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1.
Nat Commun ; 11(1): 4330, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859912

RESUMO

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.


Assuntos
Mutação , Neoplasias/genética , Oncogenes/genética , Caracteres Sexuais , Instabilidade Cromossômica , Exoma , Feminino , Genoma Humano , Instabilidade Genômica , Humanos , Modelos Logísticos , Masculino , Fases de Leitura Aberta , beta Catenina/genética
2.
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
3.
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
4.
Nat Commun ; 11(1): 3595, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681081

RESUMO

Endothelial barrier (EB) breaching is a frequent event during inflammation, and it is followed by the rapid recovery of microvascular integrity. The molecular mechanisms of EB recovery are poorly understood. Triggering of MHC molecules by migrating T-cells is a minimal signal capable of inducing endothelial contraction and transient microvascular leakage. Using this model, we show that EB recovery requires a CD31 receptor-induced, robust glycolytic response sustaining junction re-annealing. Mechanistically, this response involves src-homology phosphatase activation leading to Akt-mediated nuclear exclusion of FoxO1 and concomitant ß-catenin translocation to the nucleus, collectively leading to cMyc transcription. CD31 signals also sustain mitochondrial respiration, however this pathway does not contribute to junction remodeling. We further show that pathologic microvascular leakage in CD31-deficient mice can be corrected by enhancing the glycolytic flux via pharmacological Akt or AMPK activation, thus providing a molecular platform for the therapeutic control of EB response.


Assuntos
Células Endoteliais/metabolismo , Microvasos/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Animais , Feminino , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Masculino , Camundongos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , beta Catenina/genética , beta Catenina/metabolismo
5.
Nat Commun ; 11(1): 2984, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32533114

RESUMO

ADNP (Activity Dependent Neuroprotective Protein) is a neuroprotective protein whose aberrant expression has been frequently linked to neural developmental disorders, including the Helsmoortel-Van der Aa syndrome (also called the ADNP syndrome). However, its role in neural development and pathology remains unclear. Here, we show that ADNP is required for neural induction and differentiation by enhancing Wnt signaling. Mechanistically, ADNP functions to stabilize ß-Catenin through binding to its armadillo domain which prevents its association with key components of the degradation complex: Axin and APC. Loss of ADNP promotes the formation of the degradation complex and ß-Catenin degradation via ubiquitin-proteasome pathway, resulting in down-regulation of key neuroectoderm developmental genes. In addition, adnp gene disruption in zebrafish leads to defective neurogenesis and reduced Wnt signaling. Our work provides important insights into the role of ADNP in neural development and the pathology of the Helsmoortel-Van der Aa syndrome caused by ADNP gene mutation.


Assuntos
Diferenciação Celular/genética , Proteínas de Homeodomínio/genética , Células-Tronco Embrionárias Murinas/metabolismo , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Via de Sinalização Wnt/genética , beta Catenina/genética , Animais , Células Cultivadas , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Proteínas de Homeodomínio/metabolismo , Humanos , Hibridização In Situ/métodos , Camundongos , Camundongos Knockout , Células-Tronco Embrionárias Murinas/citologia , Mutação , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Ligação Proteica , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , beta Catenina/metabolismo
6.
PLoS One ; 15(6): e0234375, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555682

RESUMO

Renal dysplasia, the major cause of childhood renal failure, is characterized by defective branching morphogenesis and nephrogenesis. Beta-catenin, a transcription factor and cell adhesion molecule, is markedly increased in the nucleus of kidney cells in human renal dysplasia and contributes to its pathogenesis by altering target genes that are essential for kidney development. Quercetin, a naturally occurring flavonoid, reduces nuclear beta-catenin levels and reduces beta-catenin transcriptional activity. In this study, we utilized wild type and dysplastic mouse kidney organ explants to determine if quercetin reduces beta-catenin activity during kidney development and whether it improves the severity of renal dysplasia. In wild type kidney explants, quercetin treatment resulted in abnormal branching morphogenesis and nephrogenesis in a dose dependent manner. In wild type embryonic kidneys, quercetin reduced nuclear beta-catenin expression and decreased expression of beta-catenin target genes Pax2, Six2, and Gdnf, which are essential for kidney development. Our RDB mouse model of renal dysplasia recapitulates the overexpression of beta-catenin and histopathological changes observed in human renal dysplasia. RDB kidneys treated with quercetin resulted in improvements in the overall histopathology, tissue organization, ureteric branching morphogenesis, and nephrogenesis. Quercetin treatment also resulted in reduced nuclear beta-catenin and reduced Pax2 expression. These improvements were associated with the proper organization of vimentin, NCAM, and E-cadherin, and a 45% increase in the number of developing and maturing nephrons. Further, our results show that in human renal dysplasia, beta-catenin, vimentin, and e-cadherin also have abnormal expression patterns. Taken together, these data demonstrate that quercetin treatment reduces nuclear beta-catenin and this is associated with improved epithelial organization of developing nephrons, resulting in increased developing nephrons and a partial rescue of renal dysplasia.


Assuntos
Rim/anormalidades , Rim/efeitos dos fármacos , Quercetina/farmacologia , beta Catenina/metabolismo , Animais , Antígenos CD/metabolismo , Caderinas/metabolismo , Núcleo Celular/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Rim/metabolismo , Masculino , Camundongos , Camundongos Mutantes , Morfogênese/efeitos dos fármacos , Morfogênese/genética , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Técnicas de Cultura de Órgãos , Gravidez , Vimentina/metabolismo , beta Catenina/química , beta Catenina/genética
7.
Nat Commun ; 11(1): 3020, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32541686

RESUMO

The subversion of endocytic routes leads to malignant transformation and has been implicated in human cancers. However, there is scarce evidence for genetic alterations of endocytic proteins as causative in high incidence human cancers. Here, we report that Epsin 3 (EPN3) is an oncogene with prognostic and therapeutic relevance in breast cancer. Mechanistically, EPN3 drives breast tumorigenesis by increasing E-cadherin endocytosis, followed by the activation of a ß-catenin/TCF4-dependent partial epithelial-to-mesenchymal transition (EMT), followed by the establishment of a TGFß-dependent autocrine loop that sustains EMT. EPN3-induced partial EMT is instrumental for the transition from in situ to invasive breast carcinoma, and, accordingly, high EPN3 levels are detected at the invasive front of human breast cancers and independently predict metastatic rather than loco-regional recurrence. Thus, we uncover an endocytic-based mechanism able to generate TGFß-dependent regulatory loops conferring cellular plasticity and invasive behavior.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Neoplasias da Mama/fisiopatologia , Endocitose , Proteínas Adaptadoras de Transporte Vesicular/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Caderinas/genética , Caderinas/metabolismo , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Metástase Neoplásica , Transdução de Sinais , Fator de Transcrição 4/genética , Fator de Transcrição 4/metabolismo , Fator de Crescimento Transformador beta/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
8.
Gene ; 754: 144892, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32534060

RESUMO

Breast cancer is the most commonly diagnosed malignancy in women worldwide. Recently, uncontrolled expression of microRNAs was detected in several human disorders like cardiovascular, neurological, intestinal and autoimmunity diseases. MicroRNAs (miRNAs) are now investigated as novel prognostic and diagnostic biomarkers for several solid tumors like breast, lung, and gastrointestinal cancers. Current data suggest that miRNAs are implicated in various oncogenic processes implicated in breast cancer carcinogenesis trough modulating canonical Wnt pathway. Aberrant activation of Wnt/b-catenin signaling was shown to be significantly associated with tumor progression and poor prognosis in patients with breast cancer. This review presents recent findings on the molecular mechanism of microRNAs in regulation of Wnt/ß-catenin signaling involved in tumorigenesis of breast cancer.


Assuntos
Neoplasias da Mama/patologia , Carcinogênese , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Humanos , MicroRNAs/genética , Proteínas Wnt/genética , beta Catenina/genética
9.
Jpn J Clin Oncol ; 50(9): 1037-1042, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32533146

RESUMO

BACKGROUND: An accurate diagnosis is crucial to determine the treatment modality for desmoid-type fibromatosis, although the histopathological diagnosis is occasionally difficult to make. Many desmoid-type fibromatosis have been reported to have hotspot mutation of ß-catenin gene (CTNNB1). In the present study, we performed a systematic review to verify the usefulness of CTNNB1 mutation analysis in the diagnosis of desmoid-type fibromatosis. METHODS: A literature search from January 1990 to August 2017 was conducted. Three reviewers independently assessed and screened the literature for eligibility and determined the final articles to be evaluated. Data regarding the sensitivity, specificity, accuracy and usefulness of CTNNB1 mutation analysis in the diagnosis of desmoid-type fibromatosis were recorded. We rated each report according to the Grading of Recommendations Development and Evaluation approach. RESULTS: The search yielded 90 studies, seven of which were included after the first and second screenings. The positive rate of CTNNB1 mutation in desmoid-type fibromatosis was 86.8%, but the cohort of six of the seven reports was already diagnosed histopathologically as desmoid-type fibromatosis. Therefore, the usefulness of CTNNB1 mutation analysis in a cohort that is difficult to diagnose histopathologically is not clear in this review. Nevertheless, CTNNB1 mutation showed very high specificity in desmoid-type fibromatosis, indicating the usefulness of CTNNB1 mutation analysis in its diagnosis in combination with histological examination. CONCLUSION: Because the lack of data precludes any useful comparison with histological diagnosis, the evidence level is low. However, considering its specificity, CTNNB1 mutation analysis may be useful in cases in which the histopathological diagnosis is difficult.


Assuntos
Análise Mutacional de DNA/métodos , Fibromatose Agressiva/diagnóstico , beta Catenina/genética , Humanos
10.
Am J Surg Pathol ; 44(9): 1266-1273, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32590455

RESUMO

Desmoid fibromatosis (DF) is a rare, locally aggressive, nonmetastasizing fibroblastic/myofibroblastic tumor with a tendency to recur and an unpredictable clinical course. A "wait-and-see" policy is the new standard of care. DF are characterized by activating alterations of the wnt/ß-catenin pathway: CTNNB1 or adenomatous polyposis coli gene (APC) mutations (these mutations being mutually exclusive). Desmoid-type fibromatosis of the breast (DFB) is rare with an incidence of 0.2% of breast tumors. The diagnosis of DFB is difficult, as it must be distinguished from metaplastic carcinoma and other spindle cell lesions. Sequencing of 128 DFB identified a lower rate of CTNNB1 mutations using Sanger (65.6%) or Sanger+next-generation sequencing (77.7%) and a higher rate of APC mutations (11.8%) than in all-site DF. By excluding patients with familial adenomatous polyposis (n=2), the rate of APC mutations in DFB was high (10.7%). The distribution of CTNNB1 mutations in DFB was different from all-site DF, with a higher rate of T41A (68.9%), a lower rate of S45F (5.7%), and a similar rate of S45T (12.6%). By combining the 2 molecular techniques in a 2-step manner (Sanger, then next-generation sequencing), we increased the detection rate of CTNNB1 mutations and lowered the rate of wild-type tumors from 34.4% to 9.8%, therefore improving the diagnosis of DFB. The identification of the exon 3 CTNNB1 mutation in breast spindle cell lesions is a highly specific tool for the diagnosis of DFB, in addition to extensive immunohistochemical analysis. Our study also underlines the importance of APC in DFB tumorigenesis. These findings have significant implications for patient care and management.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama Masculina/genética , Neoplasias da Mama/genética , Fibromatose Agressiva/genética , Mutação , beta Catenina/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Neoplasias da Mama Masculina/patologia , Neoplasias da Mama Masculina/terapia , Feminino , Fibromatose Agressiva/patologia , Fibromatose Agressiva/terapia , França , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Fenótipo , Prognóstico , Adulto Jovem
11.
Proc Natl Acad Sci U S A ; 117(24): 13680-13688, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32493750

RESUMO

Sex determination in mammals is governed by antagonistic interactions of two genetic pathways, imbalance in which may lead to disorders/differences of sex development (DSD) in human. Among 46,XX individuals with testicular DSD (TDSD) or ovotesticular DSD (OTDSD), testicular tissue is present in the gonad. Although the testis-determining gene SRY is present in many cases, the etiology is unknown in most SRY-negative patients. We performed exome sequencing on 78 individuals with 46,XX TDSD/OTDSD of unknown genetic etiology and identified seven (8.97%) with heterozygous variants affecting the fourth zinc finger (ZF4) of Wilms' tumor 1 (WT1) (p.Ser478Thrfs*17, p.Pro481Leufs*15, p.Lys491Glu, p.Arg495Gln [x3], p.Arg495Gly). The variants were de novo in six families (P = 4.4 × 10-6), and the incidence of WT1 variants in 46,XX DSD is enriched compared to control populations (P < 1.8 × 10-4). The introduction of ZF4 mutants into a human granulosa cell line resulted in up-regulation of endogenous Sertoli cell transcripts and Wt1 Arg495Gly/Arg495Gly XX mice display masculinization of the fetal gonads. The phenotype could be explained by the ability of the mutated proteins to physically interact with and sequester a key pro-ovary factor ß-CATENIN, which may lead to up-regulation of testis-specific pathway. Our data show that unlike previous association of WT1 and 46,XY DSD, ZF4 variants of WT1 are a relatively common cause of 46,XX TDSD/OTDSD. This expands the spectrum of phenotypes associated with WT1 variants and shows that the WT1 protein affecting ZF4 can function as a protestis factor in an XX chromosomal context.


Assuntos
Transtornos Testiculares 46, XX do Desenvolvimento Sexual/metabolismo , Testículo/metabolismo , Proteínas WT1/metabolismo , Transtornos Testiculares 46, XX do Desenvolvimento Sexual/genética , Transtornos Testiculares 46, XX do Desenvolvimento Sexual/patologia , Animais , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Camundongos , Ovário/crescimento & desenvolvimento , Ovário/metabolismo , Testículo/crescimento & desenvolvimento , Testículo/patologia , Proteínas WT1/química , Proteínas WT1/genética , Dedos de Zinco , beta Catenina/genética , beta Catenina/metabolismo
12.
Proc Natl Acad Sci U S A ; 117(22): 12182-12191, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32414917

RESUMO

In multicellular organisms, paralogs from gene duplication survive purifying selection by evolving tissue-specific expression and function. Whether this genetic redundancy is also selected for within a single cell type is unclear for multimember paralogs, as exemplified by the four obligatory Lef/Tcf transcription factors of canonical Wnt signaling, mainly due to the complex genetics involved. Using the developing mouse lung as a model system, we generate two quadruple conditional knockouts, four triple mutants, and various combinations of double mutants, showing that the four Lef/Tcf genes function redundantly in the presence of at least two Lef/Tcf paralogs, but additively upon losing additional paralogs to specify and maintain lung epithelial progenitors. Prelung-specification, pan-epithelial double knockouts have no lung phenotype; triple knockouts have varying phenotypes, including defective branching and tracheoesophageal fistulas; and the quadruple knockout barely forms a lung, resembling the Ctnnb1 mutant. Postlung-specification deletion of all four Lef/Tcf genes leads to branching defects, down-regulation of progenitor genes, premature alveolar differentiation, and derepression of gastrointestinal genes, again phenocopying the corresponding Ctnnb1 mutant. Our study supports a monotonic, positive signaling relationship between CTNNB1 and Lef/Tcf in lung epithelial progenitors as opposed to reported repressor functions of Lef/Tcf, and represents a thorough in vivo analysis of cell-type-specific genetic redundancy among the four Lef/Tcf paralogs.


Assuntos
Embrião de Mamíferos/metabolismo , Células-Tronco Embrionárias/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Pulmão/metabolismo , Fator 1 de Ligação ao Facilitador Linfoide/fisiologia , Células-Tronco/metabolismo , beta Catenina/metabolismo , Animais , Diferenciação Celular , Embrião de Mamíferos/citologia , Células-Tronco Embrionárias/citologia , Feminino , Fator 1-alfa Nuclear de Hepatócito/fisiologia , Pulmão/citologia , Camundongos , Camundongos Knockout , Análise de Célula Única , Células-Tronco/citologia , Proteína 1 Semelhante ao Fator 7 de Transcrição/fisiologia , Proteína 2 Semelhante ao Fator 7 de Transcrição/fisiologia , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética
13.
Hum Cell ; 33(3): 652-662, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32350750

RESUMO

The tumor microenvironment (TM) is an essential factor of tumor progression. Mesenchymal stem cells (MSCs) are important components of the TM and play critical roles in cancer metastasis. Resveratrol (RES) is a potential antitumor drug that has attracted extensive attention. However, it remains unclear whether RES can exert its antitumor activity by targeting MSCs located in the TM. In this study, we demonstrated that the conditioned medium of gastric-cancer-derived MSCs (GC-MSCs) promoted gastric cancer (GC) metastasis and facilitated the progression of epithelialmesenchymal transition (EMT) of GC cells. However, after pretreatment with RES, the prometastatic effect of GC-MSCs on GC cells was reversed. Furthermore, RES reduced GC-MSC (IL-6, IL-8, MCP-1, VEGF) gene expression and protein secretion, and counteracted the activation of the GC-MSC-induced Wnt/ß-catenin signaling of GC cells, with less ß-catenin nuclear transport and declined expression of ß-catenin, CD44, and CyclinD3 in GC cells. Re-expression of ß-catenin impaired the inhibitory effect of RES on GC cells. In conclusion, RES restricted the mobility increase of GC cells and reversed the progress of EMT induced by GC-MSCs by inactivating the Wnt/ß-catenin signaling. GC-MSCs are promising target for RES in the inhibition of GC metastasis.


Assuntos
Células-Tronco Mesenquimais/fisiologia , Metástase Neoplásica/tratamento farmacológico , Resveratrol/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Antineoplásicos Fitogênicos , Linhagem Celular Tumoral , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Células-Tronco Mesenquimais/patologia , Terapia de Alvo Molecular , Fitoterapia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Microambiente Tumoral , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
14.
Nat Cell Biol ; 22(4): 389-400, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32231305

RESUMO

In mouse embryonic stem cells (mESCs), chemical blockade of Gsk3α/ß and Mek1/2 (2i) instructs a self-renewing ground state whose endogenous inducers are unknown. Here we show that the axon guidance cue Netrin-1 promotes naive pluripotency by triggering profound signalling, transcriptomic and epigenetic changes in mESCs. Furthermore, we demonstrate that Netrin-1 can substitute for blockade of Gsk3α/ß and Mek1/2 to sustain self-renewal of mESCs in combination with leukaemia inhibitory factor and regulates the formation of the mouse pluripotent blastocyst. Mechanistically, we reveal how Netrin-1 and the balance of its receptors Neo1 and Unc5B co-regulate Wnt and MAPK pathways in both mouse and human ESCs. Netrin-1 induces Fak kinase to inactivate Gsk3α/ß and stabilize ß-catenin while increasing the phosphatase activity of a Ppp2r2c-containing Pp2a complex to reduce Erk1/2 activity. Collectively, this work identifies Netrin-1 as a regulator of pluripotency and reveals that it mediates different effects in mESCs depending on its receptor dosage, opening perspectives for balancing self-renewal and lineage commitment.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas do Tecido Nervoso/genética , Receptores de Netrina/genética , Netrina-1/genética , Receptores de Superfície Celular/genética , Via de Sinalização Wnt/genética , Animais , Linhagem Celular , Embrião de Mamíferos , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Fator Inibidor de Leucemia/genética , Fator Inibidor de Leucemia/metabolismo , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 2/genética , MAP Quinase Quinase 2/metabolismo , Masculino , Camundongos , Camundongos Knockout , Camundongos SCID , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptores de Netrina/metabolismo , Netrina-1/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Receptores de Superfície Celular/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
15.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(2): 122-129, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32314709

RESUMO

Objective To establish and evaluate a murine lipogenic inflammation-mediated hepatocarcinoma model with hydrodynamic transfection of protein kinase B (AKT), ß-catenin, and Sleeping Beauty transposon plasmids into hepatocytes through the tail vein. Methods Isotonic physiological solution (20 µg myrAKT, 20 µg δN90-ß-catenin and 4 µg Sleeping Beauty transposase were dissolved in 2 mL of normal saline) was injected into C57BL/6 male mice aged 6-8 weeks via the tail vein in a short period of time (5-9 s) by hydrodynamic transfection, while the control plasmid was injected with the same method. Mice were then sacrificed 8, 12, or 16 weeks after the injection of these plasmids, and their serum and liver tissues were collected. RNA samples were extracted for further analysis. HE staining was used to detect liver tissue structure and inflammatory cell infiltration; oil red O staining was used to examine lipid deposition in liver cells; sirius red and Masson staining were used to identify collagen deposition in liver tissues; immunohistochemistry was performed to evaluate the proliferation abilities of the cells and microvascular density and distribution; real-time quantitative PCR was used to reflect the expression of tumor-associated genes; flow cytometry was used for immune cell phenotype identification. Results Sixteen weeks after hydrodynamic transfection, 100% (20/20) mice developed liver tumors in the experimental group. Compared with the control group, the body mass of mice in the experimental group increased slowly and liver mass increased significantly. HE staining showed that a large number of hepatocytes appeared to be steatosis, inflammatory cell infiltration increased, liver tumor cells were round or irregular-shaped, the cytoplasmic ratio was imbalanced, tumor cell atypia was obvious and tumor cells were distributed in clustering; ki67 positive cells were enhanced. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transpeptidase (γ-GT), and alkaline phosphatase (ALP) levels remarkably increased. AFP mRNA also significantly increased in liver tissue. CD31 staining showed increased vessel density and vessel structure disorganization. A large number of inflammatory cells, especially myeloid and lymphoid cells, were infiltrated into the liver tissue. Conclusion Murine lipogenic inflammation-mediated hepatocarcinoma model that is caused by non-resolving inflammation was successfully established by hydrodynamic transfection with AKT and ß-catenin plasmids. This method is easier performed and reproducible, the induction time is relatively short with a high rate of tumor formation.


Assuntos
Carcinoma Hepatocelular , Modelos Animais de Doenças , Neoplasias Hepáticas Experimentais , Animais , Hidrodinâmica , Inflamação , Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasmídeos , Proteínas Proto-Oncogênicas c-akt/genética , Transfecção , beta Catenina/genética
16.
Nat Commun ; 11(1): 1680, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245949

RESUMO

Rosettes are widely used in epithelial morphogenesis during embryonic development and organogenesis. However, their role in postnatal development and adult tissue maintenance remains largely unknown. Here, we show zona glomerulosa cells in the adult adrenal cortex organize into rosettes through adherens junction-mediated constriction, and that rosette formation underlies the maturation of adrenal glomerular structure postnatally. Using genetic mouse models, we show loss of ß-catenin results in disrupted adherens junctions, reduced rosette number, and dysmorphic glomeruli, whereas ß-catenin stabilization leads to increased adherens junction abundance, more rosettes, and glomerular expansion. Furthermore, we uncover numerous known regulators of epithelial morphogenesis enriched in ß-catenin-stabilized adrenals. Among these genes, we show Fgfr2 is required for adrenal rosette formation by regulating adherens junction abundance and aggregation. Together, our data provide an example of rosette-mediated postnatal tissue morphogenesis and a framework for studying the role of rosettes in adult zona glomerulosa tissue maintenance and function.


Assuntos
Junções Aderentes/metabolismo , Morfogênese , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Zona Glomerulosa/crescimento & desenvolvimento , beta Catenina/metabolismo , Junções Aderentes/genética , Junções Aderentes/ultraestrutura , Neoplasias das Glândulas Suprarrenais/cirurgia , Animais , Animais Recém-Nascidos , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Zona Glomerulosa/citologia , Zona Glomerulosa/metabolismo , Zona Glomerulosa/ultraestrutura , beta Catenina/genética
17.
Mol Carcinog ; 59(6): 661-669, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32339330

RESUMO

Gastrointestinal stromal tumor (GIST) is a common mesenchymal tumor in the gastrointestinal tract. Prostate cancer associated transcript 6 (PCAT6) is a long noncoding RNA (lncRNA) and plays a pivotal role in tumor formation. Present study was designed to explore the function of PCAT6 in GIST. Ki67 staining, colony formation and trypan blue staining assays revealed that PCAT6 boosted GIST cell proliferation but inhibited cell apoptosis. Also, sphere formation assay and Western blot uncovered the promoting role of PCAT6 in GIST stemness. Then, we identified that PCAT6 could activate Wnt/ß-catenin pathway. And the tumor facilitator role of Wnt/ß-catenin pathway was validated in the rescue assays. Next, miR-143-3p was identified as the downstream microRNA of PCAT6. Moreover, miR-143-3p itself served as a tumor suppressor in GIST. Subsequently, peroxiredoxin 5 (PRDX5) was verified as the target of miR-143-3p. PCAT6 promoted GIST cell proliferation and stemness via sponging miR-143-3p to upregulate PRDX5. In a word, PCAT6 promoted GIST cell proliferation and stemness but inhibited cell apoptosis via competing endogenous RNA pattern and activation of Wnt pathway, which might contribute to GIST treatment.


Assuntos
Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/patologia , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Peroxirredoxinas/metabolismo , RNA Longo não Codificante/genética , Via de Sinalização Wnt , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/metabolismo , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/metabolismo , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Peroxirredoxinas/genética , Prognóstico , Ativação Transcricional , Células Tumorais Cultivadas , beta Catenina/genética , beta Catenina/metabolismo
18.
Mol Immunol ; 121: 186-194, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32244067

RESUMO

NLRP3 (NOD-, LRR- and pyrin domain- containing protein 3) inflammasome is involved in diverse inflammatory diseases, so the activation of NLRP3 inflammasome needs to be tightly regulated to prevent excessive inflammation. However, the endogenous regulatory mechanisms of NLRP3 inflammasome are still less defined. Here, we report that ß-catenin, which is the central mediator of the canonical Wnt/ß-catenin signaling, promotes NLRP3 inflammasome activation. When we suppressed the expression of ß-catenin by siRNA or pharmacological inhibitor, the NLRP3 inflammasome activation was impaired. Accordingly, ß-catenin inhibitor attenuated LPS-induced systemic inflammation in vivo. Mechanistically, we found ß-catenin interacted with NLRP3 and promoted the association between NLRP3 and ASC. Thus, our study revealed a novel role of ß-catenin in NLRP3 inflammasome activation and suggest an endogenous crosstalk between Wnt/ß-catenin signal and NLRP3 inflammasome.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacologia , Inflamassomos/imunologia , Inflamação/prevenção & controle , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , beta Catenina/metabolismo , Animais , Proteínas Adaptadoras de Sinalização CARD/imunologia , Modelos Animais de Doenças , Células HEK293 , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Inflamassomos/efeitos dos fármacos , Inflamação/imunologia , Injeções Intraperitoneais , Lipopolissacarídeos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Cultura Primária de Células , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/imunologia , beta Catenina/antagonistas & inibidores , beta Catenina/genética
19.
J Acupunct Meridian Stud ; 13(3): 94-103, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32278077

RESUMO

BACKGROUND AND OBJECTIVE: Perimenopausal depression is caused by the impaired function of the ovarium before menopause and with a series of symptoms. Electroacupuncture (EA) therapy has been demonstrated to improve clinically depression. However, the mechanism underlying its therapeutic activity remains unknown. This study aimed to investigat the effects of EA treatment on the hippocampal neural proliferation through Wnt signaling pathway. METHODS: Chronic unpredictable mild stress (CUMS) combined with bilateral ovariectomy (OVX) were used to establish a rat model of perimenopausal depression. The open field test (OFT) and sucrose preference test (SPT) were used to assess depression-like behaviors in rats. ELISAs were used to measure estrogen (E2), luteinizing hormone (LH) and gonadotropin-releasing hormone (GnRH) levels in the serum. RT-PCR and Western blot assay were utilized for measuring the mRNA expressions and protein expressions of GSK-3ß/ß-catenin. RESULTS: Four-week EA treatment at three points including "Shenshu" (BL23), "Baihui" (GV20) and "Sanyinjiao" (SP6) simultaneously ameliorated depression-like behaviors in rats with CUMS and OVX, whereas rescued the decreased serum level of E2 and prevented the increased serum levels of GnRH and LH. EA treatment ameliorated CUMS and OVX-induced alterations of glycogen synthase kinase-3ß (GSK-3ß) and ß-catenin mRNA levels, ß-catenin and phosphorylated ß-catenin (p-ß-catenin) protein levels. CONCLUSIONS: The results showed that EA treatment promoted hippocampal neural proliferation in perimenopausal depression rats via activating the Wnt/ß-catenin signaling pathway, indicating that EA may represent an efficacious therapy for perimenopausal depression.


Assuntos
Depressão/terapia , Hipocampo/metabolismo , Neurônios/citologia , Perimenopausa/psicologia , Via de Sinalização Wnt , beta Catenina/metabolismo , Animais , Proliferação de Células , Depressão/etiologia , Depressão/genética , Depressão/metabolismo , Modelos Animais de Doenças , Eletroacupuntura , Feminino , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/fisiopatologia , Humanos , Masculino , Neurônios/metabolismo , Perimenopausa/metabolismo , Ratos , Ratos Sprague-Dawley , beta Catenina/genética
20.
Hum Cell ; 33(3): 810-818, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32274658

RESUMO

Circular RNAs (circRNAs) exert pivotal effects on regulating the progression of osteosarcoma (OS). It was found through microarray analysis that circ-0002052 is abnormally expressed in OS, but the role of circ-0002052 in OS remains obscure. The results of this research manifested that relative to that in non-tumor controls, circ-0002052 level was raised in OS tissues. Up-regulated circ-0002052 was associated with advanced stage, tumor size, and metastasis. Additionally, circ-0002052 elevation indicated a low survival rate in OS patients and silencing of circ-0002052 suppressed proliferation, migration, and invasion of OS cells. It was proved that circ-0002052 sponged miR-382 and stimulated STX6 expression, thus activating Wnt/ß-catenin. The function of circ-0002052 reduction in OS cells was effectively reversed by miR-382 suppression. To sum up, it can be concluded that circ-0002052, functioning as a sponge for miR-382, enhances the activation of Wnt/ß-catenin mediated by STX6 to stimulate the progression of OS, and circ-0002052 may be an underlying treatment target and a biomarker for prognosis of osteosarcoma.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Osteossarcoma/genética , Osteossarcoma/metabolismo , Proteínas Qa-SNARE/genética , Proteínas Qa-SNARE/metabolismo , RNA Circular/fisiologia , Linhagem Celular Tumoral , Humanos , Terapia de Alvo Molecular , Osteossarcoma/diagnóstico , Osteossarcoma/terapia , RNA Circular/genética , RNA Circular/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
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