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1.
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
2.
Dev Genes Evol ; 229(4): 125-135, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31273439

RESUMO

Posterior elongation of the developing embryo is a common feature of animal development. One group of genes that is involved in posterior elongation is represented by the Wnt genes, secreted glycoprotein ligands that signal to specific receptors on neighbouring cells and thereby establish cell-to-cell communication. In segmented animals such as annelids and arthropods, Wnt signalling is also likely involved in segment border formation and regionalisation of the segments. Priapulids represent unsegmented worms that are distantly related to arthropods. Despite their interesting phylogenetic position and their importance for the understanding of ecdysozoan evolution, priapulids still represent a highly underinvestigated group of animals. Here, we study the embryonic expression patterns of the complete sets of Wnt genes in the priapulids Priapulus caudatus and Halicryptus spinulosus. We find that both priapulids possess a complete set of 12 Wnt genes. At least in Priapulus, most of these genes are expressed in and around the posterior-located blastopore and thus likely play a role in posterior elongation. Together with previous work on the expression of other genetic factors such as caudal and even-skipped, this suggests that posterior elongation in priapulids is under control of the same (or very similar) conserved gene regulatory network as in arthropods.


Assuntos
Invertebrados/embriologia , Proteínas Wnt/genética , Animais , Artrópodes/genética , Desenvolvimento Embrionário , Redes Reguladoras de Genes , Filogenia , Transdução de Sinais
3.
Nat Cell Biol ; 21(6): 721-730, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31110287

RESUMO

Wnt signalling drives many processes in development, homeostasis and disease; however, the role and mechanism of individual ligand-receptor (Wnt-Frizzled (Fzd)) interactions in specific biological processes remain poorly understood. Wnt9a is specifically required for the amplification of blood progenitor cells during development. Using genetic studies in zebrafish and human embryonic stem cells, paired with in vitro cell biology and biochemistry, we determined that Wnt9a signals specifically through Fzd9b to elicit ß-catenin-dependent Wnt signalling that regulates haematopoietic stem and progenitor cell emergence. We demonstrate that the epidermal growth factor receptor (EGFR) is required as a cofactor for Wnt9a-Fzd9b signalling. EGFR-mediated phosphorylation of one tyrosine residue on the Fzd9b intracellular tail in response to Wnt9a promotes internalization of the Wnt9a-Fzd9b-LRP signalosome and subsequent signal transduction. These findings provide mechanistic insights for specific Wnt-Fzd signals, which will be crucial for specific therapeutic targeting and regenerative medicine.


Assuntos
Células-Tronco Hematopoéticas/citologia , Receptores de Neurotransmissores/genética , Proteínas Wnt/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Animais , Receptores ErbB/genética , Humanos , Fosforilação , Via de Sinalização Wnt , Peixe-Zebra/crescimento & desenvolvimento , beta Catenina/genética
4.
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
5.
Cytogenet Genome Res ; 157(4): 189-196, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30974434

RESUMO

Hypohidrotic or anhidrotic ectodermal dysplasia (HED/EDA) is characterized by impaired development of the hair, teeth, or sweat glands. HED/EDA is inherited in an X-linked, autosomal dominant, or autosomal recessive pattern and caused by the pathogenic variants in 4 genes: EDA, EDAR, EDARADD, and WNT10A. The aim of the present study was to perform molecular screening of these 4 genes in a cohort of Turkish individuals diagnosed with HED/EDA. We screened for pathogenic variants of WNT10A, EDA, EDAR, and EDARADD through Sanger sequencing. We further assessed the clinical profiles of the affected individuals in order to establish phenotype-genotype correlation. In 17 (63%) out of 27 families, 17 pathogenic variants, 8 being novel, were detected in the 4 well-known ectodermal dysplasia genes. EDAR and EDA variants were identified in 6 families each, WNT10A variants in 4, and an EDARADD variant in 1, accounting for 35.3, 35.3, 23.5, and 5.9% of mutation-positive families, respectively. The low mutation detection rate of the cohort and the number of the EDAR pathogenic variants being as high as the EDA ones were the most noteworthy findings which could be attributed to the high consanguinity rate.


Assuntos
Displasia Ectodérmica/genética , Ectodisplasinas/genética , Receptor Edar/genética , Proteína de Domínio de Morte Associada a Edar/genética , Mutação , Análise de Sequência de DNA/métodos , Proteínas Wnt/genética , Consanguinidade , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Linhagem , Fenótipo , Turquia
6.
Nutrients ; 11(3)2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30818817

RESUMO

This study evaluated the effects of vitamin C on osteogenic differentiation and osteoclast formation, and the effects of vitamin C concentration on bone microstructure in ovariectomized (OVX) Wistar rats. Micro-computed tomography analysis revealed the recovery of bone mineral density and bone separation in OVX rats treated with vitamin C. Histomorphometrical analysis revealed improvements in the number of osteoblasts, osteoclasts, and osteocytes; the osteoblast and osteoclast surface per bone surface; and bone volume in vitamin C-treated OVX rats. The vitamin C-treated group additionally displayed an increase in the expression of osteoblast differentiation genes, including bone morphogenetic protein-2, small mothers against decapentaplegic 1/5/8, runt-related transcription factor 2, osteocalcin, and type I collagen. Vitamin C reduced the expression of osteoclast differentiation genes, such as receptor activator of nuclear factor kappa-B, receptor activator of nuclear factor kappa-B ligand, tartrate-resistant acid phosphatase, and cathepsin K. This study is the first to show that vitamin C can inhibit osteoporosis by promoting osteoblast formation and blocking osteoclastogenesis through the activation of wingless-type MMTV integration site family/ß-catenin/activating transcription factor 4 signaling, which is achieved through the serine/threonine kinase and mitogen-activated protein kinase signaling pathways. Therefore, our results suggest that vitamin C improves bone regeneration.


Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Ácido Ascórbico/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Fator 4 Ativador da Transcrição/genética , Ração Animal , Animais , Densidade Óssea , Dieta , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Osteoporose/prevenção & controle , Ovariectomia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteínas Wnt/genética , beta Catenina/genética
8.
Biomed Khim ; 65(1): 9-20, 2019 Jan.
Artigo em Russo | MEDLINE | ID: mdl-30816092

RESUMO

Keratoconus is a chronic disorder of the cornea, characterized by its progressive thinning, stretching, and conical protrusion. Diagnostics of subclinical keratoconus, as well as its early stages (forme fruste), is a complex problem. The presence of these forms of keratoconus in a patient is one of the reasons for the development of keratectasia after laser refractive surgery. Currently, the role of genetic factors in keratoconus development has been proven. This indicates the possibility of diagnostics of subclinical and forme fruste keratoconus using genetic markers. Knowledge about the patient's genetic susceptibility to keratoconus would allow correcting the tactics of treatment of refractive anomalies and avoiding serious side effects. The studies of causal mutations indicate the genetic heterogeneity of keratoconus, which complicates the development of a diagnostic panel. Selection of candidate variants from the currently known ones based on clear criteria may be one of the approaches for diagnostic markers search. In this review, we have analyzed articles on keratoconus markers in order to form a list of candidate variants for genotyping in the Russian population. The selection criteria took into account the complexes of symptoms in which a marker was found, populations in which a particular marker was investigated, the presence and results of replication studies. The analysis included markers in VSX1, SOD1, ZEB1, LOX, CAST, DOCK9, TGFBI, HGF, MAP3K19, KCND3, COL4A3, COL4A4, COL5A1, FNDC3B, FOXO1, BANP-ZNF469, MPDZ-NF1B, WNT10A genes. Based on the results of the analysis, the following candidate variants were selected for genotyping in the Russian population of patients with keratoconus: rs1536482 and rs7044529 in the COL5A1 gene, rs5745752 and rs2286194 in the HGF gene, rs4954218 in the MAP3K19 gene, rs4839200 near the KCND3 gene, rs2721051 near the FOXO1 gene, rs1324183 between the MPDZ and the NF1B genes, and rs121908120 in the WNT10A gene.


Assuntos
Proteínas do Olho/genética , Marcadores Genéticos , Ceratocone/diagnóstico , Ceratocone/genética , Colágeno Tipo V/genética , Proteína Forkhead Box O1/genética , Predisposição Genética para Doença , Fator de Crescimento de Hepatócito/genética , Humanos , MAP Quinase Quinase Quinases/genética , Polimorfismo de Nucleotídeo Único , Federação Russa , Canais de Potássio Shal/genética , Proteínas Wnt/genética
9.
Int J Mol Sci ; 20(5)2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30862048

RESUMO

Wnt is a family of conserved glycoproteins that participate in a variety of important biological processes including embryo development, cell proliferation and differentiation, and tissue regeneration. The Wnt family is a metazoan novelty found in all animal phyla. Studies have revealed that the number of Wnt genes varies among species, presumably due to reproduction and loss of genes during evolution. However, a comprehensive inventory of Wnt genes in Lepidoptera is lacking. In this study, we identified the repertoire of Wnt genes in the silkworm and seven other species of Lepidoptera and obtained eight Wnt genes (Wnt1, Wnt5⁻Wnt7, Wnt9⁻Wnt11, and WntA) in each species. Four of these Wnt genes are clustered in two orientations (5'-Wnt9-Wnt1-Wnt6-Wnt10-3' and 5'-Wnt10-Wnt6-Wnt1-Wnt9-3') in both moths and butterflies. Transcript analysis of Wnt in silkworm embryonic stages showed that each BmWnt gene had a unique expression pattern during embryological development. Analysis of a larval stage revealed differential expression of Wnt family members in diverse tissues. Our study provides an overview of the Wnt family in Lepidoptera and will inspire further functional study of the Wnt genes in the silkworm.


Assuntos
Bombyx/genética , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Família Multigênica , Transcriptoma , Proteínas Wnt/genética , Animais , Bombyx/classificação , Bombyx/metabolismo , Mapeamento Cromossômico , Evolução Molecular , Regulação da Expressão Gênica no Desenvolvimento , Genoma de Inseto , Especificidade de Órgãos/genética , Filogenia
10.
Clin Calcium ; 29(3): 323-328, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30814377

RESUMO

Identification of responsible genes for skeletal dysplasias evidences their critical roles in the skeletal development and maintenance. Mutations in the genes encoding the components of Wnt canonical pathway, which include WNT1, LRP5, LRP4, SOST and WTX, cause the disorders characterized by abnormal in bone mass. On the other hand, mutations in the genes for the components of Wnt non-canonical pathway such as WNT5A, ROR2, DVL1 and DVL3 are associated with dysmorphic skeletal disorders which manifest short limbs and facial anomalies. Thus, both canonical and non-canonical pathways of Wnt signaling play substantial roles in the human skeletons, and it is suggested that the former mainly controls bone mass while the latter regulates skeletal morphogenesis.


Assuntos
Doenças do Desenvolvimento Ósseo/metabolismo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , Doenças do Desenvolvimento Ósseo/genética , Humanos , Mutação , Proteínas Wnt/genética
11.
Dev Genes Evol ; 229(2-3): 43-52, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30825002

RESUMO

One of the earliest patterning events in the vertebrate neural plate is the specification of mes/r1, the territory comprising the prospective mesencephalon and the first hindbrain rhombomere. Within mes/r1, an interface of gene expression defines the midbrain-hindbrain boundary (MHB), a lineage restriction that separates the mesencephalon and rhombencephalon. wnt1 is critical to mes/r1 development and functions within the MHB as a component of the MHB gene regulatory network (GRN). Despite its importance to these critical and early steps of vertebrate neurogenesis, little is known about the factors responsible for wnt1 transcriptional regulation. In the zebrafish, wnt1 and its neighboring paralog, wnt10b, are expressed in largely overlapping patterns, suggesting co-regulation. To understand wnt1 and wnt10b transcriptional control, we used a comparative genomics approach to identify relevant enhancers. We show that the wnt1-wnt10b locus contains multiple cis-regulatory elements that likely interact to generate the wnt1 and wnt10b expression patterns. Two of 11 conserved enhancers tested show activity restricted to the midbrain and MHB, an activity that is conserved in the distantly related spotted gar orthologous elements. Three non-conserved elements also play a likely role in wnt1 regulation. The identified enhancers display dynamic modes of chromatin accessibility, suggesting controlled deployment during embryogenesis. Our results suggest that the control of wnt1 and wnt10b expression is under complex regulation involving the interaction of multiple enhancers.


Assuntos
Encéfalo/embriologia , Elementos Reguladores de Transcrição , Proteínas Wnt/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/embriologia , Animais , Cromatina , Embrião não Mamífero/metabolismo , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Peixes/embriologia , Peixes/genética , Regulação da Expressão Gênica no Desenvolvimento , Genômica , Camundongos , Regiões Promotoras Genéticas , Proteínas Wnt/metabolismo , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo
12.
Nat Commun ; 10(1): 1260, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30890710

RESUMO

Osteoporosis is a devastating disease with an essential genetic component. GWAS have discovered genetic signals robustly associated with bone mineral density (BMD), but not the precise localization of effector genes. Here, we carry out physical and direct variant to gene mapping in human mesenchymal progenitor cell-derived osteoblasts employing a massively parallel, high resolution Capture C based method in order to simultaneously characterize the genome-wide interactions of all human promoters. By intersecting our Capture C and ATAC-seq data, we observe consistent contacts between candidate causal variants and putative target gene promoters in open chromatin for ~ 17% of the 273 BMD loci investigated. Knockdown of two novel implicated genes, ING3 at 'CPED1-WNT16' and EPDR1 at 'STARD3NL', inhibits osteoblastogenesis, while promoting adipogenesis. This approach therefore aids target discovery in osteoporosis, here on the example of two relevant genes involved in the fate determination of mesenchymal progenitors, and can be applied to other common genetic diseases.


Assuntos
Densidade Óssea/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Osteoporose/genética , Regiões Promotoras Genéticas/genética , Adipogenia/genética , Adulto , Diferenciação Celular/genética , Mapeamento Cromossômico , Feminino , Técnicas de Silenciamento de Genes , Loci Gênicos/genética , Células Hep G2 , Proteínas de Homeodomínio/genética , Humanos , Masculino , Proteínas de Membrana/genética , Células-Tronco Mesenquimais , Proteínas de Neoplasias/genética , Osteoblastos/fisiologia , Osteogênese/genética , Polimorfismo de Nucleotídeo Único , Cultura Primária de Células , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Wnt/genética , Adulto Jovem
13.
Genes Dev ; 33(9-10): 498-510, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30842215

RESUMO

Developmental signal transduction pathways act diversely, with context-dependent roles across systems and disease types. Glioblastomas (GBMs), which are the poorest prognosis primary brain cancers, strongly resemble developmental systems, but these growth processes have not been exploited therapeutically, likely in part due to the extreme cellular and genetic heterogeneity observed in these tumors. The role of Wnt/ßcatenin signaling in GBM stem cell (GSC) renewal and fate decisions remains controversial. Here, we report context-specific actions of Wnt/ßcatenin signaling in directing cellular fate specification and renewal. A subset of primary GBM-derived stem cells requires Wnt proteins for self-renewal, and this subset specifically relies on Wnt/ßcatenin signaling for enhanced tumor burden in xenograft models. In an orthotopic Wnt reporter model, Wnthi GBM cells (which exhibit high levels of ßcatenin signaling) are a faster-cycling, highly self-renewing stem cell pool. In contrast, Wntlo cells (with low levels of signaling) are slower cycling and have decreased self-renewing potential. Dual inhibition of Wnt/ßcatenin and Notch signaling in GSCs that express high levels of the proneural transcription factor ASCL1 leads to robust neuronal differentiation and inhibits clonogenic potential. Our work identifies new contexts for Wnt modulation for targeting stem cell differentiation and self-renewal in GBM heterogeneity, which deserve further exploration therapeutically.


Assuntos
Diferenciação Celular/genética , Células-Tronco Neoplásicas/citologia , Transdução de Sinais , Linhagem Celular Tumoral , Autorrenovação Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/fisiopatologia , Humanos , Receptores Notch/genética , Receptores Notch/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo
14.
Int J Med Sci ; 16(3): 416-423, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30911276

RESUMO

Background: We recently reported that WNT10A plays a pivotal role in wound healing by regulating collagen expression/synthesis, as the depletion of WNT10A dramatically delays skin ulcer formation. WNT signaling also has a close correlation with the cancer microenvironment and proliferation, since tumors are actually considered to be 'unhealing' or 'overhealing' wounds. To ascertain the in vivo regulatory functions of WNT10A in tumor growth, we examined the net effects of WNT10A depletion using Wnt10a-deficient mice (Wnt10a -/-). Methods and Results: We subjected C57BL/6J wild-type (WT) or Wnt10a -/- mice to murine melanoma B16-F10 cell transplantation. Wnt10a -/- mice showed a significantly smaller volume of transplanted melanoma as well as fewer microvessels and less collagen expression and more necrosis than WT mice. Conclusions: Taken together, our observations suggest that critical in vivo roles of Wnt10a-depleted anti-stromagenesis prevent tumor growth, in contrast with true wound healing/scarring.


Assuntos
Colágeno/metabolismo , Melanoma Experimental/patologia , Proteínas do Tecido Nervoso/genética , Neoplasias Cutâneas/patologia , Proteínas Wnt/genética , Animais , Linhagem Celular Tumoral , Feminino , Deleção de Genes , Masculino , Melanoma Experimental/irrigação sanguínea , Melanoma Experimental/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microvasos/metabolismo , Microvasos/patologia , Proteínas do Tecido Nervoso/metabolismo , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/metabolismo , Células Estromais/patologia , Proteínas Wnt/metabolismo
15.
Oncol Rep ; 41(3): 1749-1758, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30747225

RESUMO

Regional and distant metastases are the principal reasons underlying the high mortality rate associated with tongue squamous cell carcinoma (TSCC); however, the precise molecular mechanisms involved in tongue tumorigenesis remain unknown. The present study aimed to determine the expression and mechanism of regulation of Wnt7a in the growth and metastasis of TSCC. Wnt7a mRNA and protein expression levels were examined in TSCC tissues using reverse transcription­quantitative polymerase chain reaction and immunohistochemical staining. A loss­of­function assay was performed in TSCC cell lines using Wnt7a small interfering RNA or short hairpin RNA, after which, cell proliferation, migration and invasion were analyzed using Cell Counting Kit­8, tumorigenicity and Transwell assays, respectively. Epithelial­mesenchymal transition (EMT)­associated proteins were detected by western blotting. The mRNA and protein expression levels of Wnt7a were significantly upregulated in cancer tissues compared with in the adjacent non­cancerous tissues. Clinical analysis indicated that Wnt7a expression was associated with T classification, lymph node metastasis and pathological differentiation, and high Wnt7a expression predicted a short recurrence­free survival for patients with TSCC. Silencing Wnt7a expression suppressed cell proliferation, migration and invasion, and reversed the EMT phenotype in TSCC cell lines. The present study revealed that Wnt7a may be upregulated in TSCC, where it may participate in modulating cell proliferation, migration, invasion and the EMT of TSCC. Therefore, Wnt7a should be considered a novel oncogene, and a potential prognostic and therapeutic target for patients with TSCC.


Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Proliferação de Células/genética , Metástase Linfática/genética , Neoplasias da Língua/genética , Neoplasias da Língua/patologia , Proteínas Wnt/genética , Carcinogênese/genética , Carcinogênese/patologia , Diferenciação Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Prognóstico , Regulação para Cima/genética
16.
Curr Top Dev Biol ; 132: 417-450, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30797516

RESUMO

Distinct classes of neurons arise at different positions along the dorsal-ventral axis of the spinal cord leading to spinal neurons being segregated along this axis according to their physiological properties and functions. Thus, the neurons associated with motor control are generally located in, or adjacent to, the ventral horn whereas the interneurons (INs) that mediate sensory activities are present within the dorsal horn. Here, we review classic and recent studies examining the developmental mechanisms that establish the dorsal-ventral axis in the embryonic spinal cord. Intriguingly, while the cellular organization of the dorsal and ventral halves of the spinal cord looks superficially similar during early development, the underlying molecular mechanisms that establish dorsal vs ventral patterning are markedly distinct. For example, the ventral spinal cord is patterned by the actions of a single growth factor, sonic hedgehog (Shh) acting as a morphogen, i.e., concentration-dependent signal. Recent studies have shed light on the mechanisms by which the spatial and temporal gradient of Shh is transduced by cells to elicit the generation of different classes of ventral INs, and motor neurons (MNs). In contrast, the dorsal spinal cord is patterned by the action of multiple factors, most notably by members of the bone morphogenetic protein (BMP) and Wnt families. While less is known about dorsal patterning, recent studies have suggested that the BMPs do not act as morphogens to specify dorsal IN identities as previously proposed, rather each BMP has signal-specific activities. Finally, we consider the promise that elucidation of these mechanisms holds for neural repair.


Assuntos
Padronização Corporal/genética , Regulação da Expressão Gênica no Desenvolvimento , Neurônios/metabolismo , Medula Espinal/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Interneurônios/citologia , Interneurônios/metabolismo , Neurônios Motores/citologia , Neurônios Motores/metabolismo , Neurônios/citologia , Transdução de Sinais/genética , Medula Espinal/citologia , Medula Espinal/embriologia , Proteínas Wnt/genética , Proteínas Wnt/metabolismo
17.
Genes Cells ; 24(4): 307-317, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30801848

RESUMO

Mutations in the human receptor tyrosine kinase ROR2 are associated with Robinow syndrome (RRS) and brachydactyly type B1. Amongst others, the shortened limb phenotype associated with RRS is recapitulated in Ror2-/- mutant mice. In contrast, Ror1-/- mutant mice are viable and show no limb phenotype. Ror1-/- ;Ror2-/- double mutants are embryonic lethal, whereas double mutants containing a hypomorphic Ror1 allele (Ror1hyp ) survive up to birth and display a more severe shortened limb phenotype. Both orphan receptors have been shown to act as possible Wnt coreceptors and to mediate the Wnt5a signal. Here, we analyzed genetic interactions between the Wnt ligand, Wnt9a, and Ror2 or Ror1, as Wnt9a has also been implicated in skeletal development. Wnt9a-/- single mutants display a mild shortening of the long bones, whereas these are severely shortened in Ror2-/- mutants. Ror2-/- ;Wnt9a-/- double mutants displayed even more severely shortened long bones, and intermediate phenotypes were observed in compound Ror2;Wnt9a mutants. Long bones were also shorter in Ror1hyp/hyp ;Wnt9a-/- double mutants. In addition, Ror1hyp/hyp ;Wnt9a-/- double mutants displayed a secondary palate cleft phenotype, which was not present in the respective single mutants. Interestingly, 50% of compound mutant pups heterozygous for Ror2 and homozygous mutant for Ror1 also developed a secondary palate cleft phenotype.


Assuntos
Fissura Palatina/genética , Epistasia Genética , Deformidades Congênitas dos Membros/genética , Mutação , Osteogênese/genética , Proteínas Wnt/genética , Animais , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase
18.
Mol Med Rep ; 19(3): 2144-2152, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30664209

RESUMO

The present study aimed to investigate the role and mechanisms of microRNA (miR)­33b in endometriosis (Ems). Reverse transcription­quantitative polymerase chain reaction (RT­qPCR), MTT assays, flow cytometry, caspase­3/9 activity assays and western blotting were performed in the present study. Initially, miR­33b expression in an Ems rat model was investigated by RT­qPCR and was demonstrated to be upregulated in Ems tissue samples of rats compared with the control group. In addition, miR­33b upregulation inhibited cell growth and enhanced apoptosis in an Ems model (primary cell cultures) compared with the control group. In addition, miR­33b up­regulation reduced Wnt/ß­catenin signaling pathway and suppressed zinc finger E­box­binding homeobox 1 (ZEB1) protein expression in the in vitro Ems model (primary cell cultures) compared with the control group. Furthermore, small interfering­ZEB1 ameliorated the effects of miR­33b downregulation on Ems cell growth in the in vitro Ems model. Additionally, a Wnt agonist reduced the effects of miR­33b upregulation on Ems cell growth in the in vitro Ems model. In conclusion, the present study demonstrated that upregulation of miR­33b may promote Ems through Wnt/ß­catenin by ZEB1 expression.


Assuntos
Endometriose/genética , MicroRNAs/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , beta Catenina/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Modelos Animais de Doenças , Endometriose/tratamento farmacológico , Endometriose/patologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Ratos , Ativação Transcricional/efeitos dos fármacos , Proteínas Wnt/agonistas , Proteínas Wnt/genética , Via de Sinalização Wnt/efeitos dos fármacos
19.
Genome Med ; 11(1): 3, 2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30674341

RESUMO

BACKGROUND: Human kidney organoids hold promise for studying development, disease modelling and drug screening. However, the utility of stem cell-derived kidney tissues will depend on how faithfully these replicate normal fetal development at the level of cellular identity and complexity. METHODS: Here, we present an integrated analysis of single cell datasets from human kidney organoids and human fetal kidney to assess similarities and differences between the component cell types. RESULTS: Clusters in the combined dataset contained cells from both organoid and fetal kidney with transcriptional congruence for key stromal, endothelial and nephron cell type-specific markers. Organoid enriched neural, glial and muscle progenitor populations were also evident. Major transcriptional differences between organoid and human tissue were likely related to technical artefacts. Cell type-specific comparisons revealed differences in stromal, endothelial and nephron progenitor cell types including expression of WNT2B in the human fetal kidney stroma. CONCLUSIONS: This study supports the fidelity of kidney organoids as models of the developing kidney and affirms their potential in disease modelling and drug screening.


Assuntos
Rim/citologia , Organoides/citologia , Linhagem Celular , Linhagem da Célula , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Rim/embriologia , Organoides/metabolismo , Análise de Célula Única , Proteínas Wnt/genética , Proteínas Wnt/metabolismo
20.
Artigo em Inglês | MEDLINE | ID: mdl-30660987

RESUMO

Cellular signaling initiated by various secreted, cysteine-rich Wnt proteins plays essential roles in regulating animal development and cell stemness. By virtue of its functional diversity and importance, the Wnt gene family has received substantial research interests in a variety of animal species, from invertebrates to vertebrates. However, for bivalve molluscs, one of the ancient bilaterian groups with high morphological diversity, systematic identification and analysis of the Wnt gene family remain lacking. To shed some light on the evolutionary dynamics of this gene family and obtain a more comprehensive understanding, we analyzed the characteristics of the Wnt gene family in three bivalve molluscs, with both genome and extensive transcriptomic resources. Investigation of genomic signatures, functional domains as well as phylogenetic relationships was conducted, and 12, 11, 12 subfamilies were identified in Yesso scallop, Zhikong scallop and Pacific oyster respectively. Spatiotemporal expression profiling suggested that, some bivalve Wnts might coordinate and participate in adult organ/tissue morphogenesis and homeostasis as well as early embryonic development. The transcriptional regulation of oyster Wnt genes showed dynamic and responsive patterns under different environmental stresses, indicating that Wnts may play a role in coping with challenging intertidal environments in bivalves. To our best knowledge, this study presents the first genome-wide study of Wnt gene family in bivalves, and our findings would assist in better understanding of Wnt function and evolution in bivalve molluscs.


Assuntos
Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Moluscos/genética , Proteínas Wnt/genética , Animais , Evolução Biológica , Moluscos/classificação , Filogenia
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