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1.
Beijing Da Xue Xue Bao Yi Xue Ban ; 52(5): 815-820, 2020 Oct 18.
Artigo em Chinês | MEDLINE | ID: mdl-33047713

RESUMO

OBJECTIVE: In this study, we used genome-wide association study (GWAS) data to explore whether WNT pathway genes were associated with non-syndromic oral clefts (NSOC) considering gene-gene interaction and gene-environment interaction. METHODS: We conducted the analysis using 806 non-syndromic cleft lip with or without cleft palate (NSCL/P) case-parent trios and 202 non-syndromic cleft palate (NSCP) case-parent trios among Chinese populations selected from an international consortium established for a GWAS of non-syndromic oral clefts. Genotype data and maternal environmental exposures were collected through DNA samples and questionnaires. Conditional Logistic regression models were adopted to explore gene-gene interaction and gene-environment in teraction using trio package in R software. The threshold of significance level was set as 3.47×10-4 using Bonferroni correction. RESULTS: A total of 144 single nucleotide polymorphisms (SNPs) in seven genes passed the quality control process in NSCL/P trios and NSCP trios, respectively. Totally six pairs of SNPs interactions showed statistically significant SNP-SNP interaction (P < 3.47×10-4) after Bonferroni correction, which were rs7618735 (WNT5A) and rs10848543 (WNT5B), rs631948 (WNT11) and rs556874 (WNT5A), and rs631948 (WNT11) and rs472631 (WNT5A) among NSCL/P trios; rs589149 (WNT11) and rs4765834 (WNT5B), rs1402704 (WNT11) and rs358792 (WNT5A), and rs1402704 (WNT11) and rs358793 (WNT5A) among NSCP trios, respectively. In addition, no significant result was found for gene-environment interaction analysis in both of the NSCL/P trios and NSCP trios. CONCLUSION: Though this study failed to detect significant association based on gene-environment interactions of seven WNT pathway genes and the risk of NSOC, WNT pathway genes may influence the risk of NSOC through potential gene-gene interaction.


Assuntos
Fenda Labial , Fissura Palatina , Grupo com Ancestrais do Continente Asiático/genética , Fenda Labial/genética , Fissura Palatina/genética , Estudo de Associação Genômica Ampla , Humanos , Via de Sinalização Wnt/genética
2.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(9): 1115-1119, 2020.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33051427

RESUMO

Roof plate specific spondins (Rspos) are important activators of the Wnt signaling pathway discovered recently. Rspos include four secreted proteins: Rspo1, Rspo2, Rspo3, and Rspo4.They are mainly involved in the regulation of cell proliferation and differentiation via regulating the canonical Wnt/ß-catenin signaling pathway.The physiological functions of Rspos include regulating sex selection, limb development, organ formation and development. Rspos are involved in the pathogenesis of some malignant tumors, and the roles of Rspos vary in different types of tumors.


Assuntos
Neoplasias , Trombospondinas , Proliferação de Células , Sistema Digestório , Humanos , Via de Sinalização Wnt
3.
Ann Agric Environ Med ; 27(3): 394-400, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32955221

RESUMO

INTRODUCTION: Overweight and obesity, as well as a gonadal function, are pivotal factors influencing bone tissue metabolism. MATERIAL AND METHODS: The aim of the study was to determine the effect of dietary induced obesity (DIO) on bone tissue metabolism in sham-operated (SHO) or ovariectomized (OVX) adult female Wistar rats. Additionally, the influence of DIO in SHO or OVX on the concentration of sclerostin in the blood serum was analyzed. After SHO or OVX, the rats were placed in groups (n=8) and either received a standard diet (11.5 MJ/kg) (SHO-CON; OVX-CON) or a high-energy diet (17.6 MJ/kg) (SHO-FAT; OVX-FAT). The experiment lasted for 90 days and allowed for the establishment of osteopenia in OVX females and obesity in the rats that had received the high-energy diet. RESULTS: The results of the study demonstrate that obesity or/and ovariectomy increases the resorption of femora and tibiae, hence decreasing the densitometric and mechanical parameters affecting the bone structure in adult females rats. The strongest osteodegenerative effect was seen in the OVX-FAT females. Interestingly, the degree of bone tissue degradation caused exclusively by ovariectomy was similar to that found in the obese sham-operated rats. CONCLUSIONS: Bone losses invoked by DIO seem to be independent from the Wnt/ß-catenin pathway inhibition induced by sclerostin. While further study is necessary, the obtained results suggest that the usage of sclerostin anti-body in the treatment of osteoporosis can be ineffective, and in obese patients the undertaking of such therapy should be reassessed.


Assuntos
Proteínas Morfogenéticas Ósseas/sangue , Osso e Ossos/metabolismo , Dieta/efeitos adversos , Obesidade/complicações , Ovariectomia/efeitos adversos , Via de Sinalização Wnt , Animais , Reabsorção Óssea , Feminino , Marcadores Genéticos , Humanos , Obesidade/etiologia , Ratos , Ratos Wistar
4.
Nat Commun ; 11(1): 4586, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934222

RESUMO

Frequent mutation of the tumour suppressor RNF43 is observed in many cancers, particularly colon malignancies. RNF43, an E3 ubiquitin ligase, negatively regulates Wnt signalling by inducing degradation of the Wnt receptor Frizzled. In this study, we discover that RNF43 activity requires phosphorylation at a triplet of conserved serines. This phospho-regulation of RNF43 is required for zebrafish development and growth of mouse intestinal organoids. Cancer-associated mutations that abrogate RNF43 phosphorylation cooperate with active Ras to promote tumorigenesis by abolishing the inhibitory function of RNF43 in Wnt signalling while maintaining its inhibitory function in p53 signalling. Our data suggest that RNF43 mutations cooperate with KRAS mutations to promote multi-step tumorigenesis via the Wnt-Ras-p53 axis in human colon cancers. Lastly, phosphomimetic substitutions of the serine trio restored the tumour suppressive activity of extracellular oncogenic mutants. Therefore, harnessing phospho-regulation of RNF43 might be a potential therapeutic strategy for tumours with RNF43 mutations.


Assuntos
Carcinogênese/metabolismo , Receptores Wnt/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Carcinogênese/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Proteína Oncogênica p21(ras)/genética , Proteína Oncogênica p21(ras)/metabolismo , Fosforilação , Proteólise , Receptores Wnt/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/genética , Via de Sinalização Wnt
5.
Nat Commun ; 11(1): 4117, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807785

RESUMO

Strategies for eradicating cancer stem cells (CSCs) are urgently required because CSCs are resistant to anticancer drugs and cause treatment failure, relapse and metastasis. Here, we show that photoactive functional nanocarbon complexes exhibit unique characteristics, such as homogeneous particle morphology, high water dispersibility, powerful photothermal conversion, rapid photoresponsivity and excellent photothermal stability. In addition, the present biologically permeable second near-infrared (NIR-II) light-induced nanocomplexes photo-thermally trigger calcium influx into target cells overexpressing the transient receptor potential vanilloid family type 2 (TRPV2). This combination of nanomaterial design and genetic engineering effectively eliminates cancer cells and suppresses stemness of cancer cells in vitro and in vivo. Finally, in molecular analyses of mechanisms, we show that inhibition of cancer stemness involves calcium-mediated dysregulation of the Wnt/ß-catenin signalling pathway. The present technological concept may lead to innovative therapies to address the global issue of refractory cancers.


Assuntos
Raios Infravermelhos , Nanotecnologia/métodos , Células-Tronco Neoplásicas/efeitos da radiação , Animais , Apoptose/efeitos da radiação , Western Blotting , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Linhagem Celular Tumoral , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Microscopia de Fluorescência , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Canais de Cátion TRPV/metabolismo , Via de Sinalização Wnt
6.
PLoS One ; 15(7): e0233582, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32735620

RESUMO

The craniofacial developmental disorder Burn-McKeown Syndrome (BMKS) is caused by biallelic variants in the pre-messenger RNA splicing factor gene TXNL4A/DIB1. The majority of affected individuals with BMKS have a 34 base pair deletion in the promoter region of one allele of TXNL4A combined with a loss-of-function variant on the other allele, resulting in reduced TXNL4A expression. However, it is unclear how reduced expression of this ubiquitously expressed spliceosome protein results in craniofacial defects during development. Here we reprogrammed peripheral mononuclear blood cells from a BMKS patient and her unaffected mother into induced pluripotent stem cells (iPSCs) and differentiated the iPSCs into induced neural crest cells (iNCCs), the key cell type required for correct craniofacial development. BMKS patient-derived iPSCs proliferated more slowly than both mother- and unrelated control-derived iPSCs, and RNA-Seq analysis revealed significant differences in gene expression and alternative splicing. Patient iPSCs displayed defective differentiation into iNCCs compared to maternal and unrelated control iPSCs, in particular a delay in undergoing an epithelial-to-mesenchymal transition (EMT). RNA-Seq analysis of differentiated iNCCs revealed widespread gene expression changes and mis-splicing in genes relevant to craniofacial and embryonic development that highlight a dampened response to WNT signalling, the key pathway activated during iNCC differentiation. Furthermore, we identified the mis-splicing of TCF7L2 exon 4, a key gene in the WNT pathway, as a potential cause of the downregulated WNT response in patient cells. Additionally, mis-spliced genes shared common sequence properties such as length, branch point to 3' splice site (BPS-3'SS) distance and splice site strengths, suggesting that splicing of particular subsets of genes is particularly sensitive to changes in TXNL4A expression. Together, these data provide the first insight into how reduced TXNL4A expression in BMKS patients might compromise splicing and NCC function, resulting in defective craniofacial development in the embryo.


Assuntos
Processamento Alternativo , Atresia das Cóanas/patologia , Surdez/congênito , Regulação da Expressão Gênica no Desenvolvimento , Cardiopatias Congênitas/patologia , Células-Tronco Pluripotentes Induzidas/citologia , Modelos Biológicos , Ribonucleoproteína Nuclear Pequena U5/deficiência , Spliceossomos/fisiologia , Apoptose , Diferenciação Celular , Técnicas de Reprogramação Celular , Atresia das Cóanas/genética , Células Clonais , Surdez/genética , Surdez/patologia , Transição Epitelial-Mesenquimal , Éxons/genética , Face/embriologia , Facies , Feminino , Cabeça/embriologia , Cardiopatias Congênitas/genética , Humanos , Crista Neural/citologia , Regiões Promotoras Genéticas/genética , Sítios de Splice de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ribonucleoproteína Nuclear Pequena U5/genética , Deleção de Sequência , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Via de Sinalização Wnt
7.
Environ Pollut ; 265(Pt A): 115025, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32806417

RESUMO

Microplastics (MPs) are new persistent organic pollutants derived from the degradation of plastics. They can accumulate along the food chain and enter the human body through oral administration, inhalation and dermal exposure. To identify the impact of Polystyrene (PS) MPs on the cardiovascular system and the underlying toxicological mechanism, 32 male Wister rats were divided into control group and three model groups, which were exposed to 0.5 µm PS MPs at 0.5, 5 and 50 mg/L for 90 days. Our results suggested that PS MPs exposure increased Troponin I and creatine kinase-MB (CK-MB) levels in serum, resulted in structure damage and apoptosis of myocardium, and led to collagen proliferation of heart. Moreover, PS MPs could induce oxidative stress and thus activate fibrosis-related Wnt/ß-catenin signaling pathway. These results suggested that PS MPs could lead to cardiovascular toxicity by inducing cardiac fibrosis via activating Wnt/ß-catenin pathway and myocardium apoptosis triggered by oxidative stress. The present study provided some novelty evidence to elucidate the potential mechanism of cardiovascular toxicity induced by PS MPs.


Assuntos
Microplásticos , Poliestirenos , Animais , Apoptose , Fibrose , Humanos , Masculino , Miócitos Cardíacos , Plásticos , Ratos , Via de Sinalização Wnt
8.
Sci Total Environ ; 737: 140252, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32783850

RESUMO

Antimony (Sb), as a newly identified nerve poison, can lead to neuronal apoptosis. However, its neurotoxicological mechanisms remain largely unclear. Here, we evaluated the role and regulation of Wnt/ß-catenin pathway in Sb-mediated neurotoxicity. Under Sb treatment, ß-catenin was dramatically downregulated in vivo and in vitro. Moreover, overexpression of ß-catenin effectively attenuated Sb-induced survivin gene expression suppression and subsequent apoptosis in PC12 cells. In addition, Sb stimualted glycogen synthase kinase-3ß (GSK-3ß) activation, shown as decreased phosphorylation levels at Ser 9 both in PC12 cells and mice brain. Paramacological inhibition of GSK-3ß using lithium chloride (LiCl) significantly rescued ß-catenin expression. For upstream pathway analysis, we found Sb treatment decreased protein kinase B (Akt) phosphorylation, and Akt activator protected PC12 cells from GSK-3ß activation and subsequent ß-catenin suppression. In summary, our data provided a novel molecular mechanism of Sb-associated neurotoxicity, namely that Sb induces Wnt/ß-catenin pathway suppression through Akt inhibition, thus resulted in neuronal apoptosis.


Assuntos
Proteínas Proto-Oncogênicas c-akt , Via de Sinalização Wnt , Animais , Antimônio , Apoptose , Regulação para Baixo , Glicogênio Sintase Quinase 3 beta , Camundongos , Ratos
9.
Nat Commun ; 11(1): 3965, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770022

RESUMO

Dysregulated Wnt/ß-catenin activation plays a critical role in cancer progression, metastasis, and drug resistance. Genotoxic agents such as radiation and chemotherapeutics have been shown to activate the Wnt/ß-catenin signaling although the underlying mechanism remains incompletely understood. Here, we show that genotoxic agent-activated Wnt/ß-catenin signaling is independent of the FZD/LRP heterodimeric receptors and Wnt ligands. OTULIN, a linear linkage-specific deubiquitinase, is essential for the DNA damage-induced ß-catenin activation. OTULIN inhibits linear ubiquitination of ß-catenin, which attenuates its Lys48-linked ubiquitination and proteasomal degradation upon DNA damage. The association with ß-catenin is enhanced by OTULIN Tyr56 phosphorylation, which depends on genotoxic stress-activated ABL1/c-Abl. Inhibiting OTULIN or Wnt/ß-catenin sensitizes triple-negative breast cancer xenograft tumors to chemotherapeutics and reduces metastasis. Increased OTULIN levels are associated with aggressive molecular subtypes and poor survival in breast cancer patients. Thus, OTULIN-mediated Wnt/ß-catenin activation upon genotoxic treatments promotes drug resistance and metastasis in breast cancers.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Dano ao DNA , Resistencia a Medicamentos Antineoplásicos , Endopeptidases/metabolismo , Proteínas Proto-Oncogênicas c-abl/metabolismo , Via de Sinalização Wnt , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Células HEK293 , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Biológicos , Metástase Neoplásica , Fosforilação , Fosfotirosina/metabolismo , Ubiquitinação , beta Catenina/metabolismo
10.
Nat Commun ; 11(1): 4225, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839463

RESUMO

Gallbladder cancer (GBC) is an aggressive gastrointestinal malignancy with no approved targeted therapy. Here, we analyze exomes (n = 160), transcriptomes (n = 115), and low pass whole genomes (n = 146) from 167 gallbladder cancers (GBCs) from patients in Korea, India and Chile. In addition, we also sequence samples from 39 GBC high-risk patients and detect evidence of early cancer-related genomic lesions. Among the several significantly mutated genes not previously linked to GBC are ETS domain genes ELF3 and EHF, CTNNB1, APC, NSD1, KAT8, STK11 and NFE2L2. A majority of ELF3 alterations are frame-shift mutations that result in several cancer-specific neoantigens that activate T-cells indicating that they are cancer vaccine candidates. In addition, we identify recurrent alterations in KEAP1/NFE2L2 and WNT pathway in GBC. Taken together, these define multiple targetable therapeutic interventions opportunities for GBC treatment and management.


Assuntos
Proteínas de Ligação a DNA/genética , Mutação da Fase de Leitura , Neoplasias da Vesícula Biliar/genética , Predisposição Genética para Doença/genética , Proteínas Proto-Oncogênicas c-ets/genética , Fatores de Transcrição/genética , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Chile , Proteínas de Ligação a DNA/imunologia , Proteínas de Ligação a DNA/metabolismo , Neoplasias da Vesícula Biliar/diagnóstico , Neoplasias da Vesícula Biliar/metabolismo , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Genômica/métodos , Humanos , Índia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Proto-Oncogênicas c-ets/imunologia , Proteínas Proto-Oncogênicas c-ets/metabolismo , República da Coreia , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt/genética , beta Catenina/genética , beta Catenina/metabolismo
11.
Nat Commun ; 11(1): 4159, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855415

RESUMO

The periodic cartilage and smooth muscle structures in mammalian trachea are derived from tracheal mesoderm, and tracheal malformations result in serious respiratory defects in neonates. Here we show that canonical Wnt signaling in mesoderm is critical to confer trachea mesenchymal identity in human and mouse. At the initiation of tracheal development, endoderm begins to express Nkx2.1, and then mesoderm expresses the Tbx4 gene. Loss of ß-catenin in fetal mouse mesoderm causes loss of Tbx4+ tracheal mesoderm and tracheal cartilage agenesis. The mesenchymal Tbx4 expression relies on endodermal Wnt activation and Wnt ligand secretion but is independent of known Nkx2.1-mediated respiratory development, suggesting that bidirectional Wnt signaling between endoderm and mesoderm promotes trachea development. Activating Wnt, Bmp signaling in mouse embryonic stem cell (ESC)-derived lateral plate mesoderm (LPM) generates tracheal mesoderm containing chondrocytes and smooth muscle cells. For human ESC-derived LPM, SHH activation is required along with WNT to generate proper tracheal mesoderm. Together, these findings may contribute to developing applications for human tracheal tissue repair.


Assuntos
Endoderma/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Mesoderma/metabolismo , Traqueia/metabolismo , Via de Sinalização Wnt/genética , beta Catenina/genética , Animais , Diferenciação Celular/genética , Células Cultivadas , Endoderma/citologia , Endoderma/embriologia , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Mesoderma/citologia , Mesoderma/embriologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células-Tronco Embrionárias Murinas/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Fator Nuclear 1 de Tireoide/genética , Fator Nuclear 1 de Tireoide/metabolismo , Traqueia/citologia , Traqueia/embriologia , beta Catenina/metabolismo
12.
Nat Commun ; 11(1): 4323, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859895

RESUMO

Medulloblastoma (MB) is defined by four molecular subgroups (Wnt, Shh, Group 3, Group 4) with Wnt MB having the most favorable prognosis. Since prior reports have illustrated the antitumorigenic role of Wnt activation in Shh MB, we aimed to assess the effects of activated canonical Wnt signaling in Group 3 and 4 MBs. By using primary patient-derived MB brain tumor-initiating cell (BTIC) lines, we characterize differences in the tumor-initiating capacity of Wnt, Group 3, and Group 4 MB. With single cell RNA-seq technology, we demonstrate the presence of rare Wnt-active cells in non-Wnt MBs, which functionally retain the impaired tumorigenic potential of Wnt MB. In treating MB xenografts with a Wnt agonist, we provide a rational therapeutic option in which the protective effects of Wnt-driven MBs may be augmented in Group 3 and 4 MB and thereby support emerging data for a context-dependent tumor suppressive role for Wnt/ß-catenin signaling.


Assuntos
Neoplasias Cerebelares/terapia , Meduloblastoma/terapia , Proteínas Wnt/farmacologia , Proteínas Wnt/uso terapêutico , Animais , Carcinogênese , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Cerebelares/patologia , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Meduloblastoma/genética , Meduloblastoma/patologia , Camundongos , Células-Tronco , Proteínas Wnt/genética , Via de Sinalização Wnt , beta Catenina/uso terapêutico
13.
Biol Res ; 53(1): 33, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32758292

RESUMO

Cervical cancer is a common and fatal malignancy of the female reproductive system. Human papillomavirus (HPV) is the primary causal agent for cervical cancer, but HPV infection alone is insufficient to cause the disease. Actually, most HPV infections are sub-clinical and cleared spontaneously by the host immune system; very few persist and eventually develop into cervical cancer. Therefore, other host or environmental alterations could also contribute to the malignant phenotype. One of the candidate co-factors is the ß-catenin protein, a pivotal component of the Wnt/ß-catenin signaling pathway. ß-Catenin mainly implicates two major cellular activities: cell-cell adhesion and signal transduction. Recent studies have indicated that an imbalance in the structural and signaling properties of ß-catenin leads to various cancers, such as cervical cancer. In this review, we will systematically summarize the role of ß-catenin in cervical cancer and provide new insights into therapeutic strategies.


Assuntos
Carcinogênese , Infecções por Papillomavirus/patologia , Neoplasias do Colo do Útero/patologia , Via de Sinalização Wnt , beta Catenina/fisiologia , Feminino , Humanos
14.
Gene ; 761: 145038, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32777532

RESUMO

Neuropathic pain, which results from impairment of the somatosensory system, has affected about 8% population around the world and leads to considerable burdens for patients and world health care system. However, its underlying mechanisms remain poorly understood. In this study, we hypothesized that miR-24-3p was involved in the progression of neuropathic pain in CCI rat models. By measuring miR-24-3p expression in CCI rats, we found that miR-24-3p expression was increased in CCI rats, suggesting miR-24-3p might participate in neuropathic pain progression. Next, by conducting a serial in vitro and vivo experiments, we found that miR-24-3p regulated Wnt5a/ß-Catenin Signaling levels to promote neuropathic pain progression via targeting LPAR3 in CCI rats. Furthermore, we explored the upstream regulator of miR-24-3p by conducting bioinformatics analysis, we found that circular RNA cZRANB1 might sponge to miR-24-3p. Then we applied biotinylated RNA pull-down and luciferase reporter assays to assess the association between cZRANB1 and miR-24-3p. It was found that cZRANB1 mediated LPAR3 expression via sponging miR-24-3p. Collectively, our study suggests that cZRNAB1 regulated Wnt5a/ß-Catenin Signaling expression via miR-24-3p/LPAR3 axis in CCI rat models.


Assuntos
MicroRNAs/genética , Neuralgia/genética , Receptores de Ácidos Lisofosfatídicos/genética , Animais , Constrição Patológica/genética , Progressão da Doença , Regulação da Expressão Gênica/genética , Células HEK293 , Humanos , Inflamação/genética , Masculino , MicroRNAs/metabolismo , RNA Circular/genética , RNA Longo não Codificante/genética , Ratos , Ratos Sprague-Dawley , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/genética , Ubiquitina Tiolesterase/genética , Via de Sinalização Wnt/genética , Proteína Wnt-5a/genética , Proteína Wnt-5a/metabolismo , beta Catenina/metabolismo
15.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(4): 1256-1260, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32798408

RESUMO

OBJECTIVE: To explore the effect of miR-144 to the biological behavior of multiple myeloma cells and its mechanism. METHODS: RT-PCR was used to detect the expression of miR-144 in multiple myeloma cells and plasma of MM patients. MTT assay was used to detect the proliferation and cloning ability of myeloma cells transfected by miR-144. Flow cytometry was used to detect the cell cycle distribution of myeloma cells with over-expression of miR-144. Apoptosis of myeloma cells with over-expression of miR-144 was detected by TUNEL assay. Transwell cell invasion and migration assay was used to detect the invasion and migration ability of myeloma cells with overexpressing on miR-144.Western blot analysis was used to detect the protein expression levels of MMP-9 and MMP-2 in myeloma cells with over expression of miR-144, as well as the expression levels of proteins related to Wnt/ß-catenin signaling pathway. RESULTS: The expression level of miR-144 in MM cell lines and blood of MM patients was significantly lower than that in control group (P<0.05). The proliferation, invasion and migration of myeloma cells with over-expression of miR-144 were significantly decreased (P<0.05), and the apoptosis level was increased (P<0.05). The expression levels of MMP-9, MMP-2, Wnt/ß-catenin signaling pathway in myeloma cells with over-expression of miR-144 were significantly lower than those in control group (P<0.05). CONCLUSION: MiR-144 can inhibit the proliferation, migration and invasion of multiple myeloma cells and induce cell apoptosis. The specific mechanism may be related with the activity of inhibiting Wnt/ß-catenin signaling pathway.


Assuntos
Produtos Biológicos , MicroRNAs , Mieloma Múltiplo , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Via de Sinalização Wnt , Proteína Wnt4 , beta Catenina
16.
Life Sci ; 258: 118190, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32777299

RESUMO

AIMS: Glycolysis is an important process for cervical carcinoma development. Previous studies have indicated that stress-induced phosphoprotein 1 (STIP1) is associated with development of multiple tumors. Nevertheless, the role and mechanism of STIP1 in glycolysis of cervical carcinoma remain unclear. MAIN METHODS: The association between STIP1 and survival probability and the correlation between STIP1 expression and pyruvate kinase M2 (PKM2) as well as lactate dehydrogenase isoform A (LDHA) levels in cervical carcinoma were analyzed via The Cancer Genome Atlas (TCGA). The expression of STIP1, PKM2, LDHA, and cytochrome c (Cyt C) was measured via western blot or quantitative reverse transcription polymerase chain reaction. Cell viability and apoptosis were examined via cell counting kit 8 and flow cytometry, respectively. Glycolysis was assessed via detection of glucose consumption and lactate production. The protein involved in the Wnt/ß-catenin pathway was measured via western blot. KEY FINDINGS: STIP1 abundance was elevated in cervical carcinoma cells. High expression of STIP1 indicated poor survival probability. Knockdown of STIP1 inhibited cervical carcinoma cell viability and promoted apoptosis. STIP1 expression was positively correlated with PKM2 and LDHA levels in cervical carcinoma. Silence of STIP1 inhibited glycolysis and decreased PKM2 and LDHA expression. Down-regulation of STIP1 repressed the Wnt/ß-catenin pathway. Overexpression of ß-catenin reversed the effect of STIP1 silence on viability, apoptosis, glycolysis, and levels of PKM2 and LDHA. SIGNIFICANCE: STIP1 knockdown suppressed glycolysis in cervical carcinoma by inhibiting PKM2 and LDHA expression and activation of the Wnt/ß-catenin pathway.


Assuntos
Proteínas de Transporte/metabolismo , Regulação para Baixo/genética , Glicólise , Proteínas de Choque Térmico/metabolismo , Lactato Desidrogenase 5/metabolismo , Proteínas de Membrana/metabolismo , Hormônios Tireóideos/metabolismo , Neoplasias do Colo do Útero/genética , Via de Sinalização Wnt , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Proteínas de Choque Térmico/genética , Humanos , Modelos Biológicos , Neoplasias do Colo do Útero/patologia , Via de Sinalização Wnt/genética
17.
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
18.
Gene ; 758: 144967, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32707299

RESUMO

Bivalve mollusks are descendants of an early-Cambrian lineage and have successfully evolved unique strategies for reproduction. Nonetheless, the molecular mechanisms underlying reproductive regulation in mollusks remain to be elucidated. In this study, transcriptomes of ovary at four reproductive stages in female Chlamys farreri were characterized by RNA-Seq. Regarding signaling pathways, ECM-receptor interaction pathway, mTOR signaling pathway, Fanconi anemia pathway, FoxO signaling pathway, Wnt signaling pathway and Hedgehog signaling pathway were enriched during ovarian development processes. In addition, pathways related to energy metabolism such as Nitrogen metabolism and Arachidonic acid metabolism were enriched at spawn stage. Interestingly, Neuroactive ligand-receptor interaction was significantly enriched involved in ovarian development and spawn, and indicated the potential functions of nervous system on reproductive regulation in C. farreri. What's more, this study identified and characterized fourteen genes involved in "sex hormones synthesis and regulation", "ovarian development and spawn" and "maternal immunity" during the four reproductive stages in C. farreri. We determined that CYP17 uniquely affected gamete release by influencing the physiological balance among the steroid hormones and showed that receptors of the 5-HT and GABA neurotransmitters were tightly associated with ovarian maturation. Furthermore, to the best of our knowledge, this is the first study to report the maternal effect gene Zar1 in bivalve mollusks, likewise the maternal immunity genes displayed coordinated and cooperative expression during reproductive periods, which strengthened the environmental adaptation mechanisms of bivalves. Taken together, this study provides the first dynamic transcriptomic analysis of C. farreri at four key reproductive stages, which will assist in revealing the molecular mechanisms underlying bivalves on reproductive regulation in ovarian development and spawn.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/genética , Ovário/crescimento & desenvolvimento , Pectinidae/crescimento & desenvolvimento , Pectinidae/genética , Transcriptoma/genética , Animais , Metabolismo Energético/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Feminino , Fatores de Transcrição Forkhead/metabolismo , Proteínas Hedgehog/metabolismo , Reprodução/genética , Serina-Treonina Quinases TOR/metabolismo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/genética
19.
Gene ; 758: 144968, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32707304

RESUMO

The hair follicle is an excellent mini-system illustrating the mechanisms governing organogenesis and regeneration. Although the general mechanisms modulating skin and hair follicle development are widely studied in mouse and chicken models, the delicate network regulating skin and hair diversity remains largely unclear. Sheep is an additional model to address the various wool characteristics observed in nature. The coarse and fine wool sheep with diverse fibers were examined to show differences in the primary wool follicle size and skin thickness. The molecular dynamics in skin staged at the primary wool follicle induction between two sheep lines were investigated by RNA-sequencing analyses to generate 1994 differentially expressed genes revealing marker genes for epithelium (6 genes), dermal condensate (38 genes) and dermal fibroblast (58 genes) highly correlated with skin and wool follicle morphological differences. The DEGs were enriched in GO terms represented by epithelial cell migration and differentiation, regulation of hair follicle development and ectodermal placode formation, and KEGG pathways typified by WNT and Hedgehog signaling pathways governing the differences of skin structure. The qPCR detection of 9 genes confirmed the similar expression tendency with RNA-sequencing profiles. This comparative study of coarse and fine wool sheep skin reveals the presence of skin and wool follicle differences at primary wool follicle induction stage, and indicates the potential effectors (APCDD1, FGF20, DKK1, IGFBP3 and SFRP4) regulating the skin compartments during the early morphogenesis of primary wool follicles to shape the variable wool fiber thickness in later developmental stages.


Assuntos
Células Epiteliais/metabolismo , Folículo Piloso/crescimento & desenvolvimento , Folículo Piloso/fisiologia , Fenômenos Fisiológicos da Pele/genética , Lã/fisiologia , Animais , Proteínas Hedgehog/metabolismo , Simulação de Dinâmica Molecular , Ovinos , Transcriptoma/genética , Via de Sinalização Wnt
20.
Wei Sheng Yan Jiu ; 49(3): 473-479, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32693900

RESUMO

OBJECTIVE: To investigate the effects of PM_(2. 5) exposure on the development of synaptic plasticity and Wnt/ß-catenin pathway in hippocampus of offspring rats. METHODS: Healthy 7-week-old SPF SD rats(n=36) mated with a male to female ratio of 2∶1. Pregnant rats were randomly divided into three groups, including control group, low PM_(2. 5) group, and high PM_(2. 5) group, with eight rats in each group. The low and high PM_(2. 5) concentrations in dynamic exposure cabinet were approximately two times and four times higher than the annual average PM_(2. 5) concentration in Tangshan city respectively. The exposure started from pregnant day 0, until postnatal day 21(PND21) of offspring rats. After weaning, the offspring rats continued to be exposed to PM_(2. 5) until PND42. PND21 and PND42 pups were subjected to Morris water maze and new object recognition experiments. Western blot was used to detect post synaptic density-95(PSD-95), synaptophysin(SYN), growth associated protein(GAP-43), glycogen synthase kinase 3ß(GSK-3ß), ß-catenin protein levels and phosphorylation levels of GSK-3ß and ß-catenin in the hippocampus of offspring rats. RESULTS: Compared with the control group, the learning and memory abilities of the pups of each PM_(2. 5) group were significantly decreased with a dose dependent manner. Compared with the control group, the protein level of SYN, GAP-43 and PSD-95 in hippocampus of PND0 rats of each PM_(2. 5)groups were decreased(P<0. 05), and the protein level of SYN of each PM_(2. 5)group and PSD-95 of high PM_(2. 5) group in PND21 and PND42 were decreased(P<0. 05), and the level of GAP-43 of low PM_(2. 5) group in PND42 were decreased(P<0. 05). Compared with the low PM_(2. 5) group, the level of PSD-95 of high PM_(2. 5) group in PND0 and PND21, the level of PSD-95 of high PM_(2. 5) group in PND0 and PND42 were decreased(P<0. 05). Compared with the control group, the level of p-GSK-3ß in hippocampus of each PM_(2. 5)group in PND0, PND21 and PND42 was decreased(P<0. 05), and with the increase of PM_(2. 5) exposure dose, the trend is more obvious. The protein level of p-ß-catenin in hippocampus of high PM_(2. 5) group in PND0 and PND42 was significantly increased(P<0. 05). The level of p-ß-catenin in high-dose PND21 pups compared with the control group was significantly reduced(P<0. 05). CONCLUSION: Exposure to PM_(2. 5) in early life can damage the synaptic plasticity and decrease the protein levels of ß-catenin and p-GSK-3ß in the Wnt/ß-catenin pathway of hippocampus in offspring rats.


Assuntos
Via de Sinalização Wnt , beta Catenina , Animais , Feminino , Glicogênio Sintase Quinase 3 beta , Hipocampo , Masculino , Plasticidade Neuronal , Gravidez , Ratos , Ratos Sprague-Dawley
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