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1.
Nat Commun ; 11(1): 5400, 2020 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-33106502

RESUMO

Slug (SNAI2), a member of the well-conserved Snail family of transcription factors, has multiple developmental roles, including in epithelial-to-mesenchymal transition (EMT). Here, we show that Slug is critical for the pathological angiogenesis needed to sustain tumor growth, and transiently necessary for normal developmental angiogenesis. We find that Slug upregulation in angiogenic endothelial cells (EC) regulates an EMT-like suite of target genes, and suppresses Dll4-Notch signaling thereby promoting VEGFR2 expression. Both EC-specific Slug re-expression and reduced Notch signaling, either by γ-secretase inhibition or loss of Dll4, rescue retinal angiogenesis in SlugKO mice. Conversely, inhibition of VEGF signaling prevents excessive angiogenic sprouting of Slug overexpressing EC. Finally, endothelial Slug (but not Snail) is activated by the pro-angiogenic factor SDF1α via its canonical receptor CXCR4 and the MAP kinase ERK5. Altogether, our data support a critical role for Slug in determining the angiogenic response during development and disease.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Células Endoteliais/metabolismo , Neovascularização Patológica/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas de Ligação ao Cálcio/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Patológica/genética , Receptores Notch/genética , Receptores Notch/metabolismo , Transdução de Sinais , Fatores de Transcrição da Família Snail/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
2.
PLoS Genet ; 16(9): e1008912, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32946434

RESUMO

The mechanism(s) through which mammalian kinase MELK promotes tumorigenesis is not understood. We find that the C. elegans orthologue of MELK, PIG-1, promotes apoptosis by partitioning an anti-apoptotic factor. The C. elegans NSM neuroblast divides to produce a larger cell that differentiates into a neuron and a smaller cell that dies. We find that in this context, PIG-1 MELK is required for partitioning of CES-1 Snail, a transcriptional repressor of the pro-apoptotic gene egl-1 BH3-only. pig-1 MELK is controlled by both a ces-1 Snail- and par-4 LKB1-dependent pathway, and may act through phosphorylation and cortical enrichment of nonmuscle myosin II prior to neuroblast division. We propose that pig-1 MELK-induced local contractility of the actomyosin network plays a conserved role in the acquisition of the apoptotic fate. Our work also uncovers an auto-regulatory loop through which ces-1 Snail controls its own activity through the formation of a gradient of CES-1 Snail protein.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição/metabolismo , Actomiosina/metabolismo , Animais , Animais Geneticamente Modificados , Apoptose/fisiologia , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Morte Celular/fisiologia , Polaridade Celular/fisiologia , Proteínas do Citoesqueleto/metabolismo , Proteínas de Ligação a DNA/genética , Miosina Tipo II/metabolismo , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo , Fatores de Transcrição/genética
3.
Life Sci ; 258: 118158, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32750435

RESUMO

AIMS: Glioblastoma multiforme (GBM) is characterized by aggressive infiltration and terrible lethality. The overwhelming majority of chemotherapeutic drugs fail to exhibit the desired treatment effects. Polydatin (PD), which was initially extracted from Polygonum cuspidatum, is distinguished for its outstanding cardioprotective, hepatoprotective, and renal protective effects, as well as significant anticancer activities. However, the anti-GBM effect of PD is unclear. MATERIALS AND METHODS: Cell proliferation and apoptosis after PD intervention were estimated using MTT, colony formation and flow cytometry assays in vitro, while wound-healing and Transwell assays were applied to assess cell migration and invasion. In addition, the anti-GBM effects of PD in vivo were detected in the subcutaneous tumor model of nude mice. Moreover, Western blot, immunofluorescence and immunohistochemical staining assays were employed to elaborate the relevant molecular mechanisms. KEY FINDINGS: The present study demonstrated that PD repressed cell proliferation, migration, invasion and stemness and promoted apoptosis in GBM cells. Moreover, by correlating the molecular characteristics of cancer cells with different sensitivities to PD and employing diverse analytical methods, we ultimately verified that the cytotoxicity of PD was related to EGFR-AKT/ERK1/2/STAT3-SOX2/Snail signaling pathway inhibition, in which multiple components were vital therapeutic targets of GBM. SIGNIFICANCE: This work demonstrated that PD could inhibit proliferation, migration, invasion and stemness and induce apoptosis by restraining multiple components of the EGFR-AKT/ERK1/2/STAT3-SOX2/Snail signaling pathway in GBM cells.


Assuntos
Antineoplásicos/uso terapêutico , Glioblastoma/tratamento farmacológico , Glucosídeos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Estilbenos/uso terapêutico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Glioblastoma/metabolismo , Glucosídeos/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Fator de Transcrição STAT3/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Estilbenos/farmacologia
4.
Life Sci ; 257: 118017, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32603821

RESUMO

AIMS: Mesenchymal stem cell (MSC)-derived exosomes (MSCs-exos) regulate biological functions in different diseases, such as liver fibrosis, diabetes, and ischaemic heart injury. However, the function of MSC-derived exosomes on the intestinal barrier and the underlying mechanisms are poorly characterized. MAIN METHODS: The expression of miR-34a/c-5p, miR-29b-3p and Claudin-3 in human normal intestinal tissues and damaged intestinal tissues was evaluated by RT-qPCR. The effect of MSC-secreted exosomes on Claudins in Caco-2 cells was measured by using confocal microscopy, RT-qPCR and Western blot. Dual luciferase reporter assays and RNA immunoprecipitation (RIP) assays were performed to study the interaction between miR-34a/c-5p, miR-29b-3p and Snail. I/R-induced intestinal damage in rats was used to determine the in vivo effect of MSC-exos on intestinal barrier function. KEY FINDINGS: In this study, we found that miR-34a/c-5p, miR-29b-3p and Claudin-3 were downregulated in damaged human intestinal tissues. MSC-exos increased the expression of Claudin-3, Claudin-2 and ZO-1 in Caco-2 cells. Further studies demonstrated that MSC-exos promoted Claudin-3, Claudin-2 and ZO-1 expression in Caco-2 cells by Snail, which was targeted by miR-34a/c-5p and miR-29b-3p. In vivo experiments showed that MSC-derived exosomes could improve I/R-induced intestinal damage through the Snail/Claudins signaling pathway. SIGNIFICANCE: The findings here suggest a novel molecular basis for the therapy of intestinal barrier dysfunction.


Assuntos
Mucosa Intestinal/metabolismo , MicroRNAs/genética , Animais , Condrócitos/metabolismo , Claudinas/metabolismo , Exossomos/genética , Exossomos/metabolismo , Humanos , Intestinos/fisiologia , Masculino , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/fisiologia , MicroRNAs/fisiologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Fatores de Transcrição da Família Snail/metabolismo
5.
Life Sci ; 257: 118010, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32598932

RESUMO

Podocyte injury is an early event and core in the development of focal segmental glomerular sclerosis (FSGS) that induces poor prognosis. Epithelial-mesenchymal transition (EMT) as a response of podocyte to injury leads to podocyte depletion and proteinuria. The abnormally reactivated NOTCH pathway may be involved in podocyte EMT. Baicalin, as a natural flavonoid compound, had significant inhibitory activity on tissue fibrosis and tumor cell invasion. However, its potential role and molecular mechanisms to injured podocyte in FSGS are little known. Here we found that baicalin could inhibit podocyte EMT markers expression and cell migration induced by TGF-ß1, accompanied by the up-regulated expression of slit diaphragm (SD) proteins and cell-cell adhesion molecule. Further investigation revealed that EMT inhibition of baicalin on injured podocyte is mainly mediated by the reduction of notch1 activation and its downstream Snail expression. Using the adriamycin-induced FSGS model, we determined that baicalin suppresses the Notch1-Snail axis activation in podocytes, relieves glomerulus structural disruption and dysfunction, and reduces proteinuria. Altogether, these findings suggest that baicalin is a novel renoprotective agent against podocyte EMT in FSGS and indicate its underlying mechanism that involves in negative regulation of the Notch1-Snail axis.


Assuntos
Flavonoides/farmacologia , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Proteinúria/tratamento farmacológico , Animais , Biomarcadores/metabolismo , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Doxorrubicina/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Flavonoides/metabolismo , Glomerulosclerose Segmentar e Focal/metabolismo , Glomérulos Renais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Podócitos/metabolismo , Proteinúria/metabolismo , Receptor Notch1/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
6.
Cancer Sci ; 111(9): 3210-3221, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32519357

RESUMO

Non-small-cell lung cancer (NSCLC) is the leading global cause of cancer-related death. Due to the lack of reliable diagnostic or prognostic biomarkers, the prognosis of NSCLC remains poor. Consequently, there is an urgent need to explore the mechanisms underlying this condition in order to identify effective biomarkers. G-protein-signaling modulator 2 (GPSM2) is widely recognized as a determinant of mitotic spindle orientation. However, its role in cancer, especially NSCLC, remains uncertain. In this study, we found that GPSM2 was downregulated in NSCLC tissues and was correlated with a poor prognosis. Furthermore, the knockdown of GPSM2 promoted NSCLC cell metastasis in vitro and in vivo and accelerated the process of epithelial-mesenchymal transition (EMT). Mechanistically, we showed that silencing GPSM2 induced cell metastasis and EMT through the ERK/glycogen synthase kinase-3ß/Snail pathway. These results confirm that GPSM2 plays an important role in NSCLC. Moreover, GPSM2, as an independent prognostic factor, could be a potential prognostic biomarker and drug target for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/genética , Fatores de Transcrição da Família Snail/genética , Adulto , Idoso , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Bases de Dados Genéticas , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Camundongos , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Fatores de Transcrição da Família Snail/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Genes Dev ; 34(13-14): 965-972, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32467225

RESUMO

Graded transcription factors are pivotal regulators of embryonic patterning, but whether their role changes over time is unclear. A light-regulated protein degradation system was used to assay temporal dependence of the transcription factor Dorsal in dorsal-ventral axis patterning of Drosophila embryos. Surprisingly, the high-threshold target gene snail only requires Dorsal input early but not late when Dorsal levels peak. Instead, late snail expression can be supported by action of the Twist transcription factor, specifically, through one enhancer, sna.distal This study demonstrates that continuous input is not required for some Dorsal targets and downstream responses, such as twist, function as molecular ratchets.


Assuntos
Padronização Corporal/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/embriologia , Drosophila melanogaster/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Fatores de Transcrição/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Animais , Padronização Corporal/efeitos da radiação , Proteínas de Drosophila/genética , Embrião não Mamífero , Luz , Proteínas Nucleares/genética , Fosfoproteínas/genética , Proteólise/efeitos da radiação , Fatores de Transcrição da Família Snail/metabolismo , Fatores de Transcrição/genética , Proteína 1 Relacionada a Twist/genética
8.
Oncol Res ; 28(4): 423-438, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32331534

RESUMO

Although oxaliplatin serves as one of the first-line drugs prescribed for treating colorectal cancer (CRC), the therapeutic effect is disappointing due to drug resistance. So far, the molecular mechanisms mediating oxaliplatin resistance remain unclear. In this study, we found the chemoresistance in oxaliplatin-resistant HCT116 cells (HCT116/OXA) was mediated by the upregulation of ERCC1 expression. In addition, the acquisition of resistance induced epithelialmesenchymal transition (EMT) as well as the Slug overexpression. On the contrary, Slug silencing reversed the EMT phenotype, decreased ERCC1 expression, and ameliorated drug resistance. Further mechanistical studies revealed the enhanced Slug expression resulted from the activation of AKT/glycogen synthase kinase 3 (GSK3) signaling. Moreover, in CRC patients, coexpression of Slug and ERCC1 was observed, and increased Slug expression was significantly correlated with clinicopathological factors and prognosis. Taken together, the simultaneous inhibition of the AKT/GSK3/Slug axis may be of significance for surmounting metastasis and chemoresistance, thereby improving the therapeutic outcome of oxaliplatin.


Assuntos
Neoplasias Colorretais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Oxaliplatina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Antineoplásicos/farmacologia , Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos , Endonucleases/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/genética , Células HCT116 , Humanos , Fenótipo , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição da Família Snail/genética , Regulação para Cima/efeitos dos fármacos
9.
Environ Toxicol ; 35(9): 942-951, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32270919

RESUMO

Long noncoding RNA (lncRNA) AC026904.1 has been confirmed to be necessary for breast cancer metastasis. This work aims to investigate the effects of lncRNA AC026904.1 on lung cancer metastasis. We found that lncRNA AC026904.1 displayed a higher level in metastatic lung cancer tissues than adjacent tissues and nonmetastatic lung cancer tissues, and lung cancer cells treated with TGF-ß. The expression of AC026904.1 was increased by the non-canonical TGF-ß signaling. Additionally, AC026904.1 acts as an enhancer of the key metastatic factor Slug in the nucleus. This AC026904.1/Slug axis is necessary for TGF-ß-mediated migration and epithelial-mesenchymal transition in lung cancer cells. This work firstly uncovers that AC026904.1 increases Slug expression at transcriptional level and subsequently plays critical effects in lung cancer metastasis, providing novel evidences that AC026904.1 holds great potential to be used as a marker for metastatic lung cancer.


Assuntos
Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Neoplasias Pulmonares/patologia , Pulmão/patologia , RNA Longo não Codificante/genética , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Células A549 , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Pulmão/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Metástase Neoplásica , RNA Interferente Pequeno/genética , Transdução de Sinais , Fatores de Transcrição da Família Snail/genética , Fator de Crescimento Transformador beta/farmacologia , Regulação para Cima
10.
Arch Biochem Biophys ; 687: 108384, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32343974

RESUMO

Epithelial mesenchymal transition (EMT) is a well-known and important step in metastasis and thus can be a key target in cancer treatment. Here, we tested the EMT inhibitory actions of Selaginella tamariscina and its active component, amentoflavone (AF). EMT was examined in vitro using wound-healing and invasion assays and by monitoring changes in the expression of the EMT-related proteins, E-cadherin, Snail, and Twist. Metastasis was examined in vivo using SCID mice injected with luciferase-labeled A549 cells. We confirmed that aqueous extracts of S. tamariscina (STE) and AF inhibited EMT in human cancer cell lines. We found that STE and AF at nontoxic concentrations exerted remarkable inhibitory effects on migration (wound healing assay) and invasion (Transwell assay) in tumor necrosis factor (TGF)-ß-treated cancer cells. Western blotting and immunofluorescence imaging show that AF treatment also restored E-cadherin expression in these cells compared to cells treated with TGF-ß only. Suppression of metastasis by AF was investigated by monitoring migration of tail-vein-injected, circulating A549-luc cells to the lungs in mice. After 3 wk, fewer nodules were observed in mice co-treated with AF compared with those treated with TGF-ß only. Our findings indicate that STE and AF are promising EMT inhibitors and, ultimately, potentially potent antitumor agents.


Assuntos
Antineoplásicos/uso terapêutico , Biflavonoides/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Metástase Neoplásica/prevenção & controle , Selaginellaceae/química , Células A549 , Animais , Antígenos CD/metabolismo , Antineoplásicos/farmacologia , Biflavonoides/farmacologia , Caderinas/metabolismo , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Camundongos SCID , Proteínas Nucleares/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Proteína 1 Relacionada a Twist/metabolismo
11.
Res Vet Sci ; 131: 7-14, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32278962

RESUMO

Melanoma progression is associated with the epithelial-mesenchymal transition (EMT) when tumor cells reduce E-cadherin and increase N-cadherin expression resulting in an escape from the microenvironment via loss of cellular adhesion and gain of motility. Transcription factor proteins Snail and ZEB trigger EMT by repression of epithelial markers and activation of mesenchymal properties. This study evaluated E-cadherin, N-cadherin, Snail, ZEB1 and ZEB2 expression by IHC and investigated their relationship with morphological characteristics in cutaneous and oral canine melanoma. Results from melanoma cases demonstrated E-cadherin expression in 45% (9/20) of oral and 58% (22/38) of cutaneous tumors, while N-cadherin expression was observed in 95% (18/19) of oral and 92% (34/37) of cutaneous melanoma. Cytoplasmic and nuclear N-cadherin expression was positively correlated with ZEB1 expression, while the cell membrane N-cadherin expression was positively correlated with ZEB2. In addition, an increase in nuclear N-cadherin expression was associated with reduced Snail expression in cutaneous melanoma and an increase in Snail expression in oral melanoma, indicating that the correlation between N-cadherin and Snail expression is coincident with tumor location. Our data suggest that ZEB family protein is associated with N-cadherin translocation from cell membrane to the cytoplasm and nuclei, and may act as important transcription factors of EMT regulation in canine melanoma.


Assuntos
Doenças do Cão/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Melanoma/veterinária , Neoplasias Cutâneas/veterinária , Fatores de Transcrição da Família Snail/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Animais , Caderinas/metabolismo , Adesão Celular , Movimento Celular , Doenças do Cão/genética , Cães , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/metabolismo , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Neoplasias Bucais/veterinária , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição/metabolismo , Microambiente Tumoral , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
12.
Technol Cancer Res Treat ; 19: 1533033819898729, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32301392

RESUMO

OBJECTIVE: The aim of the present research is to study the roles of miR-203a-3p on cell proliferation, migration, invasion, and epithelial-mesenchymal transition in pancreatic cancer. METHODS: Transcription profiles were acquired from Gene Expression Omnibus database, which was used to screen out the differentially expressed microRNAs and messenger RNAs in pancreatic cancer. Pancreatic cancer tissues were used to verify the bioinformatics results by quantitative real-time polymerase chain reaction. The relationship between miR-203a-3p and SLUG was examined by TargetScan software, dual-luciferase reporter assay, and RNA immunoprecipitation. The Cell Counting Kit-8, wound healing, and transwell assays were conducted to investigate the proliferation, migration, and invasion capability of pancreatic cancer cells, respectively. The expression of epithelial-mesenchymal transition-related proteins was determined by the Western blot assay. Xenograft assay was performed to verify findings from in vitro assays. RESULTS: Bioinformatic analysis found that a total of 113 microRNAs and 1749 messenger RNAs expressed differentially in pancreatic cancer tissues. Among these microRNAs, the expression of miR-203a-3p was significantly decreased in both pancreatic cancer tissues and cells. On the other hand, the SLUG expression was remarkably upregulated in pancreatic cancer tissues and cells in comparison with normal tissues and cells. Moreover, TargetScan software, dual-luciferase reporter assay, and RNA immunoprecipitation revealed that SLUG was a target of miR-203a-3p. The upregulation of miR-203a-3p expression inhibited the proliferation, migration, and invasion ability of pancreatic cancer cells by suppressing the epithelial-mesenchymal transition process via sponging SLUG. CONCLUSION: These findings indicate that downregulation of miR-203a-3p in pancreatic cancer cells leads to high expression of SLUG, which promotes epithelial-mesenchymal transition process and induces cancer progression.


Assuntos
Apoptose , Proliferação de Células , Biologia Computacional/métodos , Transição Epitelial-Mesenquimal , MicroRNAs/genética , Neoplasias Pancreáticas/patologia , Fatores de Transcrição da Família Snail/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Bases de Dados Genéticas/estatística & dados numéricos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Am J Pathol ; 190(6): 1271-1283, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32188584

RESUMO

Snail is a transcription factor that regulates many cellular events involved in development, homeostasis, and disease. In hepatocellular carcinoma (HCC), Snail induces epithelial-to-mesenchymal transition that confers invasive properties on tumor cells during HCC progression and malignancy. Snail activation observed in HCC mouse models suggests its involvement not only in progression, but also onset of HCC. However, it remains unclear whether Snail directly contributes to HCC initiation or whether it supports HCC initiation promoted by other oncogenes. In this study, we generated mouse models for liver-specific and hepatocyte-specific overexpression of Snail to show the independent roles of Snail in liver homeostasis and disease. Enforced Snail expression resulted in liver and hepatocyte enlargement, inflammatory cell infiltration in the liver, lipid accumulation in hepatocytes, substantial increases in serum alanine aminotransferase and bile acids, yellow discoloration of tissues caused by bilirubin accumulation, and liver tumorigenesis. Snail overexpression suppressed mRNA expression of the tight junction components claudins and occludin and that of proteins associated with bile acid metabolism, leading to disruption of the biliary canaliculus formed among hepatocytes and excretion of abnormal amounts of unusual bile acids from hepatocytes. In conclusion, enforced Snail expression in hepatocytes is sufficient for induction of steatohepatitis and liver tumorigenesis through disruption of the biliary canaliculus and bile acid homeostasis in the liver.


Assuntos
Carcinogênese/metabolismo , Fígado Gorduroso/metabolismo , Hepatócitos/metabolismo , Neoplasias Hepáticas/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Carcinogênese/genética , Carcinogênese/patologia , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/fisiologia , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Regulação Neoplásica da Expressão Gênica , Hepatócitos/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Transgênicos , Fatores de Transcrição da Família Snail/genética
15.
Cancer Sci ; 111(5): 1582-1595, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32129914

RESUMO

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is an oncogenic long noncoding RNA that has been found to promote carcinogenesis and metastasis in many tumors. However, the underlying role of MALAT1 in the progression and metastasis of hepatocellular carcinoma (HCC) remains unclear. In this study, aberrantly elevated levels of MALAT1 were detected in both HCC specimens and cell lines. We found that knockdown of MALAT1 caused retardation in proliferation, migration, and invasion both in vivo and in vitro. Mechanistic investigations showed that Snail family transcriptional repressor 1 (SNAI1) is a direct target of microRNA (miR)-22 and that MALAT1 modulates SNAI1 expression by acting as a competing endogenous RNA for miR-22. Inhibition of miR-22 restored SNAI1 expression suppressed by MALAT1 knockdown. Furthermore, MALAT1 facilitated the enrichment of enhancer of zeste homolog 2 (EZH2) at the promoter region of miR-22 and E-cadherin, which was repressed by MALAT1 knockdown. Cooperating with EZH2, MALAT1 positively regulated SNAI1 by repressing miR-22 and inhibiting E-cadherin expression, playing a vital role in epithelial to mesenchymal transition. In conclusion, our results reveal a mechanism by which MALAT1 promotes HCC progression and provides a potential target for HCC therapy.


Assuntos
Carcinoma Hepatocelular/patologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Neoplasias Hepáticas/patologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Fatores de Transcrição da Família Snail/genética , Animais , Antígenos CD/genética , Sítios de Ligação , Caderinas/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Transição Epitelial-Mesenquimal/genética , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Nus , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Regiões Promotoras Genéticas , Fatores de Transcrição da Família Snail/metabolismo
16.
Biomed Res Int ; 2020: 4150735, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190664

RESUMO

Objective: The aim of this study was to investigate the expression of Snail, galectin-3, and IGF1R in benign and malignant pheochromocytoma and paraganglioma (PPGL) and explore their role in the diagnosis of malignant PPGL. Methods: We retrospectively collected and analyzed surgical tumor tissue from 226 patients initially diagnosed with PPGL who underwent surgery from Jan. 2009 to Jan. 2016 at West China Hospital, Sichuan University. We observed and quantified the expression of Snail, galectin-3, and IGF1R in paraffin-embedded samples by immunohistochemical staining. Results: The significant difference in survival time among the three groups (benign PHEO, benign PGL, and potentially malignant PPGL) was compared by Kaplan-Meier survival analysis. The positive staining of Snail, galectin-3, and IGF1R in the benign PHEO group was significantly lower than that in the other three groups (P < 0.001). The Kaplan-Meier survival plots indicated that the survival time of the patients with intense positive staining was significantly lower than that of the patients with weak positive staining. Conclusion: The intense expression of Snail, galectin-3, and IGF1R may be valuable indicators for the diagnosis of malignant PPGL.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Biomarcadores Tumorais/metabolismo , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Receptor IGF Tipo 1/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/cirurgia , Adulto , Idoso , China , Diagnóstico Diferencial , Feminino , Galectina 3/metabolismo , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Paraganglioma/metabolismo , Paraganglioma/cirurgia , Feocromocitoma/metabolismo , Feocromocitoma/cirurgia , Estudos Retrospectivos , Software
17.
Breast Cancer Res ; 22(1): 26, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32143670

RESUMO

BACKGROUND: Breast cancer stem cells (BCSCs) are typically seed cells of breast tumor that initiate and maintain tumor growth. MiR-7, as a cancer inhibitor, decreases the BCSC subset and inhibits tumor progression through mechanisms that remain unknown. METHODS: We examined miR-7 expression in breast cancer and developed a BCSC-driven xenograft mouse model, to evaluate the effects of miR-7 overexpression on the decrease of the BCSC subset in vitro and in vivo. In addition, we determined how miR-7 decreased the BCSC subset by using the ALDEFLUOR, lentivirus infection, dual-luciferase reporter, and chromatin immunoprecipitation-PCR assays. RESULTS: MiR-7 was expressed at low levels in breast cancer tissues compared with normal tissues, and overexpression of miR-7 directly inhibited lncRNA XIST, which mediates the transcriptional silencing of genes on the X chromosome, and reduced epithelium-specific antigen (ESA) expression by increasing miR-92b and inhibiting slug. Moreover, miR-7 suppressed CD44 and ESA by directly inhibiting the NF-κB subunit RELA and slug in breast cancer cell lines and in BCSC-driven xenografts, which confirmed the antitumor activity in mice injected with miR-7 agomir or stably infected with lenti-miR-7. CONCLUSIONS: The findings from this study uncover the molecular mechanisms by which miR-7 inhibits XIST, modulates the miR-92b/Slug/ESA axis, and decreases the RELA and CD44 expression, resulting in a reduced BCSC subset and breast cancer growth inhibition. These findings suggest a potentially targeted treatment approach to breast cancer.


Assuntos
Neoplasias da Mama/prevenção & controle , Molécula de Adesão da Célula Epitelial/metabolismo , MicroRNAs/genética , Células-Tronco Neoplásicas/metabolismo , RNA Longo não Codificante/antagonistas & inibidores , Fatores de Transcrição da Família Snail/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Molécula de Adesão da Célula Epitelial/genética , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/patologia , RNA Longo não Codificante/genética , Fatores de Transcrição da Família Snail/genética , Ensaios Antitumorais Modelo de Xenoenxerto
18.
PLoS Biol ; 18(2): e3000609, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32097403

RESUMO

The final body size of any given individual underlies both genetic and environmental constraints. Both mammals and insects use target of rapamycin (TOR) and insulin signaling pathways to coordinate growth with nutrition. In holometabolous insects, the growth period is terminated through a cascade of peptide and steroid hormones that end larval feeding behavior and trigger metamorphosis, a nonfeeding stage during which the larval body plan is remodeled to produce an adult. This irreversible decision, termed the critical weight (CW) checkpoint, ensures that larvae have acquired sufficient nutrients to complete and survive development to adulthood. How insects assess body size via the CW checkpoint is still poorly understood on the molecular level. We show here that the Drosophila transcription factor Snail plays a key role in this process. Before and during the CW checkpoint, snail is highly expressed in the larval prothoracic gland (PG), an endocrine tissue undergoing endoreplication and primarily dedicated to the production of the steroid hormone ecdysone. We observed two Snail peaks in the PG, one before and one after the molt from the second to the third instar. Remarkably, these Snail peaks coincide with two peaks of PG cells entering S phase and a slowing of DNA synthesis between the peaks. Interestingly, the second Snail peak occurs at the exit of the CW checkpoint. Snail levels then decline continuously, and endoreplication becomes nonsynchronized in the PG after the CW checkpoint. This suggests that the synchronization of PG cells into S phase via Snail represents the mechanistic link used to terminate the CW checkpoint. Indeed, PG-specific loss of snail function prior to the CW checkpoint causes larval arrest due to a cessation of endoreplication in PG cells, whereas impairing snail after the CW checkpoint no longer affected endoreplication and further development. During the CW window, starvation or loss of TOR signaling disrupted the formation of Snail peaks and endocycle synchronization, whereas later starvation had no effect on snail expression. Taken together, our data demonstrate that insects use the TOR pathway to assess nutrient status during larval development to regulate Snail in ecdysone-producing cells as an effector protein to coordinate endoreplication and CW attainment.


Assuntos
Ciclo Celular/fisiologia , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Fatores de Transcrição da Família Snail/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Peso Corporal , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Ecdisona/metabolismo , Células Endócrinas/metabolismo , Endorreduplicação , Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Larva/genética , Larva/crescimento & desenvolvimento , Larva/microbiologia , Metamorfose Biológica , Nutrientes/metabolismo , Transdução de Sinais , Fatores de Transcrição da Família Snail/genética , Serina-Treonina Quinases TOR/genética
19.
Life Sci ; 248: 117454, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32088211

RESUMO

AIMS: Dihydroartemisinin (DHA) is currently considered as the promising cancer therapeutic drug. In this study, we aimed to investigate the anti-proliferative and anti-metastasis effects of DHA. MAIN METHODS: Utilizing breast cancer cells MCF-7, MDA-MB-231 and BT549, cell proliferation, migration and invasion were detected. RT-qPCR was performed to detect CIZ1, TGF-ß1 and Snail expression, and the interactions of these related molecules were analyzed by GeneMANIA database. Western blot detected CIZ1, TGF-ß1/Smads signaling and Snail expression in DHA-treated cells, in TGFß1-induced cells with enhanced metastatic capacity, and in cells treated with DHA plus TGFß1/TGFß1 inhibitor SD-208. KEY FINDINGS: Results indicated DHA inhibited breast cancer cell proliferation and migration, with more potent effects compared with that of artemisinin. RT-qPCR and Western blot showed DHA inhibited CIZ1, TGF-ß1 and Snail expression, and these molecules were shown to have protein-protein interactions by bioinformatics. Furthermore, TGFß1-treatment enhanced MCF-7 migration and invasion, and CIZ1, TGF-ß1/Smads signaling and snail activities; DHA, SD-208, combination of DHA and SD-208 reversed these conditions, preliminarily proving the cascade regulation between TGF-ß1 signaling and CIZ1. MCF-7 xenografts model demonstrated the inhibition of DHA on tumor burden, and its mechanisms and well-tolerance in vivo; combination of DHA and SD-208 tried by us for the first time showed better treatment effects, but possible liver impairment made its use still keep cautious. SIGNIFICANCE: DHA treatment inhibits the proliferation and metastasis of breast cancer, through suppressing TGF-ß1/Smad signaling and CIZ1, suggesting the promising potential of DHA as a well-tolerated antitumor TGF-ß1 pathway inhibitor.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Artemisininas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/genética , Fator de Crescimento Transformador beta1/genética , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Transição Epitelial-Mesenquimal , Feminino , Humanos , Metástase Linfática , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Pteridinas/farmacologia , Transdução de Sinais , Proteínas Smad/genética , Proteínas Smad/metabolismo , Fatores de Transcrição da Família Snail/antagonistas & inibidores , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Ecotoxicol Environ Saf ; 192: 110201, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32028152

RESUMO

OBJECTIVE: This study focused on the oxidative stress effect of di-n-butyl phthalate (DBP) on development of the urinary system. METHODS: We examined the mRNA expression of genital tubercle (GT) in control and DBP induced hypospadias group by Affymetrix Rat 230 2.0 Array. Real-time PCR and Western Blot were used to detect the protein and mRNA expression levels of inositol-1,4,5-triphate-receptor (IP3R) and epithelial-mesenchymal-transition (EMT)-related molecular markers, such as E-cadherin, ß-Catenin, Snail, N-cadherin, in the GT of hypospadiac male rats and controls. The results of array were further confirmed in vitro. The changes of intracellular calcium concentration in urethral epithelial cells were detected by Fluo-3-AM before and after DBP treatment. The levels of reactive oxygen species (ROS) in urethral epithelial cells were measured by DCFH-DA with different concentrations of DBP (0, 1, 10, 100 µmol/L) treatment. RESULTS: The mRNA expression profiles of GT in control and DBP induced hypospadias group showed high expression of IP3R and the abnormalities of EMT. Compared to the control group, the expression levels of IP3R, E-cadherin and ß-Catenin increased at both the protein and mRNA levels. However the expression levels of Snail and N-cadherin decreased. The intracellular calcium concentration increased significantly after DBP treatment. The effect of DBP on urethral epithelial cells was linked to the generation of oxidative stress. CONCLUSION: DBP can influence the development of GT through its oxidative stress effect, which significantly increases the concentration of calcium and inhibits EMT in urethral epithelial cells, and block the fusion process of urethral groove, causing the occurrence of hypospadias. This study provides a new understanding of DBP's molecular mechanisms on hypospadias and may lead to new treatment strategies for the disease.


Assuntos
Dibutilftalato/toxicidade , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Hipospadia/induzido quimicamente , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Estresse Oxidativo , Plastificantes/toxicidade , Animais , Caderinas/genética , Caderinas/metabolismo , Cálcio/metabolismo , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Hipospadia/genética , Hipospadia/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/genética , Masculino , Exposição Materna , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo , Uretra/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
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