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1.
Life Sci ; 236: 116921, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610196

RESUMO

AIMS: To assess the role of glycogen synthase kinase-3ß (GSK3ß) and ß-catenin in the protection of ischemic injury by dexmedetomidine (Dex). MAIN METHODS: Adult male Sprague-Dawley rats were subjected to (middle cerebral artery occlusion, MCAO) for 2 h followed by reperfusion and Dex was administered 30min before MCAO. The neurological deficit score, cerebral infarct size and neuron survival were evaluated at 24 h after reperfusion. The expression of pAKT, pGSK3ß and ß-catenin in the ischemic penumbra was assayed by Western blot at 2 h after reperfusion. KEY FINDINGS: We found that the Dex-induced increment of neuron survival in the ischemic penumbra was diminished by the PI3K inhibitor LY294002 and the ß-catenin inhibitor XAV939, respectively. The increasing expression of pAKT, pGSK3ß and ß-catenin induced by Dex was markedly inhibited by LY294002. And the increasing expression of ß-catenin in nuclei induced by Dex was markedly inhibited by XAV939. At the same time, the GSK3ß inhibitor SB216763 also caused an increment of neuron survival and an increasing expression of pGSK3ß and ß-catenin in the ischemic penumbra. SIGNIFICANCE: Our data suggested that treatment with Dex reduced cerebral injury in rats exposed to cerebral ischemia-reperfusion (I/R) by the activation of the PI3K/AKT/GSK3ß pathways as well the activation of downstream Wnt/ß-catenin pathway. And the Wnt/ß-catenin pathway may play an important role in the protection against cerebral ischemia/reperfusion injury in rats.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Dexmedetomidina/farmacologia , Infarto da Artéria Cerebral Média/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Apoptose , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Masculino , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Proteínas Wnt/genética , beta Catenina/genética
2.
Life Sci ; 235: 116798, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31472149

RESUMO

Lung cancer is the leading cause for cancer death due to refractory nature to current treatment strategies, understanding the regulatory mechanism of therapy resistance of lung cancer is important for lung cancer therapy. Here, we aimed to study the role of SHCBP1 in lung cancer cisplatin resistance, we found SHCBP1 was upregulated in lung cancer tissues and cells, patients with high SHCBP1 had poor prognosis. SHC binding and spindle associated 1 (SHCBP1) overexpression promoted cisplatin induced apoptosis resistance, migration and invasion determined by apoptosis assay and transwell assay with or without Matrigel, while SHCBP1 knockdown inhibited cisplatin induced apoptosis resistance, migration and invasion. Wnt pathway promoted lung cancer progression, we found SHCBP1 activated Wnt pathway, characterized by promoting ß-catenin nuclear translocation. Inhibition of Wnt pathway in SHCBP1 overexpression cells reversed the effect of SHCBP1 overexpression, confirming SHCBP1 promoted lung cancer progression through activating Wnt pathway. We also found SHCBP1 expression was positively corrected with Wnt pathway activity in lung cancer samples. In summary, we found SHCBP1 promoted cisplatin induced apoptosis resistance, migration and invasion through activating Wnt pathway, providing a potential target for lung cancer therapy.


Assuntos
Apoptose , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/patologia , Proteínas Adaptadoras da Sinalização Shc/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Movimento Celular , Proliferação de Células , Células Cultivadas , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Invasividade Neoplásica , Prognóstico , Proteínas Adaptadoras da Sinalização Shc/genética , Taxa de Sobrevida , Proteínas Wnt/genética , Via de Sinalização Wnt , beta Catenina/genética
3.
Adv Clin Exp Med ; 28(10): 1293-1300, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31538414

RESUMO

BACKGROUND: MicroRNA (miRNA) is a kind of non-coding small RNA with a negative regulating function. Some miRNAs play a role in regulating the differentiation and function of osteoblasts, chondrocytes and osteoclasts. OBJECTIVES: In this study, we analyzed the role of miR-29a and dickkopf-1 (DKK-1) in osteoblast differentiation. MATERIAL AND METHODS: Specimens were collected from the surgical resection of pathological ankylosing spondylitis (AS) tissue and some normal tissues. The expression of miR-29a, DKK-1 and ß-catenin in normal and AS tissues were detected with real-time polymerase chain reaction (RT-PCR) and western blotting. Cell proliferation was detected with a Cell Counting Kit-8, cell migration and invasion were determined using a Transwell system and cell apoptosis was analyzed with flow cytometry. The luciferase reporter gene plasmid pGL3-DKK-1 and a point-mutation of the luciferase reporter gene plasmid mut-pGL3-DKK-1 were constructed. RESULTS: It was found that miR-29a could promote the proliferation of hFOB1.19 cells, while DKK-1 inhibited their proliferation. Also, miR-29a was able to inhibit the apoptosis of hFOB1.19 cells, while DKK-1 was able to promote the apoptosis of hFOB1.19 cells. When it comes to the invasion and migration of hFOB1.19 cells, miR-29a was found to promote it, while DKK-1 did not. CONCLUSIONS: These findings will lead to a better understanding of the proliferation and differentiation of osteoblasts and will provide new insights for the treatment of this disease.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , MicroRNAs/metabolismo , Osteoblastos/metabolismo , Via de Sinalização Wnt/fisiologia , Apoptose/fisiologia , Proliferação de Células , Humanos , MicroRNAs/genética , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
4.
J Agric Food Chem ; 67(37): 10285-10295, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31443611

RESUMO

Fluoride (F) is capable of promoting abnormal proliferation and differentiation in primary cultured mouse osteoblasts (OB cells), although the underlying mechanism responsible remains rare. This study aimed to explore the roles of wingless and INT-1 (Wnt) signaling pathways and screen appropriate doses of calcium (Ca2+) to alleviate the sodium fluoride (NaF)-induced OB cell toxicity. For this, we evaluated the effect of dickkopf-related protein 1 (DKK1) and Ca2+ on mRNA levels of wingless/integrated 3a (Wnt3a), low-density lipoprotein receptor-related protein 5 (LRP5), dishevelled 1 (Dv1), glycogen synthase kinase 3ß (GSK3ß), ß-catenin, lymphoid enhancer binding factor 1 (LEF1), and cellular myelocytomatosis oncogene (cMYC), as well as Ccnd1 (Cyclin D1) in OB cells challenged with 10-6 mol/L NaF for 24 h. The demonstrated data showed that F significantly increased the OB cell proliferation rate. Ectogenic 0.5 mg/L DKK1 significantly inhibited the proliferation of OB cells induced by F. The mRNA expression levels of Wnt3a, LRP5, Dv1, LEF1, ß-catenin, cMYC, and Ccnd1 were significantly increased in the F group, while significantly decreased in the 10-6 mol/L NaF + 0.5 mg/L DKK1 (FY) group. The mRNA expression levels of Wnt3a, LRP5, ß-catenin, and cMYC were significantly decreased in the 10-6 mol/L NaF + 2 mmol/L CaCl2 (F+CaII) group. The protein expression levels of Wnt3a, Cyclin D1, cMYC, and ß-catenin were significantly increased in the F group, whereas they were decreased in the F+CaII group. However, the mRNA and protein expression levels of GSK3ß were significantly decreased in the F group while significantly increased in the F+CaII group. In summary, F activated the canonical Wnt/ß-catenin pathway and changed the related gene expression and ß-catenin protein location in OB cells, promoting cell proliferation. Ca2+ supplementation (2 mmol/L) reversed the expression levels of genes and proteins related to the canonical Wnt/ß-catenin pathway.


Assuntos
Cálcio/metabolismo , Fluoretos/efeitos adversos , Osteoblastos/efeitos dos fármacos , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Suplementos Nutricionais/análise , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Camundongos , Osteoblastos/classificação , Osteoblastos/metabolismo , Proteínas Wnt/genética , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/genética
5.
Cell Prolif ; 52(5): e12664, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31343104

RESUMO

OBJECTIVES: Low back pain becomes a common orthopaedic disease today. It is mainly induced by the degeneration of the intervertebral disc. In this study, we tried to reveal the pathogenesis of the degeneration and the relative therapeutic strategy, which are still elusive. MATERIALS AND METHODS: We collected 15 degenerative intervertebral tissues and five healthy donors. Nucleus pulposus and annulus fibrosus cells were subcultured. miR-640 expression was determined by qPCR. Computer analysis and luciferase reporter assay were used to confirm miR-640 target genes. Immunohistochemical and immunocytochemical staining was used to trace the proinflammatory cytokines and key transductor of signalling pathways. We also used ß-galactosidase staining, flow cytometry, and cell viability assay to monitor the degenerative index. RESULTS: miR-640 overexpressed in patients derived degenerative nucleus pulposus tissues and cells. The inflammatory environment promoted miR-640 expression via NF-κB signalling pathway. In addition, miR-640 targeted to LRP1 and enhances NF-κB signal activity, which built a positive feedback loop. miR-640 inhibited the expression of ß-catenin and EP300, therefore, restrained WNT signal and induced the degeneration in nucleus pulposus cells. miR-640 inhibitor treatment exhibited the effects of anti-inflammation, reverse WNT signalling pathway exhaustion, and remission of degenerative characteristics in vitro. CONCLUSIONS: miR-640 plays an important role in the degeneration of intervertebral disc and the relative inflammatory microenvironment. It is a promising potential therapeutic target for the low back pain biotherapy.


Assuntos
Degeneração do Disco Intervertebral/patologia , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Proteínas Wnt/metabolismo , Adolescente , Adulto , Anel Fibroso/citologia , Anel Fibroso/metabolismo , Antagomirs/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Proteína p300 Associada a E1A/metabolismo , Humanos , Interleucina-1beta/metabolismo , Degeneração do Disco Intervertebral/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Pessoa de Meia-Idade , Núcleo Pulposo/citologia , Núcleo Pulposo/metabolismo , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Adulto Jovem , beta Catenina/metabolismo
6.
Int Arch Allergy Immunol ; 180(2): 79-90, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31340215

RESUMO

BACKGROUND: In this study, we examined whether RORA (retinoic acid receptor-related orphan receptor alpha) was capable of alleviating the progression of allergic rhinitis (AR). METHODS: In order to elucidate the possible effects of RORA and the regulatory mechanism between RORA and the Wnt/ß-catenin signaling pathway, mouse AR models were established and treated with RORA vector, siRNA against RORA, or the Wnt/ß-catenin pathway inhibitor WIF-1. Subsequently, the serum levels of inflammatory cytokines (IgE, INF-γ, IL-1ß, IL-4, and IL-17), red blood cell (RBC) immune adhesion function, the levels of RORA, ß-catenin, and GSK3ß, as well as the extent of ß-catenin and GSK-3ß phosphorylation were evaluated and measured. RESULTS: The OVA-induced AR mouse model exhibited obvious nasal mucosal injury and inflammatory cell infiltration. RORA overexpression or the inactivation of the Wnt/ß-catenin signaling pathway was uncovered as a way to ameliorate nasal mucosal injury and eosinophil infiltration of the OVA-induced AR mouse model. On the other hand, it reduced the number of eosinophils and mast cells, which also resulted in downregulated expression of IgE, INF-γ, IL-1ß, IL-4, IL-17, ß-catenin, and GSK-3ß. Moreover, this led to a decreased extent of ß-catenin and GSK-3ß phosphorylation, while the rates of C3b receptor rosette and Ic rosette were elevated. CONCLUSION: Taken together, the key findings provided evidence suggesting that the elevated RORA could potentially alleviate nasal mucosal injury and simultaneously enhance RBC immune adhesion function through the inhibition of the Wnt/ß-catenin signaling pathway activation in an OVA-induced AR mouse model. This emphasizes a novel therapeutic target for the treatment of AR.


Assuntos
Eritrócitos/imunologia , Mucosa Nasal/lesões , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Rinite Alérgica/imunologia , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Adesão Celular/fisiologia , Modelos Animais de Doenças , Eosinófilos/imunologia , Proteínas da Matriz Extracelular/metabolismo , Reação de Imunoaderência , Imunoglobulina E/sangue , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interferon gama/sangue , Interleucina-17/sangue , Interleucina-1beta/sangue , Interleucina-4/sangue , Masculino , Mastócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Interferência de RNA , RNA Citoplasmático Pequeno/genética , Rinite Alérgica/prevenção & controle , Via de Sinalização Wnt , beta Catenina/sangue
7.
Food Chem Toxicol ; 131: 110579, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31202940

RESUMO

Disintegration of the intestine caused by deoxynivalenol (DON), which is a fungal metabolite found in cereal grain-based human and animal diets, triggers severe intestinal inflammatory disease. Hydrolyzed wheat gluten (HWG) can promote the development of intestine. Therefore, HWG was administered orally to male mice on 1-14 days, and DON was administered to them on 4-11 days. Feed, water intake and body weight were recorded all over the experimental period. Blood samples were collected then the mice were sacrificed to collect the jejunum for crypt isolation and culture. The intestinal morphology was observed by electron microscopy, and Western blotting was used to investigate intestinal stem cell (ISC) proliferation and differentiation, as well as the primary regulatory mechanism of the Wnt/ß-catenin signaling. The results showed that HWG increased the average daily gain and average daily water intake of mice under DON-induced injury conditions, and increased the jejunum weight, villous height in the jejunum, and promoted jejunal crypt cell expansion. The DON-induced decrease in Wnt/ß-catenin activity, the expression of Ki67, PCNA and KRT20 were rescued by HWG in the jejunum, crypt and enteroid, as well as the number of goblet cells and Paneth cells. Furthermore, HWG increased jejunum diamine oxidase (DAO) activity. In conclusion, HWG alleviates DON-induced intestinal injury by enhancing ISC proliferation and differentiation in a Wnt/ß-catenin-dependent manner.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glutens/uso terapêutico , Enteropatias/prevenção & controle , Células-Tronco/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Líquidos/efeitos dos fármacos , Fármacos Gastrointestinais/química , Fármacos Gastrointestinais/uso terapêutico , Glutens/química , Hidrólise , Enteropatias/induzido quimicamente , Jejuno/citologia , Jejuno/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Substâncias Protetoras/química , Substâncias Protetoras/uso terapêutico , Tricotecenos , Triticum/química , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
8.
Ann Otol Rhinol Laryngol ; 128(11): 1061-1072, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31148463

RESUMO

OBJECTIVE: Juvenile nasopharyngeal angiofibroma (JNA) is a rare vascular tumor of unknown etiology. Studies investigating the molecular and genetic determinants of JNA are limited by small sample size and inconsistent approaches. The purpose of this study is to examine all eligible JNA studies in aggregate, applying qualitative analysis to highlight areas of particular relevance, including potential targets for therapeutic intervention. METHODS: The PubMed, MEDLINE, Embase, Web of Science, Cochrane, and CINAHL databases were screened with inclusion and exclusion criteria applied to all citations. Manuscripts investigating the genetic determinants, histopathogenesis, and heritability of juvenile nasopharyngeal angiofibroma were included. Non-English studies, case reports, and articles focusing on clinical management without original data were excluded. Full text articles were obtained. A qualitative synthesis of data was performed. RESULTS: A total of 59 articles met criteria for inclusion. These were divided into 6 categories based on the primary topic or target discussed, (1) steroid hormone receptors, (2) chromosomal abnormalities, (3) growth factors, (4) genetic targets, (5) molecular targets, (6) Wnt cell signaling, and (7) studies that overlapped multiple of the aforementioned categories. Although relatively low n values prevent definitive conclusions to be drawn, a predominance of certain molecular targets such as vascular endothelial growth factor (VEGF) and Wnt/ß-catenin pathway intermediaries is apparent. CONCLUSIONS: Although the etiology of JNA remains elusive, contemporary molecular genetic investigation holds promise for risk stratification and could form the basis of a modernized staging system. A multicenter clinical registry and linked tissue bank would further promote the search for JNA specific biomarkers.


Assuntos
Angiofibroma , Testes Genéticos/métodos , Neoplasias Nasofaríngeas , Fator A de Crescimento do Endotélio Vascular/genética , Proteínas Wnt/genética , Adolescente , Angiofibroma/diagnóstico , Angiofibroma/genética , Angiofibroma/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Humanos , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas Wnt/metabolismo
9.
Int J Mol Sci ; 20(11)2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31167387

RESUMO

Acute myeloid leukaemia (AML) is a heterogeneous clonal malignancy of hematopoietic progenitor cells. The Wnt pathway and its downstream targets are tightly regulated by ß-catenin. We recently discovered a new protein, FLYWCH1, which can directly bind nuclear ß-catenin. Herein, we studied the FLYWCH1/ß-catenin pathway in AML cells using qRT-PCR, Western blot, and immunofluorescence assays. In addition, the stemness activity and cell cycle were analysed by the colony-forming unit (CFU) using methylcellulose-based and Propidium iodide/flow cytometry assays. We found that FLYWCH1 mRNA and protein were differentially expressed in the AML cell lines. C-Myc, cyclin D1, and c-Jun expression decreased in the presence of higher FLYWCH1 expression, and vice versa. There appeared to be the loss of FLYWCH1 expression in dividing cells. The sub-G0 phase was prolonged and shortened in the low and high FLYWCH1 expression cell lines, respectively. The G0/G1 arrest correlated with FLYWCH1-expression, and these cell lines also formed colonies, whereas the low FLYWCH1 expression cell lines could not. Thus, FLYWCH1 functions as a negative regulator of the Wnt/ß-catenin pathway in AML.


Assuntos
Proteínas de Ligação a DNA/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Ciclo Celular/genética , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Imunofluorescência , Humanos , Células-Tronco Neoplásicas/metabolismo , RNA Mensageiro/genética , Via de Sinalização Wnt
10.
Int J Mol Sci ; 20(11)2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31181716

RESUMO

Secondary hyperparathyroidism (SHPT) relates to high turnover bone loss and is responsible for most bone fractures among chronic kidney disease (CKD) patients. Changes in the Wingless/beta-catenin signaling (Wnt/ß-catenin) pathway and Wnt inhibitors have been found to play a critical role in CKD related bone loss. A calcimimetic agent, cinacalcet, is widely used for SHPT and found to be similarly effective for parathyroidectomy clinically. A significant decrease in hip fracture rates is noted among US hemodialysis Medicare patients since 2004, which is probably related to the cinacalcet era. In our previous clinical study, it was proven that cinacalcet improved the bone mineral density (BMD) even among severe SHPT patients. In this study, the influence of cinacalcet use on bone mass among CKD mice was determined. Cinacalcet significantly reduced the cortical porosity in femoral bones of treated CKD mice. It also improved the whole-bone structural properties through increased stiffness and maximum load. Cinacalcet increased femoral bone wingless 10b (Wnt10b) expression in CKD mice. In vitro studies revealed that cinacalcet decreased osteoclast bone resorption and increased Wnt 10b release from osteoclasts. Cinacalcet increased bone mineralization when culturing the osteoblasts with cinacalcet treated osteoclast supernatant. In conclusion, cinacalcet increased bone quantity and quality in CKD mice, probably through increased bone mineralization related with osteoclast Wnt 10b secretion.


Assuntos
Reabsorção Óssea/metabolismo , Hormônios e Agentes Reguladores de Cálcio/farmacologia , Cinacalcete/farmacologia , Osteoclastos/efeitos dos fármacos , Insuficiência Renal Crônica/complicações , Proteínas Wnt/metabolismo , Animais , Densidade Óssea , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/etiologia , Hormônios e Agentes Reguladores de Cálcio/uso terapêutico , Células Cultivadas , Cinacalcete/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/metabolismo
11.
Nat Commun ; 10(1): 2481, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171792

RESUMO

Mammary stroma is essential for epithelial morphogenesis and development. Indeed, postnatal mammary gland (MG) development is controlled locally by the repetitive and bi-directional cross-talk between the epithelial and the stromal compartment. However, the signalling pathways involved in stromal-epithelial communication are not entirely understood. Here, we identify Sfrp3 as a mediator of the stromal-epithelial communication that is required for normal mouse MG development. Using Drosophila wing imaginal disc, we demonstrate that Sfrp3 functions as an extracellular transporter of Wnts that facilitates their diffusion, and thus, their levels in the boundaries of different compartments. Indeed, loss of Sfrp3 in mice leads to an increase of ductal invasion and branching mirroring an early pregnancy state. Finally, we observe that loss of Sfrp3 predisposes for invasive breast cancer. Altogether, our study shows that Sfrp3 controls MG morphogenesis by modulating the stromal-epithelial cross-talk during pubertal development.


Assuntos
Comunicação Celular/genética , Células Epiteliais/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Glândulas Mamárias Animais/crescimento & desenvolvimento , Neoplasias Mamárias Animais/genética , Células Estromais/metabolismo , Proteínas Wnt/metabolismo , Animais , Drosophila , Proteínas de Drosophila , Feminino , Discos Imaginais , Glândulas Mamárias Animais/metabolismo , Camundongos , Camundongos Knockout , Morfogênese , Gravidez , Maturidade Sexual , Fatores de Transcrição , Via de Sinalização Wnt
12.
Cell Mol Life Sci ; 76(19): 3875-3889, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30980110

RESUMO

Re-directing mesenchymal stromal cell (MSC) chondrogenesis towards a non-hypertrophic articular chondrocyte-(AC)-like phenotype is important for improving articular cartilage neogenesis to enhance clinical cartilage repair strategies. This study is the first to demonstrate that high levels of non-canonical WNT5A followed by WNT11 and LEF1 discriminated MSC chondrogenesis from AC re-differentiation. Moreover, ß-catenin seemed incompletely silenced in differentiating MSCs, which altogether suggested a role for WNT signaling in hypertrophic MSC differentiation. WNT inhibition with the small molecule IWP-2 supported MSC chondrogenesis according to elevated proteoglycan deposition and reduced the characteristic upregulation of BMP4, BMP7 and their target ID1, as well as IHH and its target GLI1 observed during endochondral differentiation. Along with the pro-hypertrophic transcription factor MEF2C, multiple hypertrophic downstream targets including IBSP and alkaline phosphatase activity were reduced by IWP-2, demonstrating that WNT activity drives BMP and hedgehog upregulation, and MSC hypertrophy. WNT inhibition almost matched the strong anti-hypertrophic capacity of pulsed parathyroid hormone-related protein application, and both outperformed suppression of BMP signaling with dorsomorphin, which also reduced cartilage matrix deposition. Yet, hypertrophic marker expression under IWP-2 remained above AC level, and in vivo mineralization and ectopic bone formation were reduced but not eliminated. Overall, the strong anti-hypertrophic effects of IWP-2 involved inhibition but not silencing of pro-hypertrophic BMP and IHH pathways, and more advanced silencing of WNT activity as well as combined application of IHH or BMP antagonists should next be considered to install articular cartilage neogenesis from human MSCs.


Assuntos
Condrogênese , Células-Tronco Mesenquimais/fisiologia , Via de Sinalização Wnt , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biomineralização/efeitos dos fármacos , Proteínas Morfogenéticas Ósseas/metabolismo , Células Cultivadas , Condrócitos/metabolismo , Regulação da Expressão Gênica , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Hipertrofia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos SCID , Pessoa de Meia-Idade , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Proteínas Wnt/antagonistas & inibidores , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Proteína Wnt-5a/metabolismo , Adulto Jovem
13.
Int J Mol Sci ; 20(9)2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31027362

RESUMO

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/ß-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. ß-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/ß-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/ß-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/ß-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.


Assuntos
Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/metabolismo , Fatores de Transcrição SOX9/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Humanos , Masculino
14.
Mol Carcinog ; 58(8): 1450-1464, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31026381

RESUMO

Gastric cancer is the second leading cause of cancer-related mortality and the fourth most common cancer globally. High intratumor heterogeneity of advanced gastric cancer poses great challenges to targeted therapy due to simultaneous activation of many redundant cancer-driving pathways. A central common signaling mechanism in cancer is proline-directed phosphorylation, which is further regulated by the unique proline isomerase Pin1. Pin1 inhibition exerts anticancer activity by blocking multiple cancer-driving pathways in some cancers, but its role in gastric cancer is not fully understood. Here we detected Pin1 protein expression in 1065 gastric cancer patients and paired normal tissues using immunohistochemistry and Western blot, and then examined the effects of Pin1 overexpression, and genetic and chemical Pin1 inhibition using Pin1 short hairpin RNA or small molecule inhibitor all-trans retinoic acid (ATRA) on tumorigenesis of human gastric cancer in vitro and in vivo, followed by biochemical analyses to elucidate Pin1 regulated oncogenic pathways. We found that Pin1 was significantly overexpressed in primary and metastasized tumors, with Pin1 overexpression being correlated with advanced stage and poor prognosis. Furthermore, whereas Pin1 overexpression promoted the transformed phenotype in immortalized and nontransformed human gastric cells, either genetic or chemical Pin1 inhibition in multiple human gastric cancer cells potently suppressed cell growth, G1/S transition and colony formation in vitro, as well as tumor growth in xenograft tumor models in vivo, which were further supported by downregulation of multiple key oncoproteins in PI3K/AKT and Wnt/ß-catenin signaling pathways. These results not only provide the first evidence for a critical role of Pin1 in the tumorigenesis of gastric cancer but also suggest that targeting Pin1 using ATRA or other inhibitors offers an effective new therapeutic approach for treating advanced gastric cancer.


Assuntos
Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/patologia , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Peptidilprolil Isomerase de Interação com NIMA/antagonistas & inibidores , Peptidilprolil Isomerase de Interação com NIMA/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Tretinoína/farmacologia , Via de Sinalização Wnt
15.
Nat Commun ; 10(1): 1665, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30971692

RESUMO

Lung cancer is the leading cause of cancer-related deaths worldwide. Tumor suppressor genes remain to be systemically identified for lung cancer. Through the genome-wide screening of tumor-suppressive transcription factors, we demonstrate here that GATA4 functions as an essential tumor suppressor in lung cancer in vitro and in vivo. Ectopic GATA4 expression results in lung cancer cell senescence. Mechanistically, GATA4 upregulates multiple miRNAs targeting TGFB2 mRNA and causes ensuing WNT7B downregulation and eventually triggers cell senescence. Decreased GATA4 level in clinical specimens negatively correlates with WNT7B or TGF-ß2 level and is significantly associated with poor prognosis. TGFBR1 inhibitors show synergy with existing therapeutics in treating GATA4-deficient lung cancers in genetically engineered mouse model as well as patient-derived xenograft (PDX) mouse models. Collectively, our work demonstrates that GATA4 functions as a tumor suppressor in lung cancer and targeting the TGF-ß signaling provides a potential way for the treatment of GATA4-deficient lung cancer.


Assuntos
Fator de Transcrição GATA4/metabolismo , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Neoplasias Pulmonares/genética , Proteínas Wnt/metabolismo , Células A549 , Animais , Senescência Celular/genética , Regulação para Baixo , Feminino , Fator de Transcrição GATA4/genética , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Prognóstico , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Transdução de Sinais/genética , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Regulação para Cima , Proteínas Wnt/genética , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Nat Commun ; 10(1): 1833, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015428

RESUMO

In response to extracellular signals, many signalling proteins associated with the plasma membrane are sorted into endosomes. This involves endosomal fusion, which depends on the complexes HOPS and CORVET. Whether and how their subunits themselves modulate signal transduction is unknown. We show that Vps11 and Vps18 (Vps11/18), two common subunits of the HOPS/CORVET complexes, are E3 ubiquitin ligases. Upon overexpression of Vps11/Vps18, we find perturbations of ubiquitination in signal transduction pathways. We specifically demonstrate that Vps11/18 regulate several signalling factors and pathways, including Wnt, estrogen receptor α (ERα), and NFκB. For ERα, we demonstrate that the Vps11/18-mediated ubiquitination of the scaffold protein PELP1 impairs the activation of ERα by c-Src. Thus, proteins involved in membrane traffic, in addition to performing their well-described role in endosomal fusion, fine-tune signalling in several different ways, including through ubiquitination.


Assuntos
Proteínas Correpressoras/metabolismo , Endossomos/metabolismo , Fatores de Transcrição/metabolismo , Complexos Ubiquitina-Proteína Ligase/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Receptor alfa de Estrogênio/metabolismo , Células HEK293 , Humanos , Células MCF-7 , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Ubiquitinação/fisiologia , Proteínas Wnt/metabolismo , Quinases da Família src/metabolismo
17.
ScientificWorldJournal ; 2019: 4714781, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30940992

RESUMO

For gastrulation to occur in human embryos, a mechanism that simultaneously regulates many different processes, such as cell differentiation, proliferation, migration, and invasion, is required to consistently and effectively create a human being during embryonic morphogenesis. The striking similarities in the processes of cancer and gastrulation have prompted speculation regarding the developmental pathways involved in their regulation. One of the fundamental requirements for the developmental pathways in gastrulation and cancer is the ability to respond to environmental stimuli, and it has been proposed that the Kaiso and noncanonical Wnt pathways participate in the mechanisms regulating these developmental pathways. In particular, these pathways might also explain the notable differences in invasive capacity between cancers of endodermal and mesodermal origins and cancers of ectodermal origin. Nevertheless, the available information indicates that cancer is an abnormal state of adult human cells in which developmental pathways are reactivated in inappropriate temporal and spatial contexts.


Assuntos
Modelos Biológicos , Neoplasias/metabolismo , Via de Sinalização Wnt/fisiologia , Diferenciação Celular , Movimento Celular , Epigênese Genética , Gastrulação , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Neoplasias/genética , Proteínas Wnt/metabolismo
18.
Front Biosci (Landmark Ed) ; 24: 947-960, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844722

RESUMO

Enhancer of zeste homolog 2 (EZH2), a catalytic component of polycomb repressive complex 2 (PRC2), epigenetically regulates chromatin structure and gene expression through trimethylation at histone H3K27 and recruitment of DNA methyltransferases for gene silencing. Despite extensive studies of the role of EZH2 in cancer progression and malignancy, increasing evidences suggest that EZH2 plays a critical role in stem cells renewal, maintenance, and differentiation into specific cell lineages. Here, we reviewed the update information regarding how EZH2 contributes to stem cell maintenance and cell lineage determination (including gonadogenesis, neurogenesis, myogenesis, osteogenesis, hematopoiesis, lymphopoiesis, adipogenesis, epidermal differentiation and hepatogenesis), and the regulation of EZH2 by phosphorylation and different signaling pathways.


Assuntos
Linhagem da Célula , Proteína Potenciadora do Homólogo 2 de Zeste/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Transdução de Sinais , Animais , Feminino , Hematopoese , Humanos , Linfopoese , Masculino , Camundongos , Desenvolvimento Muscular , Neurogênese , Oogênese , Osteogênese , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Notch/metabolismo , Fator de Transcrição STAT3/metabolismo , Espermatogênese , Células-Tronco/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
20.
Proc Natl Acad Sci U S A ; 116(11): 4989-4998, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30819898

RESUMO

WNT/ß-catenin signaling is crucial to all stages of life. It controls early morphogenetic events in embryos, maintains stem cell niches in adults, and is dysregulated in many types of cancer. Despite its ubiquity, little is known about the dynamics of signal transduction or whether it varies across contexts. Here we probe the dynamics of signaling by monitoring nuclear accumulation of ß-catenin, the primary transducer of canonical WNT signals, using quantitative live cell imaging. We show that ß-catenin signaling responds adaptively to constant WNT signaling in pluripotent stem cells, and that these dynamics become sustained on differentiation. Varying dynamics were also observed in the response to WNT in commonly used mammalian cell lines. Signal attenuation in pluripotent cells is observed even at saturating doses, where ligand stability does not affect the dynamics. TGFß superfamily ligands Activin and BMP, which coordinate with WNT signaling to pattern the gastrula, increase the ß-catenin response in a manner independent of their ability to induce new WNT ligand production. Our results reveal how variables external to the pathway, including differentiation status and cross-talk with other pathways, dramatically alter WNT/ß-catenin dynamics.


Assuntos
Diferenciação Celular , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Via de Sinalização Wnt , Ativinas/farmacologia , Adaptação Biológica/efeitos dos fármacos , Proteína Morfogenética Óssea 4/farmacologia , Sistemas CRISPR-Cas/genética , Diferenciação Celular/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Células-Tronco Embrionárias Humanas/citologia , Células-Tronco Embrionárias Humanas/efeitos dos fármacos , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Ligantes , Células-Tronco Pluripotentes/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo
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