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1.
Nat Commun ; 11(1): 5321, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087710

RESUMO

5-Fluorouracil (5-FU) remains the first-line treatment for colorectal cancer (CRC). Although 5-FU initially de-bulks the tumor mass, recurrence after chemotherapy is the barrier to effective clinical outcomes for CRC patients. Here, we demonstrate that p53 promotes WNT3 transcription, leading to activation of the WNT/ß-catenin pathway in ApcMin/+/Lgr5EGFP mice, CRC patient-derived tumor organoids (PDTOs) and patient-derived tumor cells (PDCs). Through this regulation, 5-FU induces activation and enrichment of cancer stem cells (CSCs) in the residual tumors, contributing to recurrence after treatment. Combinatorial treatment of a WNT inhibitor and 5-FU effectively suppresses the CSCs and reduces tumor regrowth after discontinuation of treatment. These findings indicate p53 as a critical mediator of 5-FU-induced CSC activation via the WNT/ß-catenin signaling pathway and highlight the significance of combinatorial treatment of WNT inhibitor and 5-FU as a compelling therapeutic strategy to improve the poor outcomes of current 5-FU-based therapies for CRC patients.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Fluoruracila/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Células HCT116 , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Camundongos Transgênicos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Organoides/efeitos dos fármacos , Organoides/metabolismo , Organoides/patologia , Pirazinas/administração & dosagem , Piridinas/administração & dosagem , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Proteína Wnt3/genética , Proteína Wnt3/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Nat Commun ; 11(1): 5357, 2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097721

RESUMO

Low-density lipoprotein receptor-related protein 6 (LRP6) is a coreceptor of the ß-catenin-dependent Wnt signaling pathway. The LRP6 ectodomain binds Wnt proteins, as well as Wnt inhibitors such as sclerostin (SOST), which negatively regulates Wnt signaling in osteocytes. Although LRP6 ectodomain 1 (E1) is known to interact with SOST, several unresolved questions remain, such as the reason why SOST binds to LRP6 E1E2 with higher affinity than to the E1 domain alone. Here, we present the crystal structure of the LRP6 E1E2-SOST complex with two interaction sites in tandem. The unexpected additional binding site was identified between the C-terminus of SOST and the LRP6 E2 domain. This interaction was confirmed by in vitro binding and cell-based signaling assays. Its functional significance was further demonstrated in vivo using Xenopus laevis embryos. Our results provide insights into the inhibitory mechanism of SOST on Wnt signaling.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/química , Animais , Sítios de Ligação , Cristalografia por Raios X , Feminino , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química , Modelos Moleculares , Peptídeos/metabolismo , Ligação Proteica , Conformação Proteica , Transcriptoma , Xenopus laevis/embriologia , Xenopus laevis/metabolismo , beta Catenina/metabolismo
3.
Life Sci ; 261: 118458, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32961231

RESUMO

AIM: Niclosamide (NIC) is an anthelmintic agent repurposed as a potent anticancer agent. However, its use is hindered by its poor solubility. We investigated the underlying mechanisms of NIC anticancer activity employing a novel oral NIC pluronic-based nanoformulation and tested its effect in thioacetamide-induced hepatocellular carcinoma (HCC) in rats. We evaluated its antitumor effect through regulating Wnt/ß-catenin and Notch signaling pathways and apoptosis. MAIN METHODS: Niclosamide-loaded pluronic nanoparticles (NIC-NPs) were optimally developed and characterized with sustained release properties up to 7 days. Sixteen weeks after HCC induction, NIC (70 mg/kg) and an equivalent dose of NIC-NPs were administered orally for 3 consecutive weeks. Hepatocyte integrity was assessed by measuring serum levels of aminotransferases, ALP, GGT, bilirubin, albumin and total protein. HCC development was detected by measuring AFP expression. Necroinflammation and fibrosis were scored by histopathological examination. Wnt/ß-catenin and Notch signaling were evaluated by measuring hepatic mRNA levels of Wnt3A, Lrp5 and Lrp6 Co-receptors, Dvl-2, Notch1 and Hes1 and ß-catenin protein levels. Apoptosis was assessed by measuring mRNA and protein levels of cyclin D1 and caspase-3. KEY FINDING: The novel NIC-NPs restored liver integrity, reduced AFP levels and showed improved anticancer and proapoptotic activities compared to drug alone. The inhibitory effect of NIC on Wnt/ß-catenin and Notch signaling pathways was potentiated by the NIC-NPs formulation. SIGNIFICANCE: We conclude that NIC acts by inhibiting Wnt/ß-catenin and Notch signaling and inducing apoptosis in HCC. Developing pluronic-based nanoformulations may be a promising approach to improve NIC solubility and offer the possibility of controlled release.


Assuntos
Anti-Helmínticos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Niclosamida/uso terapêutico , Receptores Notch/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Anti-Helmínticos/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Portadores de Fármacos/química , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Micelas , Nanopartículas/química , Niclosamida/administração & dosagem , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
4.
Life Sci ; 260: 118221, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768578

RESUMO

JLX001, a new dihydrochloride of Cyclovirobuxine D (CVB-D), has bioactivities against ischemia injury. The blood-brain barrier (BBB) disruption is involved in the pathogeneses of ischemic stroke. This study was designed to explore the effect and potential mechanism of JLX001 on the BBB after ischemic stroke. Rats were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) to mimic cerebral ischemia in vivo. In vitro, rat primary brain microvascular endothelial cells (PBMECs) were cultured and exposed to oxygen-glucose deprivation/reoxygenation (OGD/R). Posttreatment of JLX001 for 15 days after MCAO/R improved the behavior, learning and memory ability. Pretreatment of JLX001 for 3 days significantly attenuated infarct volume, lessened brain edema, mitigated BBB disruption and decreased the neurological deficit score in MCAO/R rats. Moreover, JLX001 increased cell viability and reduced sodium fluorescein leakage after OGD/R injury. In addition, JLX001 increased the expressions of Claudin-5 and Occludin, decreased the expression of MMP-9 both in vivo and in vitro. Moreover, immunofluorescence staining and western immunoblotting results showed that JLX001 increased the expressions of tight junction proteins via activating Wnt/ß-catenin signal pathway in vivo and in vitro, which may be associated with the activation of PI3K/Akt signaling. Besides, XAV939 (an inhibitor of the Wnt/ß-catenin pathway) proved the connection of JLX001 and Wnt/ß-catenin pathway. These results suggest that JLX001 alleviates BBB disruption after MCAO/R and OGD/R possibly by alleviating MMP-9 and activating the Wnt/ß-catenin signaling pathway.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Isquemia Encefálica/fisiopatologia , Infarto da Artéria Cerebral Média , Triterpenos/administração & dosagem , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Barreira Hematoencefálica/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/química , Células Endoteliais/química , Células Endoteliais/fisiologia , Ácido Glucárico/administração & dosagem , Masculino , Metaloproteinase 9 da Matriz/análise , Metaloproteinase 9 da Matriz/metabolismo , Microvasos/citologia , Fármacos Neuroprotetores , Oxigênio/administração & dosagem , Inibidores da Agregação de Plaquetas , Ratos , Ratos Sprague-Dawley , Reperfusão , Triterpenos/farmacologia , Via de Sinalização Wnt/fisiologia
5.
PLoS One ; 15(8): e0232917, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32810161

RESUMO

In human lung cancer progression, the EMT process is characterized by the transformation of cancer cells into invasive forms that migrate to other organs. Targeting to EMT-related molecules is emerging as a novel therapeutic approach for the prevention of lung cancer cell migration and invasion. Traf2- and Nck-interacting kinase (TNIK) has recently been considered as an anti-proliferative target molecule to regulate the Wnt signaling pathway in several types of cancer cells. In the present study, we evaluated the inhibitory effect of a tyrosine kinase inhibitor sunitinib and the integrin-αⅤß3 targeted cyclic peptide (cRGDfK) on EMT in human lung cancer cells. Sunitinib strongly inhibited the TGF-ß1-activated EMT through suppression of Wnt signaling, Smad and non-Smad signaling pathways. In addition, the cRGDfK also inhibited the expression of TGFß1-induced mesenchymal marker genes and proteins. The anti-EMT effect of sunitinib was enhanced when cRGDfK was treated together. When sunitinib was treated with cRGDfK, the mRNA and protein expression levels of mesenchymal markers were decreased compared to the treatment with sunitinib alone. Co-treatment of cRGDfK has shown the potential to improve the efficacy of anticancer agents in combination with therapeutic agents that may be toxic at high concentrations. These results provide new and improved therapies for treating and preventing EMT-related disorders, such as lung fibrosis and cancer metastasis, and relapse.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Peptídeos Cíclicos/administração & dosagem , Sunitinibe/administração & dosagem , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Células A549 , Trifosfato de Adenosina/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Integrina alfaVbeta3/antagonistas & inibidores , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Simulação de Acoplamento Molecular , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Smad/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
6.
Am J Physiol Renal Physiol ; 319(4): F571-F578, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32830537

RESUMO

(Pro)renin receptor [(P)RR] has multiple functions, but its regulation and role in the pathogenesis in glomerulonephritis (GN) are poorly defined. The aims of the present study were to determine the effects of direct renin inhibition (DRI) and demonstrate the role of (P)RR on the progression of crescentic GN. The anti-glomerular basement membrane nephritis rat model developed progressive proteinuria (83.64 ± 10.49 mg/day) and glomerular crescent formation (percent glomerular crescent: 62.1 ± 2.3%) accompanied by increased macrophage infiltration and glomerular expression of monocyte chemoattractant protein (MCP)-1, (P)RR, phospho-extracellular signal-regulated kinase (ERK)1/2, Wnt4, and active ß-catenin. Treatment with DRI ameliorated proteinuria (20.33 ± 5.88 mg/day) and markedly reduced glomerular crescent formation (20.9 ± 2.6%), induction of macrophage infiltration, (P)RR, phospho-ERK1/2, Wnt4, and active ß-catenin. Furthermore, primary cultured parietal epithelial cells stimulated by recombinant prorenin showed significant increases in cell proliferation. Notably, while the ERK1/2 inhibitor PD98059 or (P)RR-specific siRNA treatment abolished the elevation in cell proliferation, DRI treatment did not abrogate this elevation. Moreover, cultured mesangial cells showed an increase in prorenin-induced MCP-1 expression. Interestingly, (P)RR or Wnt4-specific siRNA treatment or the ß-catenin antagonist XAV939 inhibited the elevation of MCP-1 expression, whereas DRI did not. These results suggest that (P)RR regulates glomerular crescent formation via the ERK1/2 signaling and Wnt/ß-catenin pathways during the course of anti-glomerular basement membrane nephritis and that DRI mitigates the progression of crescentic GN through the reduction of (P)RR expression but not inhibition of prorenin binding to (P)RR.


Assuntos
Proliferação de Células , Glomerulonefrite/enzimologia , Células Mesangiais/enzimologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Receptores de Superfície Celular/metabolismo , Via de Sinalização Wnt , Amidas/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Fumaratos/farmacologia , Glomerulonefrite/patologia , Glomerulonefrite/prevenção & controle , Masculino , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/patologia , Fosforilação , Ratos Endogâmicos WKY , Via de Sinalização Wnt/efeitos dos fármacos , Proteína Wnt4/metabolismo , beta Catenina/metabolismo
7.
Toxicol Lett ; 333: 170-183, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32795487

RESUMO

Paraquat (PQ) poisoning-induced pulmonary fibrosis always results in fatal harm to patients. Our study aimed to investigate the functions of the Wnt/ß-catenin pathway in PQ-induced pulmonary fibrosis. By comparing the proteomic profiles of rat lung tissues using protein array in the absence or presence of PQ, the Wnt/ß-catenin signaling, as a fibrosis-related pathway, was discovered to be profoundly activated by PQ. The protein levels of Wnt/ß-catenin signaling components including MMP-2, ß-catenin, Wnt3a, Wnt10b, Cyclin D1, and WISP1 were increased in PQ-treated rat lung tissues. Surprisingly, PQ was found to be able to promote lung epithelial cells and fibroblasts differentiating into myofibroblasts by activating Wnt/ß-catenin signaling pathway. Dickkopf-1 (DKK1), an antagonist of Wnt/ß-catenin signaling pathway, could inhibit the myofibroblast differentiation and attenuate PQ-induced pulmonary fibrogenesis in vitro and in vivo. The expression levels of fibroblasts markers Vimentin, α-smooth muscle actin (α-SMA) and Collagen I was detected and found to be increased when PQ treated and restored with additional DKK1 treatment. In summary, these assays indicated that Wnt/ß-catenin signaling pathway played a regulatory role in the differentiation of lung epithelial cells and fibroblasts, and the pathogenesis of pulmonary fibrosis related to PQ. Inhibition of the Wnt/ß-catenin signaling pathway may be investigated further as a potential fibrosis suppressor for pulmonary fibrosis therapy.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Herbicidas/toxicidade , Miofibroblastos/efeitos dos fármacos , Paraquat/toxicidade , Fibrose Pulmonar/induzido quimicamente , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Técnicas de Cultura de Células , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Masculino , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Ratos Sprague-Dawley
8.
J Steroid Biochem Mol Biol ; 202: 105723, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32603782

RESUMO

Vitamin D (VitD) has an anti-fibrotic effect on fibrotic lungs. It reduces epithelial-mesenchymal transition (EMT) on tumors. We aimed to investigate target proteins of VitD for the regression of EMT-mediated myofibroblast differentiation. A group of A549 cells were treated with 5 % cigarette smoke extract (CSE) and 5 %CSE + TGF-ß (5 ng/ml) to induce EMT. The others were treated with 50 nM VitD 30 min before %5CSE and TGF-ß treatments. All cells were collected at 24, 48 and 72 h following 5 %CSE and TGF-ß administrations. The expression of p120ctn and NEDD9 proteins acted on E-cadherin turnover in addition to activations of TGF-ß and Wnt pathways were examined in these cells and fibrotic human lungs. CSE and TGF-ß induced EMT by reducing E-cadherin, p-VDR, SMAD7 and DKK1, increasing α-SMA, p120ctn, Kaiso, NEDD9 and stimulating TGF-ß and Wnt/ß-catenin signalings in A549 cells. VitD administration reversed these alterations and regressed EMT. Co-immunoprecipitation analysis revealed p-VDR interaction with ß-catenin and Kaiso in fibrotic and non-fibrotic human lungs. VitD pre-treatments reduced TGF-ß and Wnt/ß-catenin signalings by increasing p-VDR, protected from E-cadherin degradation and led to the regression of EMT in A549 cells treated with CSE and TGF-ß. Finally, VitD supplementation combined with anti-fibrotic therapeutics can be suggested for treatment of pulmonary fibrosis, which may be developed by smoking, in cases of VitD deficiency.


Assuntos
Antígenos CD/metabolismo , Caderinas/metabolismo , Miofibroblastos/metabolismo , Fumaça , Produtos do Tabaco , Fator de Crescimento Transformador beta/metabolismo , Vitamina D/farmacologia , Vitaminas/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Células A549 , Diferenciação Celular , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Pulmão/patologia , Miofibroblastos/citologia , Fibrose Pulmonar , Receptores de Calcitriol/metabolismo
9.
Life Sci ; 258: 118143, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32717269

RESUMO

AIMS: Kaempferol, a type of flavonoid, is widely present in fruits, vegetables and medicinal herbs. This study was designed to investigate the effects of kaempferol on proliferation and osteogenesis of periodontal ligament stem cells (PDLSCs) and to identify the related pathway. MATERIALS AND METHODS: PDLSCs were isolated from extracted premolars and cultured in vitro. Cell-counting kit-8 (CCK-8) and colony formation assays were performed to determine the effect of kaempferol, at various concentrations, on the proliferation of PDLSCs. Alkaline phosphatase (ALP) activity was analyzed both quantitatively and qualitatively, and extracellular matrix mineralization was examined by alizarin red-S staining. In addition, the mRNA and protein expression levels of ALP, RUNX Family Transcription Factor 2 (RUNX2), Sp7 Transcription Factor (SP7; Osterix), Bone Gamma-Carboxyglutamate Protein (BGLAP; osteocalcin) and catenin beta 1 (CTNNB1; ß-catenin) were monitored by qPCR and Western blot analysis. Additionally, the tankyrase inhibitor, XAV939, was used to determine the role of the Wnt/ß-catenin pathway. KEY FINDINGS: The results illustrated that 10-6 M kaempferol markedly promoted the proliferation, ALP activity and mineral deposition of PDLSCs (P < 0.05). The expression levels of ALP, RUNX2, SP7, BGLAP and ß-catenin were all upregulated (P < 0.05). After blocking the Wnt/ß-catenin pathway with XAV939, the effects of kaempferol were apparently reversed. SIGNIFICANCE: kaempferol enhanced proliferation and osteogenesis of PDLSCs by activating the Wnt/ß-catenin signaling, which suggests the potential application of kaempferol for periodontal tissue regeneration.


Assuntos
Proliferação de Células/efeitos dos fármacos , Quempferóis/farmacologia , Osteogênese/efeitos dos fármacos , Ligamento Periodontal/citologia , Via de Sinalização Wnt/efeitos dos fármacos , Adolescente , Adulto , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Ligamento Periodontal/efeitos dos fármacos , Ligamento Periodontal/metabolismo , Adulto Jovem
10.
J Nat Med ; 74(4): 767-776, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32656716

RESUMO

Traumatic brain injury (TBI) is a major cause of death and disability around the world with no effective treatments currently. The present study was aimed to investigate the neuroprotective effect of licoricidin, one of the major components of licorice extract, on TBI mice and further explore the underlying mechanism. Male C57BL/6 mice were modeled by a modified weight-drop method to mimic TBI. All animals received treatment 30 min after TBI. The modified Neurological Severity Score (NSS) tests were performed at 2 h and 1-3 days after TBI. The brain edema was analyzed by dry-wet weight method. The malonaldehyde (MDA) levels and the activities of glutathione peroxidase (GSH-PX), superoxide dismutase (SOD) and catalase (CAT) were determined by Elisa. Apoptotic neurons were detected using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) immunofluorescence and the expression of apoptotic proteins were measured by western blot. Activation of the FoxO3/Wnt/ß-catenin was evaluated by western blot. The results showed that treatment with licoricidin could significantly decline the NSS scores and reduce the brain edema, hence promote the recovery of neurological function in TBI mice. It also elevated the phosphorylation of p66shc, brought down the levels of MDA, as well as antagonized the decrement in activities of GSH-PX, SOD and CAT induced by TBI. Moreover, licoricidin decreased the TUNEL positive neurons, downregulated the expression of Cyt-C, cleaved-Caspase-3, cleaved-Caspase-9 and Bax and upregulated the Bcl-2, attenuated cellular apoptosis. Licoricidin decreased the expression of FoxO3 and increased the Wnt/ß-catenin in TBI mice. In conclusion, Licoricidin exerted neuroprotective effect on TBI model and the effect was possibly due to its antioxidative effect and antiapoptotic effect via regulating the FoxO3/Wnt/ß-catenin pathway. Licoricidin may be a candidate drug for TBI therapy.


Assuntos
Benzopiranos/uso terapêutico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Benzopiranos/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
11.
Proc Natl Acad Sci U S A ; 117(32): 19578-19589, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32727894

RESUMO

The CreER/LoxP system is widely accepted to track neural lineages and study gene functions upon tamoxifen (TAM) administration. We have observed that prenatal TAM treatment caused high rates of delayed delivery and fetal mortality. This substance could produce undesired results, leading to data misinterpretation. Here, we report that administration of TAM during early stages of cortical neurogenesis promoted precocious neural differentiation, while it inhibited neural progenitor cell (NPC) proliferation. The TAM-induced inhibition of NPC proliferation led to deficits in cortical neurogenesis, dendritic morphogenesis, synaptic formation, and cortical patterning in neonatal and postnatal offspring. Mechanistically, by employing single-cell RNA-sequencing (scRNA-seq) analysis combined with in vivo and in vitro assays, we show TAM could exert these drastic effects mainly through dysregulating the Wnt-Dmrta2 signaling pathway. In adult mice, administration of TAM significantly attenuated NPC proliferation in both the subventricular zone and the dentate gyrus. This study revealed the cellular and molecular mechanisms for the adverse effects of TAM on corticogenesis, suggesting that care must be taken when using the TAM-induced CreER/LoxP system for neural lineage tracing and genetic manipulation studies in both embryonic and adult brains.


Assuntos
Encéfalo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/patologia , Tamoxifeno/efeitos adversos , Animais , Encéfalo/embriologia , Encéfalo/patologia , Diferenciação Celular , Proliferação de Células , Giro Denteado/efeitos dos fármacos , Giro Denteado/patologia , Feminino , Ventrículos Laterais/efeitos dos fármacos , Ventrículos Laterais/patologia , Camundongos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , RNA-Seq , Análise de Célula Única , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
12.
Chem Biol Interact ; 328: 109201, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32717190

RESUMO

The caseinate and glycated caseinate generated from the transglutaminase-catalyzed reaction of caseinate and oligochitosan were digested using pepsin and trypsin, and the activity of the resultant digests was measured in rat intestinal epithelial cell line (IEC-6) using several biological responses as indicators. Compared with the caseinate digest, the glycated caseinate digest had similar contents in 17 amino acids but less reactable -NH2 contents, and 6.57 g glucosamine per kg protein; moreover, it showed higher activity in the cells (P < 0.05) to promote cell growth, accumulate the cell-cycle progression at the S-phase, and prevent the camptothecin-induced cell apoptosis. The glycated caseinate digest also showed higher differentiation activity in the cells than the caseinate digest, resulting in enhanced activities of the three brush-border membrane enzymes (P < 0.05) and increased microvilli on the cell surfaces. The real-time reverse transcription-polymerase chain reaction, Western-blot assay, and Dickkopf-1 (a receptor inhibitor of the Wnt/ß-catenin signaling pathway) were used to determine both gene and protein expression changes in the cells. A Wnt/ß-catenin signaling pathway responsible for these enhanced effects was proposed because the five genes (glycogen synthase kinase 3ß, Wnt3a, ß-catenin, c-Myc, and cyclin D1) and three proteins (nuclear and cytosolic ß-catenin, cyclin D1, and c-Myc) as part of this signaling pathway were regulated in the treated cells. The oligochitosan glycation of caseinate induced by transglutaminase is thus suggested endowing the peptic-tryptic caseinate digest with higher activity in the cells through its effects on the Wnt/ß-catenin signaling pathway.


Assuntos
Caseínas/metabolismo , Quitina/análogos & derivados , Enterócitos/metabolismo , Pepsina A/metabolismo , Tripsina/metabolismo , Via de Sinalização Wnt , Animais , Apoptose , Bovinos , Pontos de Checagem do Ciclo Celular , Diferenciação Celular/genética , Proliferação de Células , Sobrevivência Celular , Quitina/metabolismo , Enterócitos/citologia , Enterócitos/ultraestrutura , Regulação da Expressão Gênica/efeitos dos fármacos , Glicosilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/genética
13.
J Cancer Res Clin Oncol ; 146(10): 2559-2574, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32681294

RESUMO

PURPOSE: Canonical Wnt/ ß-catenin pathway is one mechanism being activated in platinum-resistant epithelial ovarian cancer (EOC). Detecting potential targets for Wnt pathway modulation as a putative future therapeutic approach was the aim of this study. METHODS: Biological effects of different Wnt modulators (SB216763, XAV939 and triptolide) on the EOC cell lines A2780 and its platinum-resistant clone A2780cis were investigated via multiple functional tests. Immunohistochemistry (IHC) was carried out to compare the expression levels of Wnt marker proteins (ß-catenin, snail/ slug, E-cadherin) in patient specimens and to correlate them with lifetime data. RESULTS: We could show that activated Wnt signaling of the platinum-resistant EOC cell line A2780cis can be reversed by Wnt manipulators through SB216763 or XAV939. All Wnt manipulators tested consecutively decreased cell proliferation and cell viability. Apoptosis of A2780 and A2780cis was enhanced by triptolide in a dose-dependent manner, whereas cell migration was inhibited by SB216763 and triptolide. IHC analyses elucidated significantly different expression patterns for Wnt markers in the serous subtype. Herein, higher plasmatic snail/ slug expression is associated with improved progression-free (PFS) and overall survival (OS). CONCLUSION: According to the described effects on EOC biology, all three Wnt manipulators seem to have the potential to augment the impact of a platinum-based chemotherapy in EOC. This is promising as a dominance of this pathway was confirmed in serous histology.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/metabolismo , Compostos Organoplatínicos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Antígenos CD/biossíntese , Antígenos CD/metabolismo , Caderinas/biossíntese , Caderinas/metabolismo , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Diterpenos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Compostos de Epóxi/farmacologia , Feminino , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Indóis/farmacologia , Maleimidas/farmacologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Neoplasias Ovarianas/patologia , Fenantrenos/farmacologia , beta Catenina/biossíntese , beta Catenina/metabolismo
14.
PLoS One ; 15(6): e0234078, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32484838

RESUMO

BACKGROUND: Despite new drugs, metastatic prostate cancer remains fatal. Growing interest in the latest approved cabazitaxel taxane drug has markedly increased due to the survival benefits conferred when used at an earlier stage of the disease, its promising new therapeutic combination and formulation, and its differential toxicity. Still cabazitaxel's mechanisms of resistance are poorly characterized. The goal of this study was thus to generate a new model of acquired resistance against cabazitaxel in order to unravel cabazitaxel's resistance mechanisms. METHODS: Du145 cells were cultured with increasing concentrations of cabazitaxel, docetaxel/ taxane control or placebo/age-matched control. Once resistance was reached, Epithelial-to-Mesenchymal Translation (EMT) was tested by cell morphology, cell migration, and E/M markers expression profile. Cell transcriptomics were determined by RNA sequencing; related pathways were identified using IPA, PANTHER or KEGG software. The Wnt pathway was analyzed by western blotting, pharmacological and knock-down studies. RESULTS: While age-matched Du145 cells were sensitive to both taxane drugs, docetaxel-resistant cells were only resistant to docetaxel and cabazitaxel-resistant cells showed a partial cross-resistance to both drugs concomitant to EMT. Using RNA-sequencing, the Wnt non-canonical pathway was identified as exclusively activated in cabazitaxel resistant cells while the Wnt canonical pathway was restricted to docetaxel-resistant cells. Cabazitaxel-resistant cells showed a minimal crossover in the Wnt-pathway-related genes linked to docetaxel resistance validating our unique model of acquired resistance to cabazitaxel. Pharmacological and western blot studies confirmed these findings and suggest the implication of the Tyrosine kinase Ror2 receptor in cabazitaxel resistant cells. Variation in Ror2 expression level altered the sensitivity of prostate cancer cells to both drugs identifying a possible new target for taxane resistance. CONCLUSION: Our study represents the first demonstration that while Wnt pathway seems to play an important role in taxanes resistance, Wnt effectors responsible for taxane specificity remain un-identified prompting the need for more studies.


Assuntos
Antineoplásicos/farmacologia , Taxoides/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Masculino , Neoplasias da Próstata/patologia , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Transcriptoma/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
15.
Nat Commun ; 11(1): 2797, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493999

RESUMO

Fat distribution is an independent cardiometabolic risk factor. However, its molecular and cellular underpinnings remain obscure. Here we demonstrate that two independent GWAS signals at RSPO3, which are associated with increased body mass index-adjusted waist-to-hip ratio, act to specifically increase RSPO3 expression in subcutaneous adipocytes. These variants are also associated with reduced lower-body fat, enlarged gluteal adipocytes and insulin resistance. Based on human cellular studies RSPO3 may limit gluteofemoral adipose tissue (AT) expansion by suppressing adipogenesis and increasing gluteal adipocyte susceptibility to apoptosis. RSPO3 may also promote upper-body fat distribution by stimulating abdominal adipose progenitor (AP) proliferation. The distinct biological responses elicited by RSPO3 in abdominal versus gluteal APs in vitro are associated with differential changes in WNT signalling. Zebrafish carrying a nonsense rspo3 mutation display altered fat distribution. Our study identifies RSPO3 as an important determinant of peripheral AT storage capacity.


Assuntos
Adipócitos/citologia , Adipócitos/metabolismo , Distribuição da Gordura Corporal , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Trombospondinas/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Adipócitos/efeitos dos fármacos , Tecido Adiposo/metabolismo , Adiposidade/genética , Adulto , Alelos , Animais , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Tamanho Celular/efeitos dos fármacos , Doxiciclina/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Caracteres Sexuais , Células-Tronco/metabolismo , Trombospondinas/genética , Relação Cintura-Quadril , Via de Sinalização Wnt/efeitos dos fármacos , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
16.
Toxicol Lett ; 331: 159-166, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32522577

RESUMO

Cadmium, which is extensively distributed in the environment, accumulates in organisms through the trophic chain. Although cadmium can cause bone injury, its role in osteogenesis of human bone marrow mesenchymal stem cells (hBMSCs) remains unclear. The present study investigated the effect of cadmium chloride (CdCl2) on osteogenesis of hBMSCs and the underlying mechanism. CdCl2 dose-dependently reduced the viability of hBMSCs. Concentrations of CdCl2 (2.5 and 5.0 µM) increased miR-143-3p levels; decreased levels of adenosine diphosphate-ribosylation factor-like protein 6 (ARL6); inhibited Wnt family member 3A (Wnt3a), ß-catenin, lymphoid enhancer factor (LEF1), and T-cell factor 1 (TCF1); and suppressed osteogenesis of hBMSCs. Inhibition of miR-143-3p or overexpression of ARL6 with lentivirus blocked these CdCl2-induced changes. Luciferase reporter assays confirmed that miR-143-3p binds to the 3'-UTR regions of ARL6 mRNA. Reduced-expression of miR-143-3p enhanced the CdCl2-induced suppression of the osteogenesis of hBMSCs and inhibition of the Wnt/ß-catenin pathway, effects that were reversed by down-regulated expression of ARL6. Thus, miR-143-3p targets ARL6 to down-regulate the Wnt/ß-catenin pathway, which is involved in the suppression of osteogenic differentiation of hBMSCs. The results provide new directions for clinical treatment of bone diseases resulting from cadmium toxicity.


Assuntos
Fatores de Ribosilação do ADP/metabolismo , Cádmio/toxicidade , Diferenciação Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Células-Tronco Mesenquimais/efeitos dos fármacos , MicroRNAs/genética , Osteogênese/efeitos dos fármacos , Regiões 3' não Traduzidas , Fatores de Ribosilação do ADP/genética , Técnicas de Cultura de Células , Diferenciação Celular/genética , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Osteogênese/genética , Via de Sinalização Wnt/efeitos dos fármacos
17.
Int J Oral Sci ; 12(1): 18, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32555173

RESUMO

Once pulp necrosis or apical periodontitis occurs on immature teeth, the weak root and open root apex are challenging to clinicians. Berberine (BBR) is a potential medicine for bone disorders, therefore, we proposed to apply BBR in root canals to enhance root repair in immature teeth. An in vivo model of immature teeth with apical periodontitis was established in rats, and root canals were filled with BBR, calcium hydroxide or sterilized saline for 3 weeks. The shape of the roots was analyzed by micro-computed tomography and histological staining. In vitro, BBR was introduced into stem cells from apical papilla (SCAPs). Osteogenic differentiation of stem cells from apical papilla was investigated by alkaline phosphatase activity, mineralization ability, and gene expression of osteogenic makers. The signaling pathway, which regulated the osteogenesis of SCAPs was evaluated by quantitative real time PCR, Western blot analysis, and immunofluorescence. In rats treated with BBR, more tissue was formed, with longer roots, thicker root walls, and smaller apex diameters. In addition, we found that BBR promoted SCAPs osteogenesis in a time-dependent and concentration-dependent manner. BBR induced the expression of ß-catenin and enhanced ß-catenin entering into the nucleus, to up-regulate more runt-related nuclear factor 2 downstream. BBR enhanced root repair in immature teeth with apical periodontitis by activating the canonical Wnt/ß-catenin pathway in SCAPs.


Assuntos
Berberina/farmacologia , Osteogênese/efeitos dos fármacos , Periodontite Periapical/terapia , Células-Tronco/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Papila Dentária , Masculino , Ratos , Células-Tronco/citologia , Células-Tronco/metabolismo , Proteína Wnt3A/genética , Proteína Wnt3A/metabolismo , Microtomografia por Raio-X
18.
Acta Orthop Traumatol Turc ; 54(3): 320-329, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32544068

RESUMO

OBJECTIVE: This study aimed to determine the effects of a natural diterpenoid, kirenol, on fracture healing in vivo in an experimental rat model of femur fracture and investigate its potential mechanism of action via the Wnt/ß-catenin pathway. METHODS: In this study, 64 male Wistar albino rats aged 5-7 weeks and weighing 261-348 g were randomly divided into 8 groups from A to L, with eight rats in each group. Standardized fractures were created in the right femurs of the rats and then fixed with an intramedullary Kirschner wire. Four experimental groups were administered 2 mg/kg/day kirenol (Groups C and G) and 4 mg/kg/day (Groups D and H) kirenol by oral gavage.Thereafter, the animals were sacrificed at two time points as follows: on the 10th day (Groups B, C and D) and on the 21st day (Groups F, G and H) after the surgery; fracture healing in each group was assessed radiologically and histopathologically. The Radiographic Union scale of tibia fracture scoring system was used in the radiological examination; callus volume and density were measured using computed tomography. In the histopathologic examination, the scoring system described by Huo et al. was used. Additionally, the mechanism of action was evaluated based on the analyses of protein expression of Wnt3a, LRP5, TCF-LEF1, ß-catenin, and Runx-2 proteins using western blot analysis. RESULTS: Among the animals sacrificed on the 10th day after the surgery, the highest histopathological and radiological scores were observed in Group D (p<0.05). Furthermore, the callus density (p<0.05) was highest in Group D. Among the animals sacrificed on the 21st day, the highest histopathological and radiological scores were found in Group H, although the differences among the groups were not significant (p>0.05). The callus volume and density were the highest in Groups G and H, respectively, although the differences among groups were not significant. CONCLUSION: Kirenol may improve fracture healing in a dose-dependent manner with the early activation of the Wnt/ß-catenin pathway and the activation of the Runx-2 pathway.


Assuntos
Calo Ósseo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Diterpenos/farmacologia , Fraturas do Fêmur , Consolidação da Fratura , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Antirreumáticos/farmacologia , Calo Ósseo/diagnóstico por imagem , Calo Ósseo/efeitos dos fármacos , Calo Ósseo/metabolismo , Fraturas do Fêmur/metabolismo , Fraturas do Fêmur/cirurgia , Fixação Intramedular de Fraturas/métodos , Consolidação da Fratura/efeitos dos fármacos , Consolidação da Fratura/fisiologia , Masculino , Ratos , Ratos Wistar , Resultado do Tratamento
19.
Exp Mol Pathol ; 115: 104451, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32417392

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is a leading cause of non-Hodgkin lymphomas. Existing researches have verified that long non-coding RNAs (lncRNAs) play crucial roles in the development of DLBCL, nevertheless, whether lncRNA OR3A4 has influences on the progression of DCBCL needs further exploration. In our study, it was revealed that the expression of OR3A4 was upregulated in DLBCL tumors and cell lines, and patients with high OR3A4 expression suffered from poor prognosis. Knockdown of OR3A4 suppressed cell proliferation and promoted cell apoptosis in DLBCL. Moreover, knockdown of OR3A4 inactivated Wnt/ß-catenin signaling pathway, and Riluzole treatment could partially rescue the inhibitive effect of OR3A4 silencing on DLBCL cell proliferation. Furthermore, FOXM1 expression was discovered to be upregulated in DLBCL tissues, and it positively modulated the expression of OR3A4 at transcriptional leve. It was also revealed that FOXM1 knockdown inactivated Wnt/ß-catenin signaling pathway. Finally, rescue assays confirmed that OR3A4 overexpression or the treatment of Riluzole could partially countervail the inhibitive effect of FOXM1 silencing on DLBCL progression. Taken together, FOXM1-induced upregulation of OR3A4 enhances the occurrence of DLBCL via Wnt/ß-catenin signaling pathway.


Assuntos
Progressão da Doença , Proteína Forkhead Box M1/metabolismo , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , RNA Longo não Codificante/metabolismo , Regulação para Cima/genética , Via de Sinalização Wnt , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Proteína Forkhead Box M1/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Modelos Biológicos , RNA Longo não Codificante/genética , Riluzol/farmacologia , Riluzol/uso terapêutico , Transcrição Genética/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/genética
20.
Environ Toxicol ; 35(9): 1015-1028, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32420678

RESUMO

Breast cancer (BC) is the leading cause of cancer-related death in women worldwide and one of the most prevalent malignancy. In recent years, increasing evidence had illuminated that long noncoding RNAs (lncRNAs) serve as critical factors in multiple tumor progression, including BC. Emerging references had indicated that the lncRNA H19 acts as significant roles in tumor progression and epithelial-mesenchymal transition (EMT). However, the underlying molecular mechanisms and biological roles of H19 in BC invasion, metastasis and EMT are still unclear. In this study, it was detected that the expression level of H19 was increased in BC paclitaxel-resistant (PR) cells subline (MCF-7/PR) in comparison with MCF-7 parental cells. In vitro, there were demonstrated that H19 overexpression promoted BC cells proliferation, metastasis, invasion and EMT procedures, and suppressed cells apoptosis. Whereas, H19 suppression resulted in the contrary biological effects. Besides, bioinformatics tools and dual-luciferase reporters assays indicated that miR-340-3p could act as a potential target gene of H19, the underlying mechanism studies proved that H19 could act as a competing endogenous RNA (ceRNA) via competitively binding miR-340-3p to promote BC cell proliferation, metastasis and EMT by regulating tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) and potentiate the Wnt/ß-catenin signaling in BC cells. In summary, our findings demonstrated that H19 could act as a ceRNA in BC progression, metastasis and EMT through modulating miR-340-3p/YWHAZ axis and activating the canonical Wnt/ß-catenin signaling pathway, indicating that H19 might act as an underlying therapeutic target and prognostic biomarker for BC therapy.


Assuntos
Proteínas 14-3-3/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , MicroRNAs/genética , Paclitaxel/farmacologia , RNA Longo não Codificante/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/genética
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