end joining (NHEJ) pathway 1 (LINP1) in pediatric and adolescent acute myeloid leukemia (AML). The expression of LINP1 was examined in AML patient samples by qRT-PCR. Cell proliferation was examined by CCK-8 and Edu assays. ß-Galactosidase senescence assay, mGlucose uptake assay, lactate production assay, and Gene Ontology (GO) analysis were performed for functional analysis. We found that LINP1 was significantly overexpressed in AML patients at diagnosis, whereas downregulated after complete remission (CR). Furthermore, knockdown of LINP1 expression remarkably suppressed glucose uptake and AML cell maintenance. Mechanistically, LINP1 was found to inhibit the glucose metabolism by suppressing the expression of HNF4a. Both LINP1 and HNF4a knockdown reduced the expression levels of AMPK phosphorylation and WNT5A, indicating for the first time that LINP1 strengthened the HNF4a-AMPK/WNT5A signaling pathway involved in cell glucose metabolism modulation and AML cell survival. Taken together, our results indicated that LINP1 promotes the malignant phenotype of AML cells and stimulates glucose metabolism, which can be regarded as a potential prognostic marker and therapeutic target for AML.


Assuntos
Adenilato Quinase/fisiologia , Fator 4 Nuclear de Hepatócito/fisiologia , Leucemia Mieloide Aguda/genética , RNA Longo não Codificante/fisiologia , RNA Neoplásico/fisiologia , Transdução de Sinais/fisiologia , Proteína Wnt-5a/fisiologia , Adolescente , Animais , Medula Óssea/patologia , Divisão Celular , Criança , Regulação Leucêmica da Expressão Gênica , Técnicas de Silenciamento de Genes , Ontologia Genética , Glucose/metabolismo , Fator 4 Nuclear de Hepatócito/biossíntese , Fator 4 Nuclear de Hepatócito/genética , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Púrpura Trombocitopênica Idiopática/metabolismo , Interferência de RNA , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , RNA Interferente Pequeno/genética , Distribuição Aleatória , Indução de Remissão , Transdução de Sinais/genética , Células THP-1
3.
Exp Mol Pathol ; 106: 116-122, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30615851

RESUMO

The acquired chemoresistance during long term chemotherapy is one of the most important factors to limit the application of Doxorubicin (Dox) on clinical treatment of hepatocellular carcinoma (HCC) patients. Our present study found that Dox resistant HCC (HCC/Dox) cells had greater capability of in vitro migration and invasion compared to their parental cells. HCC/Dox cells exhibited mesenchymal characteristics, which was evidenced by the up regulation of fibronectin, vimentin while down regulation of E-Cadherin. Zeb1, one powerful epithelial mesenchymal transition related transcription factor (EMT-TF), was markedly upregulated in HCC/Dox cells. Targeted inhibition of Zeb1 via siRNA can suppress the cell migration and re-sensitized cells to Dox treatment. The upregulation of Zeb1 in HCC/Dox cells was due to the increasing protein and mRNA stability of Zeb1. In HCC/Dox cells, the down regulation of SIAH1 mediated the upregulation of protein stability of Zeb1, while decreased levels of miR-3129-5p was responsible for the increasing mRNA stability of Zeb1. Collectively, our data suggested that SIAH1 and miR-3129-5p induced upregulation of Zeb1 mediated the Dox resistance of HCC cells. Targeted inhibition of Zeb1 might be helpful to overcome of Dox resistance of HCC.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Carcinoma Hepatocelular/patologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Neoplasias Hepáticas/patologia , Proteínas de Neoplasias/fisiologia , Homeobox 1 de Ligação a E-box em Dedo de Zinco/fisiologia , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 2 da Matriz/genética , MicroRNAs/fisiologia , Invasividade Neoplásica , Proteínas Nucleares/fisiologia , Estabilidade de RNA , RNA Neoplásico/fisiologia , Ubiquitina-Proteína Ligases/fisiologia
4.
Oncogene ; 38(3): 360-374, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30093634

RESUMO

The role of the tumour-suppressor miR-34 family in breast physiology and in mammary stem cells (MaSCs) is largely unknown. Here, we revealed that miR-34 family, and miR-34a in particular, is implicated in mammary epithelium homoeostasis. Expression of miR-34a occurs upon luminal commitment and differentiation and serves to inhibit the expansion of the pool of MaSCs and early progenitor cells, likely in a p53-independent fashion. Mutant mice (miR34-KO) and loss-of-function approaches revealed two separate functions of miR-34a, controlling both proliferation and fate commitment in mammary progenitors by modulating several pathways involved in epithelial cell plasticity and luminal-to-basal conversion. In particular, miR-34a acts as endogenous inhibitor of the Wnt/beta-catenin signalling pathway, targeting up to nine upstream regulators at the same time, thus modulating the expansion of the MaSCs/early progenitor pool. These multiple roles of miR-34a are maintained in a model of human breast cancer, in which chronic expression of miR-34a in triple-negative mesenchymal-like cells (enriched in cancer stem cells-CSCs) could promote a luminal-like differentiation programme, restrict the CSC pool, and inhibit tumour propagation. Hence, activation of miR-34a-dependent programmes could provide a therapeutic opportunity for the subset of breast cancers, which are rich in CSCs and respond poorly to conventional therapies.


Assuntos
Neoplasias da Mama/patologia , Glândulas Mamárias Animais/citologia , MicroRNAs/fisiologia , RNA Neoplásico/fisiologia , Animais , Neoplasias da Mama/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Autorrenovação Celular/fisiologia , Células Epiteliais/metabolismo , Feminino , Humanos , Glândulas Mamárias Animais/anormalidades , Glândulas Mamárias Animais/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Knockout , MicroRNAs/genética , Células-Tronco Neoplásicas/metabolismo , Esferoides Celulares , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Via de Sinalização Wnt
5.
Oncogene ; 38(3): 445-453, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30104710

RESUMO

Although it has been demonstrated that transformed progenitor cell population can contribute to tumor initiation, factors contributing to this malignant transformation are poorly known. Using in vitro and xenograft-based models, previous studies demonstrated that miR-489 acts as a tumor suppressor miRNA by targeting various oncogenic pathways. It has been demonstrated that miR-489 directly targets HER2 and inhibits the HER2 signaling pathway; however, its role in mammary gland development and HER2-induced tumor initiation hasn't been studied. To dissect the role of miR-489, we sorted different populations of mammary epithelial cells and determined that miR-489 was highly expressed in mammary stem cells. MMTV-miR-489 mice that overexpressed miR-489 in mammary epithelial cells were developed and these mice exhibited an inhibition of mammary gland development in early ages with a specific impact on highly proliferative cells. Double transgenic MMTV-Her2-miR489 mice were then generated to observe how miR-489 overexpression affects HER2-induced tumorigenesis. miR-489 overexpression delayed HER2-induced tumor initiation significantly. Moreover, miR-489 overexpression inhibited tumor growth and lung metastasis. miR-489 overexpression reduced mammary progenitor cell population significantly in preneoplastic mammary glands of MMTV-Her2 mice which showed a putative transformed population in HER2-induced tumorigenesis. The miR-489 overexpression reduced CD49fhiCD61hi populations in tumors that have stem-like properties, and miR-489 overexpression altered the HER2 signaling pathway in mammary tumors. Altogether, these data indicate that the inhibition of HER2-induced tumorigenesis by miR-489 overexpression was due to altering progenitor cell populations while decreasing tumor growth and metastasis via influencing tumor promoting genes DEK and SHP2.


Assuntos
Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Glândulas Mamárias Animais/metabolismo , Neoplasias Mamárias Experimentais/patologia , MicroRNAs/fisiologia , RNA Neoplásico/fisiologia , Receptor ErbB-2/fisiologia , Animais , Antígenos CD/análise , Diferenciação Celular , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células Epiteliais/metabolismo , Feminino , Neoplasias Pulmonares/secundário , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Vírus do Tumor Mamário do Camundongo/genética , Camundongos , Camundongos Transgênicos , MicroRNAs/biossíntese , MicroRNAs/genética , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Gravidez , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Receptor ErbB-2/genética , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/metabolismo , Células-Tronco/metabolismo , Ensaio Tumoral de Célula-Tronco , Regulação para Cima
6.
Oncogene ; 38(3): 406-420, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30115976

RESUMO

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. The poor survival may be due to a high proportions of tumor recurrence and metastasis. Kinesin family member C1 (KIFC1) is highly expressed in a variety of neoplasms and is a potential marker for non-small cell lung cancer or ovarian adenocarcinoma metastasis. Nevertheless, the role of KIFC1 in HCC metastasis remains obscure. We investigated this in the present study using HCC cell lines and clinical specimens. Our results indicated that increased levels of KIFC1 were associated with poor prognosis and metastasis in HCC. In addition, KIFC1 induced epithelial-to-mesenchymal transition (EMT) and HCC metastasis both in vitro and in vivo. This tumorigenic effect depended on gankyrin; inhibiting gankyrin activity reversed EMT via activation of protein kinase B (AKT)/Twist family BHLH transcription factor 1 (AKT/TWIST1). We also found that KIFC1 was directly regulated by the microRNA miR-532-3p, whose downregulation was associated with metastatic progression in HCC. These results denote that a decrease in miR-532-3p levels results in increased KIFC1 expression in HCC, leading to metastasis via activation of the gankyrin/AKT/TWIST1 signaling pathway.


Assuntos
Carcinoma Hepatocelular/secundário , Transição Epitelial-Mesenquimal/fisiologia , Cinesina/fisiologia , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/secundário , MicroRNAs/fisiologia , Proteínas de Neoplasias/fisiologia , RNA Neoplásico/fisiologia , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Linhagem Celular Tumoral , Regulação para Baixo , Xenoenxertos , Humanos , Estimativa de Kaplan-Meier , Cinesina/antagonistas & inibidores , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Neoplasias Pulmonares/fisiopatologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/biossíntese , MicroRNAs/genética , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas Nucleares/fisiologia , Prognóstico , Complexo de Endopeptidases do Proteassoma/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Interferência de RNA , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Transdução de Sinais , Proteína 1 Relacionada a Twist/fisiologia
7.
Oncogene ; 38(3): 421-444, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30120411

RESUMO

Expression levels of retinoic acid receptor gamma (NR1B3/RARG, encodes RARγ) are commonly reduced in prostate cancer (PCa). Therefore, we sought to establish the cellular and gene regulatory consequences of reduced RARγ expression, and determine RARγ regulatory mechanisms. RARG shRNA approaches in non-malignant (RWPE-1 and HPr1-AR) and malignant (LNCaP) prostate models revealed that reducing RARγ levels, rather than adding exogenous retinoid ligand, had the greatest impact on prostate cell viability and gene expression. ChIP-Seq defined the RARγ cistrome, which was significantly enriched at active enhancers associated with AR binding sites. Reflecting a significant genomic role for RARγ to regulate androgen signaling, RARγ knockdown in HPr1-AR cells significantly regulated the magnitude of the AR transcriptome. RARγ downregulation was explained by increased miR-96 in PCa cell and mouse models, and TCGA PCa cohorts. Biochemical approaches confirmed that miR-96 directly regulated RARγ expression and function. Capture of the miR-96 targetome by biotin-miR-96 identified that RARγ and a number of RARγ interacting co-factors including TACC1 were all targeted by miR-96, and expression of these genes were prominently altered, positively and negatively, in the TCGA-PRAD cohort. Differential gene expression analyses between tumors in the TCGA-PRAD cohort with lower quartile expression levels of RARG and TACC1 and upper quartile miR-96, compared to the reverse, identified a gene network including several RARγ target genes (e.g., SOX15) that significantly associated with worse disease-free survival (hazard ratio 2.23, 95% CI 1.58 to 2.88, p = 0.015). In summary, miR-96 targets a RARγ network to govern AR signaling, PCa progression and disease outcome.


Assuntos
Adenocarcinoma/patologia , Androgênios , MicroRNAs/fisiologia , Proteínas de Neoplasias/fisiologia , Neoplasias Hormônio-Dependentes/patologia , Neoplasias da Próstata/patologia , RNA Neoplásico/fisiologia , Receptores do Ácido Retinoico/fisiologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Animais , Linhagem Celular Tumoral , Progressão da Doença , Elementos Facilitadores Genéticos , Proteínas Fetais/metabolismo , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Neoplasias Hormônio-Dependentes/genética , Neoplasias Hormônio-Dependentes/metabolismo , Neoplasias Hormônio-Dependentes/mortalidade , Proteínas Nucleares/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/mortalidade , Interferência de RNA , RNA Interferente Pequeno/genética , Receptores Androgênicos/metabolismo , Transdução de Sinais
8.
Oncogene ; 38(4): 564-580, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30166592

RESUMO

Platinum drugs are used in first-line to treat ovarian cancer, but most of the patients eventually generate resistance after treatment with these drugs. Although both c-Myc and EZH2 have been implicated in regulating cisplatin resistance in ovarian cancer, the interplay between these two regulators is poorly understood. Using RNA sequence analysis (RNA-seq), for the first time we find that miR-137 level is extremely low in cisplatin resistant ovarian cancer cells, correlating with higher levels of c-Myc and EZH2 expression. Further analyses indicate that in resistant cells c-Myc enhances the expression of EZH2 by directly suppressing miR-137 that targets EZH2 mRNA, and increased expression of EZH2 activates cellular survival pathways, resulting in the resistance to cisplatin. Inhibition of c-Myc-miR-137-EZH2 pathway re-sensitizes resistant cells to cisplatin. Both in vivo and in vitro analyses indicate that cisplatin treatment activates c-Myc-miR-137-EZH2 pathway. Importantly, elevated c-Myc-miR-137-EZH2 pathway in resistant cells is sustained by dual oxidase maturation factor 1 (DUOXA1)-mediated production of reactive oxygen species (ROS). Significantly, clinical studies further confirm the activated c-Myc-miR-137-EZH2 pathway in platinum drug-resistant or recurrent ovarian cancer patients. Thus, our studies elucidate a novel role of miR-137 in regulating c-Myc-EZH2 axis that is crucial to the regulation of cisplatin resistance in ovarian cancer.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Proteína Potenciadora do Homólogo 2 de Zeste/fisiologia , MicroRNAs/fisiologia , Proteínas de Neoplasias/fisiologia , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myc/fisiologia , RNA Neoplásico/fisiologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , MicroRNAs/genética , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Regiões Promotoras Genéticas , RNA Neoplásico/genética , Proteínas Recombinantes de Fusão/metabolismo , Análise de Sequência de RNA , Transdução de Sinais/fisiologia
9.
Exp Hematol ; 68: 80-88.e2, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30195077

RESUMO

BCR-ABL1-independent mechanisms had been thought to mediate drug resistance to tyrosine kinase inhibitors (TKIs) in patients with chronic myelogenous leukemia (CML). The pro-oncogenic anterior gradient 2 (AGR2) mediates drug resistance of cancer cells. In this study, we observed an increased level of AGR2 in TKI-resistant CML cells. Silence of AGR2 in dasatinib-resistant K562 (K562DR) cells led to restored sensitivity to dasatinib both in vitro and in vivo. Exposure to dasatinib induced upregulation of AGR2 in K562 cells, which indicated a probable treatment-related drug resistance. We further investigated the potential interaction between microRNA (miRNA) and AGR2 in K562DR cells and found that downregulation of miR-217 was associated with overexpression of AGR2 in K562DR cells. Luciferase reporter assay identified that miR-217 negatively regulated expression of AGR2 through binding the 3'-untranslated region of AGR2. Hypermethylation of the CpG island on the promoter region of the MIR217 gene is a probable reason for the downregulation of miR-217 in dasatinib-treated K562 cells. Forced expression of miR-217 led to decreased expression of AGR2 as well as compromised TKI-resistant potential of K562DR cells. Similarly, overexpression of miR-217 resensitized K562DR cells to dasatinib treatment in a murine xenograft transplantation model. TKI treatment-induced drug resistance is correlated with a decrease of miR-217 and upregulation of AGR2. The miR-217/AGR2 interaction might be a potential therapeutic target in treating CML patients with TKI resistance.


Assuntos
Antineoplásicos/farmacologia , Regulação Leucêmica da Expressão Gênica , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , MicroRNAs/fisiologia , Proteínas de Neoplasias/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas/genética , RNA Neoplásico/fisiologia , Regiões 3' não Traduzidas , Animais , Linhagem Celular Tumoral , Metilação de DNA , Dasatinibe/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Camundongos , Camundongos Endogâmicos NOD , MicroRNAs/biossíntese , MicroRNAs/genética , Proteínas de Neoplasias/metabolismo , Regiões Promotoras Genéticas , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas/metabolismo , RNA/metabolismo , Interferência de RNA , RNA Neoplásico/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Organismos Livres de Patógenos Específicos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Exp Hematol ; 68: 66-79.e3, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30208330

RESUMO

The selection of chemotherapy regimen for elderly patients with acute myeloid leukemia (AML) remains challenging. Here, we report that granulocyte colony-stimulating factor (G-CSF) upregulates the expression of microRNA (miR)-146a in a nuclear factor kappaB-dependent manner, leading to direct decreases in the expression of the target proteins CXCR4 and Smad4 in AML cells in vitro. The reduction in CXCR4 expression suppressed the migration abilities of leukemia cells. Downregulation of Smad4 promoted cell cycle entry in leukemia cells. Furthermore, an increase in apoptosis was observed when leukemia cells were treated sequentially with G-CSF and cytosine arabinoside in vitro. These findings suggest that G-CSF treatment may disrupt the protection of bone marrow niches from leukemia cells. In a review of data from 78 cases of primary AML, we found that a high miR-146a expression and/or upregulation of this miRNA during G-CSF priming chemotherapy was predictive of better clinical outcomes. Our findings suggest that miR-146a may be a novel biomarker for evaluating the clinical prognosis and treatment effects of a G-CSF priming protocol in elderly patients with AML.


Assuntos
Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , MicroRNAs/fisiologia , RNA Neoplásico/fisiologia , Aclarubicina/administração & dosagem , Aclarubicina/efeitos adversos , Aclarubicina/farmacologia , Fatores Etários , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiotaxia/efeitos dos fármacos , Técnicas de Cocultura , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Citarabina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Células HL-60 , Humanos , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Masculino , MicroRNAs/biossíntese , MicroRNAs/genética , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Prognóstico , Interferência de RNA , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , RNA Interferente Pequeno/genética , Receptores CXCR4/biossíntese , Receptores CXCR4/genética , Proteína Smad4/biossíntese , Proteína Smad4/genética , Nicho de Células-Tronco , Microambiente Tumoral , Regulação para Cima/efeitos dos fármacos
11.
Exp Hematol ; 67: 32-40.e3, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30172749

RESUMO

Acute myeloid leukemia (AML) is a heterogeneous hematopoietic disorder initiated from a small subset of leukemia stem cell (LSC), which presents unrestricted self-renewal and proliferation. Long non-coding RNA HOTAIR is abundantly expressed and plays oncogenic roles in solid cancer and AML. However, whether HOTAIR regulates the self-renewal of LSC is largely unknown. Here, we reported that the expression of HOTAIR was increased in LSC than in normal hematological stem and progenitor cells (HSPCs). HOTAIR inhibition by short hairpin RNAs (shRNAs) decreased colony formation in leukemia cell lines and primary AML blasts. We then investigated the role of HOTAIR in leukemia in vivo. HOTAIR knockdown extends the survival time in U937-transplanted NSG mice. Furthermore, HOTAIR knockdown reduced infiltration of leukemic blasts, decreased frequency of LSC, and prolonged overall survival in MLL-AF9-induced murine leukemia, suggesting that HOTAIR is required for the maintenance of AML. Mechanistically, HOTAIR inhibited p15 expression through zeste homolog 2 (EZH2)-enrolled tri-methylation of Lys 27 of histone H3 (H3K27me3) in p15 promoter. In addition, p15 partially reversed the decrease of colony and proliferation induced by HOTAIR knockdown, suggesting that p15 plays an important role in the leukemogenesis by HOTAIR. In conclusion, our study suggests that HOTAIR facilitates leukemogenesis by enhancing self-renewal of LSC. HOTAIR might be a potential target for anti-LSC therapy.


Assuntos
Autorrenovação Celular/fisiologia , Transformação Celular Neoplásica/genética , Inibidor de Quinase Dependente de Ciclina p15/antagonistas & inibidores , Inativação Gênica , Código das Histonas/genética , Leucemia Mieloide Aguda/patologia , Células-Tronco Neoplásicas/citologia , RNA Longo não Codificante/fisiologia , RNA Neoplásico/fisiologia , Animais , Transplante de Medula Óssea , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor de Quinase Dependente de Ciclina p15/fisiologia , Proteína Potenciadora do Homólogo 2 de Zeste/fisiologia , Regulação Leucêmica da Expressão Gênica , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Leucemia Mieloide Aguda/genética , Camundongos , Terapia de Alvo Molecular , Proteínas de Fusão Oncogênica/genética , Regiões Promotoras Genéticas , Ensaio Tumoral de Célula-Tronco , Células U937
12.
Cell Mol Biol (Noisy-le-grand) ; 64(6): 48-52, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29808800

RESUMO

Hepatocellular carcinoma (HCC) is a common human malignancy. In this study, we aimed to investigate the serum levels of visfatin and miR-21 in HCC patients, to analysis the relationship between the pathological features and the plasma level of visfatin or miR-21, and to explore the roles of visfatin and miR-21 in migration of HCC cells. Our results showed that the serum levels of visfatin and miR-21 were significant higher in HCC patients than healthy subjects. The diagnostic sensitivity of serum visfatin was 82.5% and the specificity was 65.0%. The serum visfatin was significantly associated with the histology and metastasis. Visfatin induced miR-21 expression and cell migration in HepG2 cells. Transfection of miR-21 inhibitor suppressed the visfatin-induced migration in HCC cells. These results suggested that visfatin induced HCC cell migration via upregulation of miR-21, which provides a novel basis for the diagnosis of HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Citocinas/fisiologia , Neoplasias Hepáticas/patologia , MicroRNAs/fisiologia , Proteínas de Neoplasias/fisiologia , Nicotinamida Fosforribosiltransferase/fisiologia , RNA Neoplásico/fisiologia , Gordura Abdominal/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/epidemiologia , Citocinas/sangue , Citocinas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/epidemiologia , Masculino , MicroRNAs/biossíntese , MicroRNAs/sangue , MicroRNAs/genética , Pessoa de Meia-Idade , Metástase Neoplásica , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/metabolismo , Nicotinamida Fosforribosiltransferase/sangue , Nicotinamida Fosforribosiltransferase/metabolismo , RNA Neoplásico/biossíntese , RNA Neoplásico/sangue , RNA Neoplásico/genética , Proteínas Recombinantes/metabolismo , Sensibilidade e Especificidade , Regulação para Cima
13.
Cell Mol Biol (Noisy-le-grand) ; 64(6): 42-47, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29808799

RESUMO

Retinoblastoma (RB) is a childhood intraocular tumor, affecting millions of patients worldwide. MicroRNA-140-5p (miR-140-5p) was demonstrated to be involved in the tumorigenesis of various human cancers; however, its role in RB remains undetermined. In this study, quantitative real-time PCR (qRT-PCR) and Western blot assays were used to determine the expression levels of miR-140-5p, cell migration-inducing protein (CEMIP), and cell adhesion molecule 3 (CADM3) in RB tissues and cell-lines. The proliferation ability was detected by cell-counting kit 8 (CCK-8), Edu staining, and colony formation assay. The cell cycle and migration and invasion abilities were measured by flow cytometry, wound-healing assay and Transwell assays, respectively. The correlation between miR-140-5p and CEMIP/CADM3 were then confirmed by immunofluorescence (IF) and dual-luciferase reporter assays. The results showed that miR-140-5p expression was significantly decreased; however, CEMIP and CADM3 expression was increased in RB tissues and cells. Overexpression of miR-140-5p inhibited proliferation, migration, and invasion of RB cells. We also found that miR-140-5p inhibited CEMIP and CADM3 expressions in RB cells. In addition, we demonstrated that miR-140-5p might negatively regulate the transcriptional activities of CEMIP and CADM3 by targeting their 3'-UTR. Therefore, we suggested that miR-140-5p could be a potential therapeutic target for the treatment of RB through CEMIP and CADM3.


Assuntos
Moléculas de Adesão Celular/antagonistas & inibidores , Neoplasias Oculares/patologia , Regulação Neoplásica da Expressão Gênica , MicroRNAs/fisiologia , Proteínas de Neoplasias/fisiologia , Proteínas/antagonistas & inibidores , RNA Neoplásico/fisiologia , Retinoblastoma/patologia , Moléculas de Adesão Celular/metabolismo , Divisão Celular , Linhagem Celular Tumoral , Movimento Celular , Neoplasias Oculares/genética , Genes Reporter , Humanos , Hialuronoglucosaminidase , Imunoglobulinas/metabolismo , MicroRNAs/genética , Terapia de Alvo Molecular , Invasividade Neoplásica , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Proteínas Recombinantes/metabolismo , Retinoblastoma/genética , Células Tumorais Cultivadas , Ensaio Tumoral de Célula-Tronco
14.
Exp Hematol ; 62: 1-6, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29601851

RESUMO

Acute myeloid leukemia (AML) arises when immature myeloid blast cells acquire multiple, recurrent genetic and epigenetic changes that result in dysregulated proliferation. Acute leukemia is the most common form of pediatric cancer, with AML accounting for ~20% of all leukemias in children. The genomic aberrations that drive AML inhibit myeloid differentiation and activate signal transduction pathways that drive proliferation. MicroRNAs, a class of small (~22 nucleotide) noncoding RNAs that posttranscriptionally suppress the expression of specifically targeted transcripts, are also frequently dysregulated in AML, which may prove useful for the purposes of disease classification, prognosis, and future therapeutic approaches. MicroRNA expression profiles are associated with patient prognosis and responses to standard chemotherapy, including predicting therapy resistance in AML. miR-155 is the primary focus of this review because it has been repeatedly associated with poorer survival across multiple cohorts of adult and pediatric AML. We discuss some novel features of miR-155 expression in AML, in particular how the levels of expression can critically influence function. Understanding the role of microRNAs in AML and the ways in which microRNA expression influences AML biology is one means to develop novel and more targeted therapies.


Assuntos
Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/genética , MicroRNAs/fisiologia , RNA Neoplásico/fisiologia , Adulto , Animais , Criança , Redes Reguladoras de Genes , Humanos , Inflamação/genética , Camundongos , MicroRNAs/biossíntese , MicroRNAs/genética , Fenótipo , Prognóstico , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Transcrição Genética , Transcriptoma , Carga Tumoral
15.
J Ovarian Res ; 10(1): 33, 2017 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-28476165

RESUMO

BACKGROUND: Ovarian cancer is the leading lethal, gynecological malignancy in the United States. No doubt, the continued morbidity and mortality of ovarian cancer reflects a poor understanding of invasive mechanisms. Recent studies reveal that ovarian cancers express aberrant microRNAs (miRNAs or miRs), some of which have oncogenic or tumor suppressor properties. Several studies suggested that miR-205 is involved in tumorigenesis. Presently, we investigate the molecular mechanisms and target of miR-205 in ovarian cancer. METHODS: Quantitative real-time polymerase chain reaction and western blot were performed to assess miR-205 and transcription factor 21 (TCF21) expression in ovarian cancer and normal ovary samples. The effect of miR-205 on TCF21 was determined by luciferase reporter assay and western blot. The effect of miR-205 and TCF21 on cell invasion was quantitated using transwell invasion assay. RESULT: miR-205 expression was increased in ovarian cancer and it promoted the invasive behavior of ovarian cancer cell lines (OVCAR-5, OVCAR-8 and SKOV-3). miR-205 directly targeted TCF21, which was significantly decreased in ovarian cancer tissue. miR-205 inhibited TCF21 expression and as a consequence blunted the inhibitory effect of TCF21 on cell invasion. Matrix Metalloproteinases (MMPs) play an important role in cancer invasion and metastasis. TCF21 inhibited MMP-2 and MMP-10 and decreased ovarian cancer cell invasion. Co-transfection of TCF21 expression plasmid with miR-205 mimic diminished the inhibitory effect of TCF21 on MMP-2 and MMP-10 in ovarian cancer cells. CONCLUSION: miR-205 appears to have an important role in the spread of ovarian cancer by targeting TCF21. These findings offer a new mechanism of ovarian cancer tumorigenesis, which could be useful for the development of new therapeutic approaches to ovarian cancer treatment.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , MicroRNAs/fisiologia , Neoplasias Ovarianas/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Transformação Celular Neoplásica/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metaloproteinases da Matriz/fisiologia , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Ovário/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/fisiologia , Células Tumorais Cultivadas , Regulação para Cima
16.
Exp Biol Med (Maywood) ; 242(7): 709-717, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28299977

RESUMO

This study aimed to screen lymphatic metastasis-related microRNAs (miRNAs) in lung adenocarcinoma and explore their underlying mechanisms using bioinformatics. The miRNA expression in primary lung adenocarcinoma, matched adjacent non-tumorigenic and lymph node metastasis tissues of patients were profiled via microarray. The screened metastasis-related miRNAs were then validated using quantitative real-time PCR in a second cohort of lung adenocarcinoma patients with lymphatic metastasis. Significance was determined using a paired t-test. Target genes of the metastasis-related miRNAs were predicted using TargetScan, and transcription factors (TFs) were predicted based on the TRANSFAC and ENCODE databases. Furthermore, the related long non-coding RNAs (lncRNAs) were screened with starBase v2.0. The miRNA-TF-mRNA and lncRNA-miRNA-mRNA networks were constructed to determine the key interactions associated with lung adenocarcinoma metastasis. According to the miRNA microarray results, there were 10 miRNAs that were differentially expressed in metastatic tissues compared with primary tumor and adjacent non-tumorigenic tissues. Among them were increased levels of miR-146a-5p, miR-342-3p, and miR-150-5p, which were validated in the second cohort. Based on the miRNA-TF-mRNA network, vascular endothelial growth factor A and transcription factors (TFs) including TP53, SMAD4, and EP300 were recognized as critical targets of the three miRNAs. Interactions involving SNHG16-miR-146a-5p-SMAD4 and RP6-24A23.7-miR-342-3p/miR-150-5p-EP300 were highlighted according to the lncRNA-miRNA-mRNA network. miR-146a-5p, miR-342-3p, and miR-150-5p are lymphatic metastasis-related miRNAs in lung adenocarcinoma. Bioinformatics analyses demonstrated that SNHG16 might inhibit the interaction between miR-146a-5p and SMAD4, while RP6-24A23.7 might weaken miR-342-3p-EP300 and miR-150-5p-EP300 interactions in metastasis.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias Pulmonares/metabolismo , MicroRNAs/fisiologia , Adenocarcinoma/patologia , Estudos de Casos e Controles , Biologia Computacional/métodos , Feminino , Humanos , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , RNA Neoplásico/fisiologia , Reação em Cadeia da Polimerase em Tempo Real
17.
Int J Cancer ; 140(6): 1457-1464, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-27914101

RESUMO

Ultraconserved regions (UCRs) are non-protein coding gene sequences that are strictly conserved across among different species. Emerging evidence demonstrates that transcribed ultraconserved regions (TUCRs) encoding noncoding RNAs serve as regulators of gene expression. In recent decades, increasing evidence implicates the involvement of UCRs in carcinogenesis. The role of TUC.338 in cervical cancers was an oncogene in previous studies. Until now, the role of TUC.338 in colorectal cancers remains undefined. This study revealed that TUC.338 is significantly up-regulated in colorectal cancers (CRC) tissue and CRC cell lines, and the up-regulated TUC.338 is associated with lymph node metastasis. Transfection with small interfering RNA (siRNA) markedly inhibited cell migration and invasion in SW480 and HCT116 colorectal cancer cell lines. TIMP-1 was demonstrated to be negatively regulated by TUC.338 at the posttranscriptional level, via a specific target site within the 3' untranslated region by dual-luciferase reporter assay. The expression of TIMP-1 was also observed to inversely correlate with TUC.338 expression in CRC tissues. Over-expression of TIMP-1 with migRI-TIMP-1-GFP inhibited CRC cell migration and invasion and down-regulates MMP9, resembling that of TUC.338-siRNA. Thus, these findings suggested that TUC.338 acts as a novel oncogene by targeting the TIMP-1 gene thus promoting colorectal cancer cell migration and invasion.


Assuntos
Adenocarcinoma/patologia , Neoplasias Colorretais/patologia , RNA Longo não Codificante/fisiologia , RNA Neoplásico/fisiologia , Regiões 3' não Traduzidas/genética , Adenocarcinoma/genética , Adulto , Idoso , Linhagem Celular Tumoral , Movimento Celular , Neoplasias Colorretais/genética , Sequência Conservada/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Metaloproteinase 9 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/genética , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Oncogenes , Interferência de RNA , RNA Longo não Codificante/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , RNA Interferente Pequeno/genética , Inibidor Tecidual de Metaloproteinase-1/biossíntese , Inibidor Tecidual de Metaloproteinase-1/genética
18.
Arch. bronconeumol. (Ed. impr.) ; 52(10): 505-511, oct. 2016. graf
Artigo em Espanhol | IBECS | ID: ibc-156370

RESUMO

Introducción: El microARN (miR) se ha relacionado con la génesis tumoral en muchos tipos de cáncer, pero ningún estudio ha examinado el rol exacto del miR-133 en el cáncer de pulmón. Métodos: Identificamos el miR-133 como posible regulador de la expresión de la FOXQ1 e investigamos la posible implicación del miR-133 en la migración y la invasión de células de cáncer de pulmón, y el mecanismo molecular subyacente. Resultados: El miR-133 se dirigió directamente y redujo la expresión de la FOXQ1, que a su vez redujo la concentración de TGF-β. El miR-133 disminuyó en líneas celulares de cáncer de pulmón A549 y HCC827, y su reexpresión inhibió significativamente la migración y la invasión de células de cáncer de pulmón. Investigaciones subsiguientes revelaron que dicha inhibición estaba provocada por una inversión de la transición epitelio-mesenquimatosa, constatada por una elevación del marcador epitelial E-cadherina inducida por el miR-133 y una reducción del marcador vimentina. Conclusiones: Nuestro estudio es el primero que ha identificado el miR-133 como biomarcador del cáncer de pulmón. Su función es reducir la FOXQ1 e inhibir la transición epitelio-mesenquimatosa, la cual antagoniza la génesis tumoral en el cáncer de pulmón. Por consiguiente, nuestros datos respaldan el papel del miR-133 como posible instrumento terapéutico molecular en el tratamiento del cáncer de pulmón


Introduction: MicroRNA (miR) was implicated in the tumorigenesis of many types of cancer, but no study was conducted on the exact role of miR-133 in lung cancer. Methods: We have identified miR-133 as a putative regulator of FOXQ1 expression, and investigated the potential involvement of miR-133 in the migration and invasion of lung cancer cells, as well as the underlying molecular mechanism. Results: MiR-133 directly targeted and down-regulated FOXQ1 expression, which in turn reduced TGF-β level. MiR-133 was down-regulated in lung cancer cell lines A549 and HCC827, and its re-expression significantly inhibited the migration and invasion of the lung cancer cells. Further investigation revealed that this inhibition was caused by reversing the epithelial-mesenchymal transition, evidenced by miR-133 induced elevation of epithelial marker E-cadherin, and reduction of mesenchymal marker Vimentin. Conclusions: Our study is the first to identify miR-133 as a biomarker for lung cancer. It functions to down-regulate FOXQ1, and inhibit epithelial mesenchymal transition, which antagonizes lung cancer tumorigenesis. Therefore our data support the role of miR-133 as a potential molecular therapeutic tool in treating lung cancer


Assuntos
Humanos , Transição Epitelial-Mesenquimal/fisiologia , Fatores de Transcrição Forkhead/biossíntese , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/patologia , MicroRNAs/fisiologia , Proteínas de Neoplasias/biossíntese , RNA Neoplásico/fisiologia , Caderinas , Regiões 3' não Traduzidas , Adesão Celular , Linhagem Celular Tumoral , Invasividade Neoplásica , Fator de Crescimento Transformador beta , Vimentina
19.
Urol Oncol ; 34(12): 533.e21-533.e27, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27427222

RESUMO

AIM: Clear cell renal cell carcinoma (ccRCC) is the third most common urological cancer after prostate and bladder cancer but has the highest rate of mortality affecting over 40% of patients. microRNAs (miRNAs) are small noncoding RNAs that have become potential biomarkers and molecular targets for cancer treatment. Molecular markers such as miRNAs may have a role in the diagnosis of ccRCC. In this study, we examined the expressions of miRNA-21 and miRNA-221 in renal cancer patients׳ tumor and adjacent paired normal tissues investigating the possible role of these miRNAs in the development of ccRCC. MATERIALS AND METHODS: Renal tumors (n = 24) and paired normal renal tissue (n = 24) samples, obtained from the Department of Urology, University of Debrecen, were analyzed for miRNA-21 and miRNA-221 expressions with quantitative real-time polymerase chain reaction. RESULTS: miRNA-21 and miRNA-221 expressions were significantly up-regulated in tumor specimens compared to normal tissue (P<0.05). miRNA-21 and miRNA-221 showed coexpression pattern in 19 (79.2%) cases of tumor samples and 8 (33.3%) cases of paired normal renal tissues. Increased miRNA pattern showed a positive correlation with pathological status of the patients. CONCLUSIONS: Expression of oncogenic miRNA-21 and miRNA-221 in human ccRCC tumor tissue samples compared to adjacent nontumorous tissues might suggest that these miRNAs are involved in the development of ccRCC.


Assuntos
Carcinoma de Células Renais/genética , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , MicroRNAs/biossíntese , RNA Neoplásico/biossíntese , Adulto , Idoso , Biomarcadores Tumorais , Carcinoma de Células Renais/etiologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Feminino , Humanos , Rim/metabolismo , Neoplasias Renais/etiologia , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , MicroRNAs/genética , MicroRNAs/fisiologia , Pessoa de Meia-Idade , Gradação de Tumores , RNA Neoplásico/genética , RNA Neoplásico/fisiologia , Reação em Cadeia da Polimerase em Tempo Real , Regulação para Cima
20.
Sci Rep ; 6: 26788, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27245437

RESUMO

One of greatest challenges to the successful treatment of cancer is drug resistance. An exciting approach is the eradication of cancer stem cells (CSCs). However, little is known about key signals regulating the formation and expansion of CSCs. Moreover, lack of a reliable predictive preclinical model has been a major obstacle to discover new cancer drugs and predict their clinical activity. Here, in ovarian cancer, a highly chemoresistant tumor that is rapidly fatal, we provide the first evidence demonstrating the causal involvement of mechanical stimulus in the CSC phenotype using a customizable microfluidic platform and three-dimensional spheroids, which most closely mimic tumor behavior. We found that ovarian cancer cells significantly acquired the expression of epithelial-to-mesenchymal transition and CSC markers and a remarkable chemoresistance to clinically relevant doses of frontline chemotherapeutic drugs cisplatin and paclitaxel when grown under fluid shear stress, which corroborates with the physiological attainable levels in the malignant ascites, but not under static condition. Furthermore, we uncovered a new link of microRNA-199a-3p, phosphatidylinositol 3-kinase/Akt, and multidrug transporter activation in shear stress-induced CSC enrichment. Our findings shed new light on the significance of hydrodynamics in cancer progression, emphasizing the need of a flow-informed framework in the development of therapeutics.


Assuntos
Carcinoma/patologia , Resistencia a Medicamentos Antineoplásicos , Hidrodinâmica , Células-Tronco Neoplásicas/citologia , Neoplasias Ovarianas/patologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/fisiologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/fisiologia , Animais , Ascite/patologia , Transição Epitelial-Mesenquimal , Feminino , Xenoenxertos , Humanos , Dispositivos Lab-On-A-Chip , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/fisiologia , Proteínas de Neoplasias/fisiologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/transplante , RNA Neoplásico/fisiologia , Resistência ao Cisalhamento , Transdução de Sinais , Esferoides Celulares , Células Tumorais Cultivadas
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