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1.
Nat Commun ; 11(1): 6314, 2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33298956

RESUMO

Blood and lymphatic vessels structurally bear a strong resemblance but never share a lumen, thus maintaining their distinct functions. Although lymphatic vessels initially arise from embryonic veins, the molecular mechanism that maintains separation of these two systems has not been elucidated. Here, we show that genetic deficiency of Folliculin, a tumor suppressor, leads to misconnection of blood and lymphatic vessels in mice and humans. Absence of Folliculin results in the appearance of lymphatic-biased venous endothelial cells caused by ectopic expression of Prox1, a master transcription factor for lymphatic specification. Mechanistically, this phenotype is ascribed to nuclear translocation of the basic helix-loop-helix transcription factor Transcription Factor E3 (TFE3), binding to a regulatory element of Prox1, thereby enhancing its venous expression. Overall, these data demonstrate that Folliculin acts as a gatekeeper that maintains separation of blood and lymphatic vessels by limiting the plasticity of committed endothelial cells.


Assuntos
Plasticidade Celular , Vasos Linfáticos/embriologia , Proteínas Proto-Oncogênicas/deficiência , Proteínas Supressoras de Tumor/deficiência , Veias/embriologia , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Núcleo Celular/metabolismo , Embrião de Mamíferos , Células Endoteliais/metabolismo , Endotélio Linfático/citologia , Endotélio Linfático/embriologia , Endotélio Vascular/citologia , Endotélio Vascular/embriologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Vasos Linfáticos/citologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas Proto-Oncogênicas/genética , Interferência de RNA , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Veias/citologia
2.
Nat Commun ; 11(1): 6118, 2020 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-33257658

RESUMO

Inhibitors of poly-ADP-ribose polymerase 1 (PARPi) are highly effective in killing cells deficient in homologous recombination (HR); thus, PARPi have been clinically utilized to successfully treat BRCA2-mutant tumors. However, positive response to PARPi is not universal, even among patients with HR-deficiency. Here, we present the results of genome-wide CRISPR knockout and activation screens which reveal genetic determinants of PARPi response in wildtype or BRCA2-knockout cells. Strikingly, we report that depletion of the ubiquitin ligase HUWE1, or the histone acetyltransferase KAT5, top hits from our screens, robustly reverses the PARPi sensitivity caused by BRCA2-deficiency. We identify distinct mechanisms of resistance, in which HUWE1 loss increases RAD51 levels to partially restore HR, whereas KAT5 depletion rewires double strand break repair by promoting 53BP1 binding to double-strand breaks. Our work provides a comprehensive set of putative biomarkers that advance understanding of PARPi response, and identifies novel pathways of PARPi resistance in BRCA2-deficient cells.


Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Inibidores de Poli(ADP-Ribose) Polimerases/isolamento & purificação , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/efeitos dos fármacos , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Biomarcadores , Dano ao DNA , Reparo do DNA , Técnicas de Inativação de Genes , Células HeLa , Recombinação Homóloga/efeitos dos fármacos , Humanos , Lisina Acetiltransferase 5/metabolismo , Proteínas Mad2/metabolismo , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53 , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
3.
PLoS Genet ; 16(11): e1009187, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33137092

RESUMO

Germline mutations in the folliculin (FLCN) tumor suppressor gene are linked to Birt-Hogg-Dubé (BHD) syndrome, a dominantly inherited genetic disease characterized by predisposition to fibrofolliculomas, lung cysts, and renal cancer. Most BHD-linked FLCN variants include large deletions and splice site aberrations predicted to cause loss of function. The mechanisms by which missense variants and short in-frame deletions in FLCN trigger disease are unknown. Here, we present an integrated computational and experimental study that reveals that the majority of such disease-causing FLCN variants cause loss of function due to proteasomal degradation of the encoded FLCN protein, rather than directly ablating FLCN function. Accordingly, several different single-site FLCN variants are present at strongly reduced levels in cells. In line with our finding that FLCN variants are protein quality control targets, several are also highly insoluble and fail to associate with the FLCN-binding partners FNIP1 and FNIP2. The lack of FLCN binding leads to rapid proteasomal degradation of FNIP1 and FNIP2. Half of the tested FLCN variants are mislocalized in cells, and one variant (ΔE510) forms perinuclear protein aggregates. A yeast-based stability screen revealed that the deubiquitylating enzyme Ubp15/USP7 and molecular chaperones regulate the turnover of the FLCN variants. Lowering the temperature led to a stabilization of two FLCN missense proteins, and for one (R362C), function was re-established at low temperature. In conclusion, we propose that most BHD-linked FLCN missense variants and small in-frame deletions operate by causing misfolding and degradation of the FLCN protein, and that stabilization and resulting restoration of function may hold therapeutic potential of certain disease-linked variants. Our computational saturation scan encompassing both missense variants and single site deletions in FLCN may allow classification of rare FLCN variants of uncertain clinical significance.


Assuntos
Síndrome de Birt-Hogg-Dubé/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Síndrome de Birt-Hogg-Dubé/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Biologia Computacional , Mutação em Linhagem Germinativa , Humanos , Mutação com Perda de Função , Mutação de Sentido Incorreto , Agregados Proteicos , Ligação Proteica/genética , Dobramento de Proteína , Estabilidade Proteica , Proteólise , Proteínas Proto-Oncogênicas/genética , Saccharomyces cerevisiae , Proteínas Supressoras de Tumor/genética , Peptidase 7 Específica de Ubiquitina/metabolismo
4.
Environ Health Prev Med ; 25(1): 68, 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33153431

RESUMO

BACKGROUND: Particulate matter (PM) < 2.5 µm (PM2.5) or fine PM is a serious public health concern. It affects DNA methylation and heightens carcinogenesis. Deleted in lung and esophageal cancer 1 (DLEC1) is a tumor suppressor gene. However, aberrant methylation of the gene is associated with several cancers. We evaluated the association between PM2.5 and DLEC1 promoter methylation in Taiwanese adults based on regular outdoor exercise. METHODS: We obtained DNA methylation and exercise data of 496 participants (aged between 30 and 70 years) from the Taiwan Biobank (TWB) database. We also extracted PM2.5 data from the Air Quality Monitoring Database (AQMD) and estimated participants' exposure using residential addresses. RESULTS: DLEC1 methylation and PM2.5 were positively associated: beta coefficient (ß) = 0.114 × 10-3; p value = 0.046. The test for interaction between exercise and PM2.5 on DLEC1 methylation was significant (p value = 0.036). After stratification by exercise habits, PM2.5 and DLEC1 methylation remained significantly associated only among those who exercised regularly (ß = 0.237 × 10-3; p value = 0.007). PM2.5 quartile-stratified analyses revealed an inverse association between regular exercise and DLEC1 methylation at PM2.5 < 27.37 µg/m3 (ß = - 5.280 × 10-3; p value = 0.009). After combining exercise habits and PM2.5 quartiles, one stratum (i.e., regular exercise and PM2.5 < 27.37 µg/m3) was inversely associated with DLEC1 methylation (ß = -5.160 × 10-3, p value = 0.007). CONCLUSIONS: We found significant positive associations between PM2.5 and DLEC1 promoter methylation. Regular exercise at PM2.5 < 27.37 µg/m3 seemingly regulated DLEC1 promoter methylation.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Metilação de DNA/efeitos dos fármacos , Exposição Ambiental/efeitos adversos , Exercício Físico , Material Particulado/efeitos adversos , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taiwan
5.
J Steroid Biochem Mol Biol ; 204: 105769, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33065277

RESUMO

Expression of transcription factors is crucial for the regulation of steroidogenesis and gonadal development in fish. SRY-related box (SOX) proteins regulate gene expression of various events related to vertebrate reproduction. This study reports the role of sox30 and its influence on sox9a/b in regulating testicular steroidogenesis of the common carp, Cyprinus carpio. Tissue distribution showed predominant expression of sox30 in gonads, while gonadal ontogeny indicated significant dimorphic expression of sox30 from 120 days post hatch. Higher sox30 transcripts during the spawning season, an elevation of sox30 after human chorionic gonadotropin induction, and 11-ketotestosterone (11-KT) treatment authenticate gonadotropin dependency. Treatment of 17α-methyl-di-hydroxy-testosterone to juvenile common carp for mono-sex induction, vis-à-vis elevated sox30 expression. Sox30 protein was detected abundantly in spermatocytes and spermatid/sperm of carp testis. Transient silencing of sox30 using small interfering RNAs decreased sox9a/b expression, lead to downregulation of certain molecule/factor, transcription factor, germ/stem cell marker, and steroidogenesis-related enzyme genes. Serum testosterone and 11-KT decreased significantly upon transient silencing of sox30, in vivo. Concomitantly, a reduction in testicular microsomal 11-ß hydroxysteroid dehydrogenase activity was observed. These results demonstrate the influence of sox30 as well as sox9a/b in the regulation of testicular steroidogenesis in common carp.


Assuntos
Carpas , Proteínas de Peixes , Fatores de Transcrição SOX , Testículo/metabolismo , Proteínas Supressoras de Tumor , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Animais , Carpas/genética , Carpas/metabolismo , Feminino , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Inativação Gênica , Masculino , Fatores de Transcrição SOX/genética , Fatores de Transcrição SOX/metabolismo , Testosterona/análogos & derivados , Testosterona/sangue , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
6.
Oncogene ; 39(47): 7019-7033, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32999444

RESUMO

Among the more than 160 PDZ containing proteins described in humans, the cytoplasmic scaffold Scribble stands out because of its essential role in many steps of cancer development and dissemination. Its fame has somehow blurred the importance of homologous proteins, Erbin and Lano, all belonging to the LRR and PDZ (LAP) protein family first described twenty years ago. In this review, we will retrace the history of LAP family protein research and draw attention to their contribution in cancer by detailing the features of its members at the structural and functional levels, and highlighting their shared-but also different-implication in the tumoral process.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias/patologia , Sialoglicoproteínas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Sequência de Aminoácidos , Animais , Proteínas de Caenorhabditis elegans/genética , Proteínas de Transporte/genética , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Humanos , Proteínas de Membrana/genética , Domínios Proteicos/genética , Mapas de Interação de Proteínas , Processamento de Proteína Pós-Traducional , Homologia de Sequência de Aminoácidos , Sialoglicoproteínas/genética , Proteínas Supressoras de Tumor/genética
7.
Proc Natl Acad Sci U S A ; 117(44): 27412-27422, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33087562

RESUMO

Nuclear receptor Nur77 participates in multiple metabolic regulations and plays paradoxical roles in tumorigeneses. Herein, we demonstrated that the knockout of Nur77 stimulated mammary tumor development in two mouse models, which would be reversed by a specific reexpression of Nur77 in mammary tissues. Mechanistically, Nur77 interacted and recruited corepressors, the SWI/SNF complex, to the promoters of CD36 and FABP4 to suppress their transcriptions, which hampered the fatty acid uptake, leading to the inhibition of cell proliferation. Peroxisome proliferator-activated receptor-γ (PPARγ) played an antagonistic role in this process through binding to Nur77 to facilitate ubiquitin ligase Trim13-mediated ubiquitination and degradation of Nur77. Cocrystallographic and functional analysis revealed that Csn-B, a Nur77-targeting compound, promoted the formation of Nur77 homodimer to prevent PPARγ binding by steric hindrance, thereby strengthening the Nur77's inhibitory role in breast cancer. Therefore, our study reveals a regulatory function of Nur77 in breast cancer via impeding fatty acid uptake.


Assuntos
Neoplasias da Mama/patologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , PPAR gama/metabolismo , Fenilacetatos/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Ácidos Graxos/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Metabolismo dos Lipídeos/efeitos dos fármacos , Glândulas Mamárias Animais/patologia , Camundongos , Pessoa de Meia-Idade , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/agonistas , PPAR gama/agonistas , Cultura Primária de Células , Prognóstico , Proteólise/efeitos dos fármacos , Análise Serial de Tecidos , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor/metabolismo , Ubiquitinação/efeitos dos fármacos
8.
Medicine (Baltimore) ; 99(41): e22678, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031336

RESUMO

BACKGROUND: As a member of the N-myc down-regulated gene family, N-Myc downstream-regulated gene 2 (NDRG2) contributes to the tumorigenesis of various types of cancers. However, the correlation between NDRG2 expression and the prognosis of solid tumor remains to be elucidated because of small sample sizes and inconsistent results in previous studies. In the present study, we conducted a systematic review and meta-analysis to explore the prognostic significance of NDRG2 in human solid tumors. METHODS: PubMed, Web of Science, Embase, Chinese National Knowledge Infrastructure, and WanFang databases (up to April 2020) were searched for relevant studies that evaluated the impact of NDRG2 on clinical outcomes, including overall survival (OS), and disease-free survival (DFS), in solid tumors. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled to assess the association between NDRG2 expression and the survival of patients with solid tumors. Odds ratios (ORs) with 95% CIs were pooled to estimate the correlation between NDRG2 expression and clinicopathologic characteristics in the patients. RESULTS: A total of 13 eligible studies with 1980 patients were included in this meta-analysis. Low NDRG2 expression was significantly associated with poor OS (HR = 1.96, 95% CI: 1.60-2.40, P < .001) and DFS (HR = 2.70, 95% CI: 1.42-5.13, P = .002) in solid tumor. Furthermore, low NDRG2 expression was related to some phenotypes of tumor aggressiveness, such as clinical stage (OR = 3.21, 95% CI: 1.96-5.26, P < .001), lymph node metastasis (OR = 2.14, 95% CI: 1.49-3.07, P < .001), and degree of differentiation (OR = 0.60, 95% CI: 0.45-0.81, P = .001). CONCLUSIONS: NDRG2 may be a meaningful biomarker of poor prognosis and a potential therapeutic target for human solid tumors.


Assuntos
Neoplasias/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Estudos de Coortes , Humanos , Neoplasias/diagnóstico , Prognóstico
9.
Nat Commun ; 11(1): 5007, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024116

RESUMO

p50, the mature product of NFKB1, is constitutively produced from its precursor, p105. Here, we identify BARD1 as a p50-interacting factor. p50 directly associates with the BARD1 BRCT domains via a C-terminal phospho-serine motif. This interaction is induced by ATR and results in mono-ubiquitination of p50 by the BARD1/BRCA1 complex. During the cell cycle, p50 is mono-ubiquitinated in S phase and loss of this post-translational modification increases S phase progression and chromosomal breakage. Genome-wide studies reveal a substantial decrease in p50 chromatin enrichment in S phase and Cycln E is identified as a factor regulated by p50 during the G1 to S transition. Functionally, interaction with BARD1 promotes p50 protein stability and consistent with this, in human cancer specimens, low nuclear BARD1 protein strongly correlates with low nuclear p50. These data indicate that p50 mono-ubiquitination by BARD1/BRCA1 during the cell cycle regulates S phase progression to maintain genome integrity.


Assuntos
Neoplasias da Mama/metabolismo , Ciclo Celular/fisiologia , Instabilidade Genômica , Subunidade p50 de NF-kappa B/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Sítios de Ligação , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Feminino , Fibroblastos , Humanos , Lisina/metabolismo , Camundongos , Subunidade p50 de NF-kappa B/genética , Neuroblastoma/metabolismo , Domínios Proteicos , Processamento de Proteína Pós-Traducional , Serina/metabolismo , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
10.
Nat Commun ; 11(1): 5156, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33056990

RESUMO

The most frequent genetic alterations across multiple human cancers are mutations in TP53 and the activation of the PI3K/AKT pathway, two events crucial for cancer progression. Mutations in TP53 lead to the inhibition of the tumour and metastasis suppressor TAp63, a p53 family member. By performing a mouse-human cross species analysis between the TAp63 metastatic mammary adenocarcinoma mouse model and models of human breast cancer progression, we identified two TAp63-regulated oncogenic lncRNAs, TROLL-2 and TROLL-3. Further, using a pan-cancer analysis of human cancers and multiple mouse models of tumour progression, we revealed that these two lncRNAs induce the activation of AKT to promote cancer progression by regulating the nuclear to cytoplasmic translocation of their effector, WDR26, via the shuttling protein NOLC1. Our data provide preclinical rationale for the implementation of these lncRNAs and WDR26 as therapeutic targets for the treatment of human tumours dependent upon mutant TP53 and/or the PI3K/AKT pathway.


Assuntos
Adenocarcinoma/genética , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Mamárias Experimentais/genética , RNA Longo não Codificante/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenocarcinoma/patologia , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Glândulas Mamárias Animais/citologia , Neoplasias Mamárias Experimentais/patologia , Camundongos , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA-Seq , Transdução de Sinais/genética , Análise Serial de Tecidos , Transativadores/genética , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Ideggyogy Sz ; 73(9-10): 317-325, 2020 Sep 30.
Artigo em Húngaro | MEDLINE | ID: mdl-33035418

RESUMO

Background and purpose: Glioblastoma is the most common malignant CNS tumor, its surgical removal is hindered by the tumors invasive nature, while current anti-tumor therapies show limited effectiveness - mean overall survival is 16-24 months. Some patients show minimal response towards standard oncotherapy, however there are no routinely available prognostic and predictive markers in clinical practice to identify the background of mentioned differences in prognosis. This research aims to identify the prognostic significance of invasion-related extracellular (ECM) components. Methods: Patient groups with different prognoses were created (OS: group A <16 months, group B > 16 months), and internationally recognized prognostic markers (IDH1 mutation and MGMT promoter hyper-methylation) were tested in the flash-frozen tumor samples. Furthermore, the mRNA levels of 46 invasion-related ECM molecules were measured. Results: Clinical data of the patients who have been operated on at the University of Debrecen Clinical Center Department of Neurosurgery and treated at the Department of Clinical Oncology showed no significant differences except for survival data (OS and PFS), and reoperation rate. All samples were IDH wild type. MGMT promoter hypermethylation rate showed significant differences (28.6% vs 68.8%). The expressional pattern of the invasion-related ECM molecules, i.e. the invasion spectrum also showed major differences, integrin ß2, cadherin-12, FLT4/VEGFR-3 and versican molecules having signficantly different mRNA levels. The accuracy of the inivasion spectrum was tested by statistical classifier, 83.3% of the samples was sorted correctly, PPV was 0.93. Conclusion: The difference found in the reoperation rate when comparing different prognostic groups aligns with literature data. MGMG promoter region methylation data in Hungarian samples has not been published yet, and further confirming current knowledge urges the implementation of MGMT promoter analysis in clinical practice. Studying the invasion spectrum provides extra information on tumors, as a prognostic marker it helps recognizing more aggressive tumors, and calls attention to the necessity of using anti-invasive agents in GBM therapies in the future.


Assuntos
Neoplasias Encefálicas/patologia , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Glioblastoma/fisiopatologia , Isocitrato Desidrogenase/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Biomarcadores Tumorais/metabolismo , Glioblastoma/metabolismo , Glioblastoma/cirurgia , Humanos , Prognóstico , RNA Mensageiro
12.
Nat Commun ; 11(1): 5270, 2020 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-33077732

RESUMO

Pancreatic cancer is often detected late, when curative therapies are no longer possible. Here, we present non-invasive detection of pancreatic ductal adenocarcinoma (PDAC) by 5-hydroxymethylcytosine (5hmC) changes in circulating cell free DNA from a PDAC cohort (n = 64) in comparison with a non-cancer cohort (n = 243). Differential hydroxymethylation is found in thousands of genes, most significantly in genes related to pancreas development or function (GATA4, GATA6, PROX1, ONECUT1, MEIS2), and cancer pathogenesis (YAP1, TEAD1, PROX1, IGF1). cfDNA hydroxymethylome in PDAC cohort is differentially enriched for genes that are commonly de-regulated in PDAC tumors upon activation of KRAS and inactivation of TP53. Regularized regression models built using 5hmC densities in genes perform with AUC of 0.92 (discovery dataset, n = 79) and 0.92-0.94 (two independent test sets, n = 228). Furthermore, tissue-derived 5hmC features can be used to classify PDAC cfDNA (AUC = 0.88). These findings suggest that 5hmC changes enable classification of PDAC even during early stage disease.


Assuntos
5-Metilcitosina/análogos & derivados , Ácidos Nucleicos Livres/metabolismo , Neoplasias Pancreáticas/genética , 5-Metilcitosina/metabolismo , Adulto , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Fator de Transcrição GATA4/genética , Fator de Transcrição GATA4/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
13.
Cancer Sci ; 111(12): 4371-4380, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32969571

RESUMO

Protein phosphatase 6 (PP6) is an essential serine/threonine protein phosphatase that acts as an important tumor suppressor. However, increased protein levels of PP6 have been observed in some cancer types, and they correlate with poor prognosis in glioblastoma. This raises a question about how PP6 protein levels are regulated in normal and transformed cells. In this study, we show that PP6 protein levels increase in response to pharmacologic and genetic inhibition of autophagy. PP6 associates with autophagic adaptor protein p62/SQSTM1 and is degraded in a p62-dependent manner. Accordingly, protein levels of PP6 and p62 fluctuate in concert under different physiological and pathophysiological conditions. Our data reveal that PP6 is regulated by p62-dependent autophagy and suggest that accumulation of PP6 protein in tumor tissues is caused at least partially by deficiency in autophagy.


Assuntos
Autofagia/fisiologia , Fosfoproteínas Fosfatases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Inibidores de Cisteína Proteinase/farmacologia , Inibidores Enzimáticos/farmacologia , Células HeLa , Humanos , Leupeptinas/farmacologia , Macrolídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteólise , Proteínas de Ligação a RNA/metabolismo , Proteína Sequestossoma-1/metabolismo
14.
Development ; 147(21)2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-32994166

RESUMO

The Hippo-YAP/TAZ pathway is an important regulator of tissue growth, but can also control cell fate or tissue morphogenesis. Here, we investigate the function of the Hippo pathway during the development of cartilage, which forms the majority of the skeleton. Previously, YAP was proposed to inhibit skeletal size by repressing chondrocyte proliferation and differentiation. We find that, in vitro, Yap/Taz double knockout impairs murine chondrocyte proliferation, whereas constitutively nuclear nls-YAP5SA accelerates proliferation, in line with the canonical role of this pathway in most tissues. However, in vivo, cartilage-specific knockout of Yap/Taz does not prevent chondrocyte proliferation, differentiation or skeletal growth, but rather results in various skeletal deformities including cleft palate. Cartilage-specific expression of nls-YAP5SA or knockout of Lats1/2 do not increase cartilage growth, but instead lead to catastrophic malformations resembling chondrodysplasia or achondrogenesis. Physiological YAP target genes in cartilage include Ctgf, Cyr61 and several matrix remodelling enzymes. Thus, YAP/TAZ activity controls chondrocyte proliferation in vitro, possibly reflecting a regenerative response, but is dispensable for chondrocyte proliferation in vivo, and instead functions to control cartilage morphogenesis via regulation of the extracellular matrix.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Osso e Ossos/embriologia , Osso e Ossos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Morfogênese , Proteínas Serina-Treonina Quinases/metabolismo , Transativadores/metabolismo , Animais , Osso e Ossos/anormalidades , Osso e Ossos/patologia , Cartilagem/patologia , Núcleo Celular/metabolismo , Proliferação de Células , Condrócitos/metabolismo , Condrócitos/patologia , Fissura Palatina/patologia , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Lâmina de Crescimento/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfogênese/genética , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo
15.
Adv Exp Med Biol ; 1268: 285-306, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32918224

RESUMO

Cutaneous malignancies including melanomas and keratinocyte carcinomas (KC) are the most common types of cancer, occurring at a rate of over one million per year in the United States. KC, which include both basal cell carcinomas and squamous cell carcinomas, are substantially more common than melanomas and form the subject of this chapter. Ultraviolet radiation (UVR), both UVB and UVA, as occurs with sunlight exposure is generally regarded as causal for these malignancies, but UVB is also required for vitamin D synthesis in the skin. Keratinocytes are the major cell in the epidermis. These cells not only produce vitamin D but contain the enzymatic machinery to metabolize vitamin D to its active metabolite, 1,25(OH)2D, and express the receptor for this metabolite, the vitamin D receptor (VDR). This allows the cell to respond to the 1,25(OH)2D that it produces. Based on our own data and that reported in the literature, we conclude that vitamin D signaling in the skin suppresses UVR-induced epidermal tumor formation. In this chapter we focus on four mechanisms by which vitamin D signaling suppresses tumor formation. They are inhibition of proliferation/stimulation of differentiation with discussion of the roles of hedgehog, Wnt/ß-catenin, and hyaluronan/CD44 pathways in mediating vitamin D regulation of proliferation/differentiation, regulation of the balance between oncogenic and tumor suppressor long noncoding RNAs, immune regulation, and promotion of DNA damage repair (DDR).


Assuntos
Receptores de Calcitriol/metabolismo , Pele/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Humanos , Queratinócitos/metabolismo , Pele/citologia , Neoplasias Cutâneas/metabolismo , Raios Ultravioleta/efeitos adversos , Vitamina D/metabolismo
16.
Nat Rev Endocrinol ; 16(11): 669-674, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32792644

RESUMO

Lipoedema is associated with widespread adipose tissue expansion, particularly in the proximal extremities. The mechanisms that drive the development of lipoedema are unclear. In this Perspective article, we propose a new model for the pathophysiology of lipoedema. We suggest that lipoedema is an oestrogen-dependent disorder of adipose tissue, which is triggered by a dysfunction of caveolin 1 (CAV1) and subsequent uncoupling of feedback mechanisms between CAV1, the matrix metalloproteinase MMP14 and oestrogen receptors. In addition, reduced CAV1 activity also leads to the activation of ERα and impaired regulation of the lymphatic system through the transcription factor prospero homeobox 1 (PROX1). The resulting upregulation of these factors could effectively explain the main known features of lipoedema, such as adipose hypertrophy, dysfunction of blood and lymphatic vessels, the overall oestrogen dependence and the associated sexual dimorphism, and the mechanical compliance of adipose tissue.


Assuntos
Lipedema/genética , Lipedema/metabolismo , Metaloproteinase 14 da Matriz/genética , Metaloproteinase 14 da Matriz/metabolismo , Tecido Adiposo/metabolismo , Animais , Caveolina 1/genética , Caveolina 1/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Obesidade/genética , Obesidade/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
17.
Mol Carcinog ; 59(10): 1199-1208, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32808708

RESUMO

Long noncoding RNAs (lncRNAs) can act as oncogene and tumor suppressor genes in many types of cancers including breast cancer (BC). Our previous study has indicated microRNA (miR)-125a-5p was downregulated and function as a tumor suppressor in BC. However, its upstream regulation mechanism is still unclear. In this study, we used bioinformatics algorithms, RNA pulldown assay, and dual-luciferase reports assay to predict and confirm lncRNA CERS6-AS1 interacted with miR-125a-5p. Then we found CERS6-AS1 was upregulated in BC tissues. Experimental results of tumor growth in nude mice show that CERS6-AS1 promotes tumor growth. Furthermore, CERS6-AS1 regulated BC susceptibility gene 1-associated protein 1 (BAP1) expression via sponging miR-125a-5p via Western blot analysis and quantitative polymerase chain reaction arrays. Finally, we showed that miR-125a-5p had opposing effects to those of CERS6-AS1 on BC cells, demonstrating that CERS6-AS1 may promote cell proliferation and inhibit cell apoptosis via sponging miR-125a-5p. Our results indicated CERS6-AS1 promote BC cell proliferation and inhibit cell apoptosis via sponging miR-125a-5p to upregulate BAP1 expression.


Assuntos
Neoplasias da Mama/patologia , Proliferação de Células , Proteínas de Membrana/antagonistas & inibidores , MicroRNAs/genética , Oligonucleotídeos Antissenso/genética , RNA Longo não Codificante/genética , Esfingosina N-Aciltransferase/antagonistas & inibidores , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Nus , Esfingosina N-Aciltransferase/genética , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Life Sci ; 259: 118277, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32800832

RESUMO

AIMS: Cervical cancer (CC) is one of the most common malignant tumours in the world and a serious threat to women's health. The dysregulation of protein degradation mediated by F-box proteins is involved in tumorigenesis, and F-box protein FBXO31 has been reported to play an important role in various human cancers. However, the role of FBXO31 in CC remains unclear. This study aimed to investigate the function and underlying regulatory mechanism of FBXO31 in CC. MAIN METHODS: In this study, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were used to measure target gene expression; the Cell Counting Kit-8, cell death ELISA, Transwell invasion assay, wound-healing assay and western blot were applied to assess cell viability, apoptosis, invasion, migration and epithelial-mesenchymal transition (EMT), respectively. KEY FINDINGS: FBXO31 was expressed at a low level in 37 pairs of CC tissues and three types of CC cell lines. Overexpression of FBXO31 inhibited cell viability, invasion, migration, EMT and induced apoptosis in SiHa cells. FBXO31 promoted p53 activity through suppression of murine double minute 2 (MDM2) expression. Overexpression of MDM2 ameliorated the inhibitory effect of FBXO31 on SiHa cells, while the MDM2/p53 axis-specific inhibitor Nutlin-3a facilitated this inhibitory effect. Further, we confirmed that FBXO31 inactivated MDM2/p53 axis dependence on the phospholipid inositol 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway. SIGNIFICANCE: Collectively, our results reveal that FBXO31 down-regulates CC progression by blocking the PI3K/AKT-mediated MDM2/p53 axis, suggesting that FBXO31 may serve as a promising therapeutic target for CC treatment.


Assuntos
Proteínas F-Box/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Neoplasias do Colo do Útero/metabolismo , Adulto , Apoptose/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Transição Epitelial-Mesenquimal , Proteínas F-Box/genética , Feminino , Humanos , Pessoa de Meia-Idade , Transdução de Sinais , Proteínas Supressoras de Tumor/genética , Neoplasias do Colo do Útero/patologia
19.
Nat Commun ; 11(1): 3883, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32753598

RESUMO

Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that the MGMT genomic rearrangements contribute to TMZ resistance both in vitro and in vivo. Lastly, we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Rearranjo Gênico , Glioma/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Temozolomida/farmacologia , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Animais , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Adutos de DNA/efeitos dos fármacos , Adutos de DNA/metabolismo , Metilação de DNA , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Regiões Promotoras Genéticas/genética , RNA-Seq , Temozolomida/uso terapêutico , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima , Sequenciamento Completo do Genoma , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
20.
Oncogene ; 39(37): 5995-6008, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32770142

RESUMO

Avoiding immune destruction is essential for tumorigenesis. Current research into the interaction between tumor and immunological niches complement tumor pathology beyond cancer genetics. Intrinsic host defense immunity is a specialized innate immunity component to restrict viral infection. However, whether intrinsic immunity participates in tumor pathology is unclear. Previously, we identified a zinc-finger antiviral protein ZAP that is commonly downregulated in a panel of clinical cancer specimens. However, whether ZAP has an impact on tumor development was unknown. Here we report ZAP as a genuine tumor suppressor. Pan-caner analysis with TCGA data from 712 patients and large-scale immunohistochemistry in tissue microarrays from 1552 patients reveal that ZAP is prevalently downregulated, and associated with poor survival in liver, colon, and bladder cancer patients. Ectopic over-expression of ZAP inhibits the malignant phenotypes of colorectal tumor by cell cycle arrest. Using RNA immunoprecipitation and RNA decay assays, we demonstrate that ZAP directly and specifically binds to and degrades the transcript of TRAILR4, which in turn represses TRAILR4 expression and inhibits the aggressiveness of colorectal cancer cells. Furthermore, our CRISPR-engineered mice models show that loss-of-function of ZAP synergizes with APC-deficiency to drive malignant colorectal cancer in vivo. Overall, we identify a previously unknown function of the antiviral factor ZAP in colorectal tumorigenesis, linking intrinsic immunity to tumor pathogenetics.


Assuntos
Neoplasias Colorretais/etiologia , Proteínas Supressoras de Tumor/genética , Dedos de Zinco/genética , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Mutação com Perda de Função , Camundongos , Fenótipo , Prognóstico , Ligação Proteica , Estabilidade de RNA , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Proteínas Repressoras/genética , Receptores Chamariz do Fator de Necrose Tumoral/genética , Proteínas Supressoras de Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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