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1.
Life Sci Alliance ; 7(6)2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38565287

RESUMO

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), pose significant risks of severe fibrosis, cirrhosis, and hepatocellular carcinoma. Despite their widespread prevalence, the molecular mechanisms underlying the development and progression of these common chronic hepatic conditions are not fully understood. Here, we conducted the most extensive meta-analysis of hepatic gene expression datasets from liver biopsy samples to date, integrating 10 RNA-sequencing and microarray datasets (1,058 samples). Using a random-effects meta-analysis model, we compared over 12,000 shared genes across datasets. We identified 685 genes differentially expressed in MASLD versus normal liver, 1,870 in MASH versus normal liver, and 3,284 in MASLD versus MASH. Integrating these results with genome-wide association studies and coexpression networks, we identified two functionally relevant, validated coexpression modules mainly driven by SMOC2, ITGBL1, LOXL1, MGP, SOD3, and TAT, HGD, SLC25A15, respectively, the latter not previously associated with MASLD and MASH. Our findings provide a comprehensive and robust analysis of hepatic gene expression alterations associated with MASLD and MASH and identify novel key drivers of MASLD progression.


Assuntos
Carcinoma Hepatocelular , Fígado Gorduroso , Neoplasias Hepáticas , Humanos , Estudo de Associação Genômica Ampla , Transcriptoma/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Integrina beta1
2.
Front Immunol ; 13: 1007647, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36311782

RESUMO

The immunomodulatory effects of HLA-G expression and its role in cancers, human liver infections and liver transplantation are well documented, but so far, there are only a few reports addressing autoimmune liver diseases, particularly autoimmune hepatitis (AIH). Method and materials: We analyzed the genetic and phenotypic characteristics of HLA-G in 205 type 1 AIH patients (AIH-1) and a population of 210 healthy controls from Sardinia (Italy). Results: Analysis of the HLA-G locus showed no substantial differences in allele frequencies between patients and the healthy control population. The HLA-G UTR-1 haplotype was the most prevalent in both AIH-1 patients and controls (40.24% and 34.29%). Strong linkage was found between the HLA-G UTR-1 haplotype and HLA-DRB1*03:01 in AIH-1 patients but not controls (D' = 0.92 vs D' = 0.50 respectively; P = 1.3x10-8). Soluble HLA-G (sHLA-G) levels were significantly lower in AIH-1 patients compared to controls [13.9 (11.6 - 17.4) U/mL vs 21.3 (16.5 - 27.8) U/mL; P = 0.011]. Twenty-four patients with mild or moderate inflammatory involvement, as assessed from liver biopsy, showed much higher sHLA-G levels compared to the 28 patients with severe liver inflammation [33.5 (23.6 - 44.8) U/mL vs 8.8 (6.1 - 14.5) U/mL; P = 0.003]. Finally, immunohistochemistry analysis of 52 liver biopsies from AIH-1 patients did not show expression of HLA-G molecules in the liver parenchyma. However, a percentage of 69.2% (36/52) revealed widespread expression of HLA-G both in the cytoplasm and the membrane of plasma cells labeled with anti-HLA-G monoclonal antibodies. Conclusion: This study highlights the positive immunomodulatory effect of HLA-G molecules on the clinical course of AIH-1 and how this improvement closely correlates with plasma levels of sHLA-G. However, our results open the debate on the ambiguous role of HLA-G molecules expressed by plasma cells, which are pathognomonic features of AIH-1.


Assuntos
Hepatite Autoimune , Humanos , Hepatite Autoimune/genética , Predisposição Genética para Doença , Cadeias HLA-DRB1/genética , Haplótipos , Antígenos HLA-G/genética
3.
Int J Mol Sci ; 23(16)2022 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-36012560

RESUMO

Choline deficiency causes hepatic fat accumulation, and is associated with a higher risk of nonalcoholic fatty liver disease (NAFLD) and more advanced NAFLD-related hepatic fibrosis. Reduced expression of hepatic phosphatidylethanolamine N-methyltransferase (PEMT), which catalyzes the production of phosphatidylcholine, causes steatosis, inflammation, and fibrosis in mice. In humans, common PEMT variants impair phosphatidylcholine synthesis, and are associated with NAFLD risk. We investigated hepatic PEMT expression in a large cohort of patients representing the spectrum of NAFLD, and examined the relationship between PEMT genetic variants and gene expression. Hepatic PEMT expression was reduced in NAFLD patients with inflammation and fibrosis (i.e., nonalcoholic steatohepatitis or NASH) compared to participants with normal liver histology (ß = −1.497; p = 0.005). PEMT levels also declined with increasing severity of fibrosis with cirrhosis < incomplete cirrhosis < bridging fibrosis (ß = −1.185; p = 0.011). Hepatic PEMT expression was reduced in postmenopausal women with NASH compared to those with normal liver histology (ß = −3.698; p = 0.030). We detected a suggestive association between rs7946 and hepatic fibrosis (p = 0.083). Although none of the tested variants were associated with hepatic PEMT expression, computational fine mapping analysis indicated that rs4646385 may impact PEMT levels in the liver. Hepatic PEMT expression decreases with increasing severity of NAFLD in obese individuals and postmenopausal women, and may contribute to disease pathogenesis in a subset of NASH patients.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Fosfatidiletanolamina N-Metiltransferase , Feminino , Fibrose , Humanos , Inflamação/patologia , Fígado/enzimologia , Cirrose Hepática/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fosfatidilcolinas/metabolismo , Fosfatidiletanolamina N-Metiltransferase/genética , Fosfatidiletanolamina N-Metiltransferase/metabolismo
4.
J Neuroinflammation ; 19(1): 193, 2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-35897073

RESUMO

BACKGROUND: Herbicides are environmental contaminants that have gained much attention due to the potential hazards they pose to human health. Glyphosate, the active ingredient in many commercial herbicides, is the most heavily applied herbicide worldwide. The recent rise in glyphosate application to corn and soy crops correlates positively with increased death rates due to Alzheimer's disease and other neurodegenerative disorders. Glyphosate has been shown to cross the blood-brain barrier in in vitro models, but has yet to be verified in vivo. Additionally, reports have shown that glyphosate exposure increases pro-inflammatory cytokines in blood plasma, particularly TNFα. METHODS: Here, we examined whether glyphosate infiltrates the brain and elevates TNFα levels in 4-month-old C57BL/6J mice. Mice received either 125, 250, or 500 mg/kg/day of glyphosate, or a vehicle via oral gavage for 14 days. Urine, plasma, and brain samples were collected on the final day of dosing for analysis via UPLC-MS and ELISAs. Primary cortical neurons were derived from amyloidogenic APP/PS1 pups to evaluate in vitro changes in Aß40-42 burden and cytotoxicity. RNA sequencing was performed on C57BL/6J brain samples to determine changes in the transcriptome. RESULTS: Our analysis revealed that glyphosate infiltrated the brain in a dose-dependent manner and upregulated TNFα in both plasma and brain tissue post-exposure. Notably, glyphosate measures correlated positively with TNFα levels. Glyphosate exposure in APP/PS1 primary cortical neurons increases levels of soluble Aß40-42 and cytotoxicity. RNAseq revealed over 200 differentially expressed genes in a dose-dependent manner and cell-type-specific deconvolution analysis showed enrichment of key biological processes in oligodendrocytes including myelination, axon ensheathment, glial cell development, and oligodendrocyte development. CONCLUSIONS: Collectively, these results show for the first time that glyphosate infiltrates the brain, elevates both the expression of TNFα and soluble Aß, and disrupts the transcriptome in a dose-dependent manner, suggesting that exposure to this herbicide may have detrimental outcomes regarding the health of the general population.


Assuntos
Doença de Alzheimer , Glicina , Herbicidas , Fator de Necrose Tumoral alfa , Animais , Encéfalo , Cromatografia Líquida , Citocinas/genética , Glicina/análogos & derivados , Glicina/toxicidade , Herbicidas/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Espectrometria de Massas em Tandem , Glifosato
5.
JCI Insight ; 6(23)2021 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-34673573

RESUMO

Medulloblastoma (MB), one of the most malignant brain tumors of childhood, comprises distinct molecular subgroups, with p53 mutant sonic hedgehog-activated (SHH-activated) MB patients having a very severe outcome that is associated with unfavorable histological large cell/anaplastic (LC/A) features. To identify the molecular underpinnings of this phenotype, we analyzed a large cohort of MB developing in p53-deficient Ptch+/- SHH mice that, unexpectedly, showed LC/A traits that correlated with mTORC1 hyperactivation. Mechanistically, mTORC1 hyperactivation was mediated by a decrease in the p53-dependent expression of mTORC1 negative regulator Tsc2. Ectopic mTORC1 activation in mouse MB cancer stem cells (CSCs) promoted the in vivo acquisition of LC/A features and increased malignancy; accordingly, mTORC1 inhibition in p53-mutant Ptch+/- SHH MB and CSC-derived MB resulted in reduced tumor burden and aggressiveness. Most remarkably, mTORC1 hyperactivation was detected only in p53-mutant SHH MB patient samples, and treatment with rapamycin of a human preclinical model phenocopying this subgroup decreased tumor growth and malignancy. Thus, mTORC1 may act as a specific druggable target for this subset of SHH MB, resulting in the implementation of a stringent risk stratification and in the potentially rapid translation of this precision medicine approach into the clinical setting.


Assuntos
Proteínas Hedgehog/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Meduloblastoma/genética , Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Meduloblastoma/patologia , Camundongos
6.
Acta Neuropathol ; 142(2): 279-294, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33978814

RESUMO

Evidence indicates that tau hyper-phosphorylation and subsequent neurofibrillary tangle formation contribute to the extensive neuronal death in Alzheimer's disease (AD) and related tauopathies. Recent work has identified that increased tau acetylation can promote tau phosphorylation. Tau acetylation occurs at lysine 280 resulting from increased expression of the lysine acetyltransferase p300. The exact upstream mechanisms mediating p300 expression remain elusive. Additional work highlights the role of the epigenome in tau pathogenesis, suggesting that dysregulation of epigenetic proteins may contribute to acetylation and hyper-phosphorylation of tau. Here, we identify and focus on the histone-binding subunit of the Nucleosome Remodeling and Deacetylase (NuRD) complex: Retinoblastoma-Binding Protein 7 (Rbbp7). Rbbp7 chaperones chromatin remodeling proteins to their nuclear histone substrates, including histone acetylases and deacetylases. Notably, Rbbp7 binds to p300, suggesting that it may play a role in modulating tau acetylation. We interrogated Rbbp7 in post-mortem brain tissue, cell lines and mouse models of AD. We found reduced Rbbp7 mRNA expression in AD cases, a significant negative correlation with CERAD (neuritic plaque density) and Braak Staging (pathogenic tau inclusions) and a significant positive correlation with post-mortem brain weight. We also found a neuron-specific downregulation of Rbbp7 mRNA in AD patients. Rbbp7 protein levels were significantly decreased in 3xTg-AD and PS19 mice compared to NonTg, but no decreases were found in APP/PS1 mice that lack tau pathology. In vitro, Rbbp7 overexpression rescued TauP301L-induced cytotoxicity in immortalized hippocampal cells and primary cortical neurons. In vivo, hippocampal Rbbp7 overexpression rescued neuronal death in the CA1 of PS19 mice. Mechanistically, we found that increased Rbbp7 reduced p300 levels, tau acetylation at lysine 280 and tau phosphorylation at AT8 and AT100 sites. Collectively, these data identify a novel role of Rbbp7, protecting against tau-related pathologies, and highlight its potential as a therapeutic target in AD and related tauopathies.


Assuntos
Acetilação , Neurônios/patologia , Proteína 7 de Ligação ao Retinoblastoma/metabolismo , Tauopatias/patologia , Proteínas tau/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Camundongos , Neurônios/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Proteína 7 de Ligação ao Retinoblastoma/genética
7.
Biol Open ; 10(1)2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-32878879

RESUMO

The organic anion transporter Adenosine triphosphate binding cassette subfamily C member 1 (ABCC1), also known as MRP1, has been demonstrated in murine models of Alzheimer's disease (AD) to export amyloid beta (Abeta) from the endothelial cells of the blood-brain barrier to the periphery, and that pharmaceutical activation of ABCC1 can reduce amyloid plaque deposition in the brain. Here, we show that ABCC1 is not only capable of exporting Abeta from the cytoplasm of human cells, but also that its overexpression significantly reduces Abeta production and increases the ratio of alpha- versus beta-secretase mediated cleavage of the amyloid precursor protein (APP), likely via indirect modulation of alpha-, beta- and gamma-secretase activity.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Expressão Gênica , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Linhagem Celular , Ativação Enzimática , Perfilação da Expressão Gênica , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteólise , Transcriptoma
8.
Front Immunol ; 11: 1820, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013832

RESUMO

Galectin-3 (Gal-3) is an extracellular matrix glycan-binding protein with several immunosuppressive and pro-tumor functions. The role of Galectin-3 in cancer stem-like cells (CSCs) is poorly investigated. Here, we show that prostate CSCs also colonizing prostate-draining lymph nodes of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice overexpress Gal-3. Gal-3 contributes to prostate CSC-mediated immune suppression because either Gal-3 silencing in CSCs, or co-culture of CSCs and T cells in the presence of the Gal-3 inhibitor N-Acetyl-D-lactosamine rescued T cell proliferation. N-Acetyl-D-lactosamine also rescued the proliferation of T cells in prostate-draining lymph nodes of TRAMP mice affected by prostate intraepithelial neoplasia. Additionally, Gal-3 impacted prostate CSC tumorigenic and metastatic potential in vivo, as Gal-3 silencing in prostate CSCs reduced both primary tumor growth and secondary invasion. Gal-3 was also found expressed in more differentiated prostate cancer cells, but with different intracellular distribution as compared to CSCs, which suggests different functions of Gal-3 in the two cell populations. In fact, the prevalent nuclear and cytoplasmic distribution of Gal-3 in prostate CSCs made them less susceptible to apoptosis, when compared to more differentiated prostate cancer cells, in which Gal-3 was predominantly intra-cytoplasmic. Finally, we found Gal-3 expressed in human and mouse prostate intraepithelial neoplasia lesions and in metastatic lymph nodes. All together, these findings identify Gal-3 as a key molecule and a potential therapeutic target already in the early phases of prostate cancer progression and metastasis.


Assuntos
Adenocarcinoma/metabolismo , Galectina 3/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasia Prostática Intraepitelial/metabolismo , Neoplasias da Próstata/metabolismo , Evasão Tumoral , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma/secundário , Animais , Proteínas Sanguíneas , Linhagem Celular Tumoral , Proliferação de Células , Técnicas de Cocultura , Galectina 3/genética , Galectinas , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células-Tronco Neoplásicas/imunologia , Neoplasia Prostática Intraepitelial/genética , Neoplasia Prostática Intraepitelial/imunologia , Neoplasia Prostática Intraepitelial/secundário , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , Transdução de Sinais , Microambiente Tumoral
9.
Genes (Basel) ; 11(6)2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32486318

RESUMO

Canine idiopathic pulmonary fibrosis (CIPF) is a chronic fibrotic lung disease that is observed at a higher frequency in the West Highland White Terrier dog breed (WHWT) and may have molecular pathological overlap with human lung fibrotic disease. We conducted a genome-wide association study (GWAS) in the WHWT using whole genome sequencing (WGS) to discover genetic variants associated with CIPF. Saliva-derived DNA samples were sequenced using the Riptide DNA library prep kit. After quality controls, 28 affected, 44 unaffected, and 1,843,695 informative single nucleotide polymorphisms (SNPs) were included in the GWAS. Data were analyzed both at the single SNP and gene levels using the GEMMA and GATES methods, respectively. We detected significant signals at the gene level in both the cleavage and polyadenylation specific factor 7 (CPSF7) and succinate dehydrogenase complex assembly factor 2 (SDHAF2) genes (adjusted p = 0.016 and 0.024, respectively), two overlapping genes located on chromosome 18. The top SNP for both genes was rs22669389; however, it did not reach genome-wide significance in the GWAS (adjusted p = 0.078). Our studies provide, for the first time, candidate loci for CIPF in the WHWT. CPSF7 was recently associated with lung adenocarcinoma, further highlighting the potential relevance of our results because IPF and lung cancer share several pathological mechanisms.


Assuntos
Doenças do Cão/genética , Estudos de Associação Genética , Fibrose Pulmonar Idiopática/genética , Proteínas com Motivo de Reconhecimento de RNA/genética , Animais , Doenças do Cão/patologia , Cães , Predisposição Genética para Doença , Humanos , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/veterinária , Proteínas Mitocondriais/genética , Poliadenilação/genética , Polimorfismo de Nucleotídeo Único/genética
10.
Am J Hum Genet ; 105(3): 509-525, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31422817

RESUMO

The human RNA helicase DDX6 is an essential component of membrane-less organelles called processing bodies (PBs). PBs are involved in mRNA metabolic processes including translational repression via coordinated storage of mRNAs. Previous studies in human cell lines have implicated altered DDX6 in molecular and cellular dysfunction, but clinical consequences and pathogenesis in humans have yet to be described. Here, we report the identification of five rare de novo missense variants in DDX6 in probands presenting with intellectual disability, developmental delay, and similar dysmorphic features including telecanthus, epicanthus, arched eyebrows, and low-set ears. All five missense variants (p.His372Arg, p.Arg373Gln, p.Cys390Arg, p.Thr391Ile, and p.Thr391Pro) are located in two conserved motifs of the RecA-2 domain of DDX6 involved in RNA binding, helicase activity, and protein-partner binding. We use functional studies to demonstrate that the first variants identified (p.Arg373Gln and p.Cys390Arg) cause significant defects in PB assembly in primary fibroblast and model human cell lines. These variants' interactions with several protein partners were also disrupted in immunoprecipitation assays. Further investigation via complementation assays included the additional variants p.Thr391Ile and p.Thr391Pro, both of which, similarly to p.Arg373Gln and p.Cys390Arg, demonstrated significant defects in P-body assembly. Complementing these molecular findings, modeling of the variants on solved protein structures showed distinct spatial clustering near known protein binding regions. Collectively, our clinical and molecular data describe a neurodevelopmental syndrome associated with pathogenic missense variants in DDX6. Additionally, we suggest DDX6 join the DExD/H-box genes DDX3X and DHX30 in an emerging class of neurodevelopmental disorders involving RNA helicases.


Assuntos
RNA Helicases DEAD-box/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas/genética , RNA/genética , Humanos
11.
PLoS One ; 14(7): e0219764, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31299062

RESUMO

Factors governing the development of liver fibrosis in nonalcoholic steatohepatitis (NASH) are only partially understood. We recently identified adipocyte enhancer binding protein 1 (AEBP1) as a member of a core set of dysregulated fibrosis-specific genes in human NASH. Here we sought to investigate the relationship between AEBP1 and hepatic fibrosis. We confirmed that hepatic AEBP1 expression is elevated in fibrosis compared to lobular inflammation, steatosis, and normal liver, and increases with worsening fibrosis in NASH patients. AEBP1 expression was upregulated 5.8-fold in activated hepatic stellate cells and downregulated during chemical and contact induction of biological quiescence. In LX-2 and HepG2 cells treated with high glucose (25 mM), AEBP1 expression increased over 7-fold compared to normal glucose conditions. In response to treatment with either fructose or palmitate, AEBP1 expression in primary human hepatocytes increased 2.4-fold or 9.6-fold, but was upregulated 55.8-fold in the presence of fructose and palmitate together. AEBP1 knockdown resulted in decreased expression of nine genes previously identified to be part of a predicted AEBP1-associated NASH co-regulatory network and confirmed to be upregulated in fibrotic tissue. We identified binding sites for two miRNAs known to be downregulated in NASH fibrosis, miR-372-3p and miR-373-3p in the AEBP1 3' untranslated region. Both miRNAs functionally interacted with AEBP1 to regulate its expression. These findings indicate a novel AEBP1-mediated pathway in the pathogenesis of hepatic fibrosis in NASH.


Assuntos
Carboxipeptidases/metabolismo , Glucose/metabolismo , Cirrose Hepática/metabolismo , MicroRNAs/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Palmitatos/metabolismo , Proteínas Repressoras/metabolismo , Regiões 3' não Traduzidas , Biópsia , Carboxipeptidases/genética , Diferenciação Celular , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Células Hep G2 , Células Estreladas do Fígado/metabolismo , Hepatócitos/metabolismo , Humanos , Fígado/patologia , RNA Interferente Pequeno/metabolismo , Proteínas Repressoras/genética
12.
Cell Death Differ ; 26(9): 1813-1831, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30538287

RESUMO

Achaete-scute homolog 1 gene (ASCL1) is a gene classifier for the proneural (PN) transcriptional subgroup of glioblastoma (GBM) that has a relevant role in the neuronal-like differentiation of GBM cancer stem cells (CSCs) through the activation of a PN gene signature. Besides prototypical ASCL1 PN target genes, the molecular effectors mediating ASCL1 function in regulating GBM differentiation and, most relevantly, subgroup specification are currently unknown. Here we report that ASCL1 not only promotes the acquisition of a PN phenotype in CSCs by inducing a glial-to-neuronal lineage switch but also concomitantly represses mesenchymal (MES) features by directly downregulating the expression of N-Myc downstream-regulated gene 1 (NDRG1), which we propose as a novel gene classifier of MES GBMs. Increasing the expression of ASCL1 in PN CSCs results in suppression of self-renewal, promotion of differentiation and, most significantly, decrease in tumorigenesis, which is also reproduced by NDRG1 silencing. Conversely, both abrogation of ASCL1 expression in PN CSCs and enforcement of NDRG1 expression in either PN or MES CSCs induce proneural-to-mesenchymal transition (PMT) and enhanced mesenchymal features. Surprisingly, ASCL1 overexpression in MES CSCs increases malignant features and gives rise to a neuroendocrine-like secretory phenotype. Altogether, our results propose that the fine interplay between ASCL1 and its target NDRG1 might serve as potential subgroup-specific targetable vulnerability in GBM; enhancing ASCL1 expression in PN GBMs might reduce tumorigenesis, whereas repressing NDRG1 expression might be actionable to hamper the malignancy of GBM belonging to the MES subgroup.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinogênese/genética , Proteínas de Ciclo Celular/genética , Glioblastoma/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Autorrenovação Celular/genética , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/patologia , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neurônios/metabolismo , Neurônios/patologia , Transdução de Sinais
13.
Stem Cells ; 33(5): 1377-89, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25639612

RESUMO

microRNAs (miRNAs) are short noncoding RNAs, which regulate gene expression post-transcriptionally and play crucial roles in relevant biological and pathological processes. Here, we investigated the putative role of miRNAs in modulating the tumor-initiating potential of mouse medulloblastoma (MB)-derived cancer stem cells (CSCs). We first subjected bona fide highly tumorigenic (HT) CSCs as well as lowly tumorigenic MB CSCs and normal neural stem cells to miRNA profiling, which identified a HT CSC-specific miRNA signature. Next, by cross-checking CSC mRNA/miRNA profiles, we pinpointed miR-135a as a potential tumor suppressor gene, which was strongly downregulated in HT CSCs as well as in the highly malignant experimental tumors derived from them. Remarkably, enforced expression of miR-135a in HT CSCs strongly inhibited tumorigenesis by repressing the miR-135a direct target gene Arhgef6. Considering the upregulation of Arhgef6 in human MBs and its involvement in mediating experimental medulloblastomagenesis, its efficient suppression by miR-135a might make available an effective therapeutic strategy to selectively impair the tumorigenic potential of MB CSCs. Stem Cells 2015;33:1377-1389.


Assuntos
Carcinogênese/patologia , Meduloblastoma/patologia , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Animais , Carcinogênese/genética , Agregação Celular , Transformação Celular Neoplásica/genética , Regulação para Baixo , Perfilação da Expressão Gênica , Meduloblastoma/genética , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Células-Tronco Neoplásicas/patologia , Células-Tronco Neurais/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Proteína Supressora de Tumor p53/metabolismo
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