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1.
Adv Exp Med Biol ; 1255: 99-108, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949393

RESUMO

Lung carcinoma is the most frequently diagnosed malignant neoplasms and mainly consists of small-cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC). Large number of lung carcinoma patients have poor outcomes due to the late diagnosis and the limited therapeutic options. Previous attempts have proved that the evolution of lung carcinoma is a multistep molecular aberration which various genetic or epigenetic alterations may be take part in. Among these molecular aberrations, the inactivation of tumor suppressor gene has been widely observed in all types of carcinoma including lung carcinoma. As a vital inactivated mechanism, DNA methylation of tumor suppressor gene is frequently found in lung cancer. To gain exhaustive comprehension of the carcinogenesis of lung carcinoma, we summarize our current knowledge on DNA methylation of RASSF1 (RAS-Association Domain Family 1) and its clinical significance in lung carcinoma.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Metilação de DNA , Neoplasias Pulmonares/genética , Proteínas Supressoras de Tumor/genética , Genes Supressores de Tumor , Humanos
2.
Medicine (Baltimore) ; 99(37): e22092, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925750

RESUMO

Pancreatic cancer (PaCa) is one of the most fatal cancers in the world. Although great efforts have made to explore the mechanisms of PaCa oncogenesis, the prognosis of PaCa patients is still unsatisfactory. Thus, it is imperative to further understand the potential carcinogenesis of PaCa and reliable prognostic models.The gene expression profile and clinical information of GSE21501 were downloaded from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was applied to explore the potent genes associated with the overall survival (OS) events of PaCa patients. Cox regression model was applied to selecting prognostic genes and establish prognostic model. The prognostic values of six-gene signature were validated in TCGA-PAAD cohort.According to the WGCNA analysis, a total of 19 modules were identified and 115 hub genes in the mostly associated module were reserved for next analysis. According to the univariate and multivariate Cox regression analysis, we established a six-gene signature (FTSJ3, STAT1, STX2, CDX2, RASSF4, MACF1) which could effectively evaluate the overall survival (OS) of PaCa patients. In validated patients' cohorts, the six-gene signature exhibited excellent prognostic value in TCGA-PAAD cohort as well.We developed a six-gene signature to exactly predict OS of PaCa patients and provide a novel personalized strategy for evaluating prognosis. The findings may be contributed to medical customization and therapeutic decision in clinical practice.


Assuntos
Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Fator de Transcrição CDX2/genética , Perfilação da Expressão Gênica , Humanos , Metiltransferases/genética , Proteínas dos Microfilamentos/genética , Modelos Estatísticos , Neoplasias Pancreáticas/patologia , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Fator de Transcrição STAT1/genética , Sintaxina 1/genética , Proteínas Supressoras de Tumor/genética
3.
Am J Hum Genet ; 107(3): 473-486, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32781046

RESUMO

Africa contains more human genetic variation than any other continent, but the majority of the population-scale analyses of the African peoples have focused on just two of the four major linguistic groups, the Niger-Congo and Afro-Asiatic, leaving the Nilo-Saharan and Khoisan populations under-represented. In order to assess genetic variation and signatures of selection within a Nilo-Saharan population and between the Nilo-Saharan and Niger-Congo and Afro-Asiatic, we sequenced 50 genomes from the Nilo-Saharan Lugbara population of North-West Uganda and 250 genomes from 6 previously unsequenced Niger-Congo populations. We compared these data to data from a further 16 Eurasian and African populations including the Gumuz, another putative Nilo-Saharan population from Ethiopia. Of the 21 million variants identified in the Nilo-Saharan population, 3.57 million (17%) were not represented in dbSNP and included predicted non-synonymous mutations with possible phenotypic effects. We found greater genetic differentiation between the Nilo-Saharan Lugbara and Gumuz populations than between any two Afro-Asiatic or Niger-Congo populations. F3 tests showed that Gumuz contributed a genetic component to most Niger-Congo B populations whereas Lugabara did not. We scanned the genomes of the Lugbara for evidence of selective sweeps. We found selective sweeps at four loci (SLC24A5, SNX13, TYRP1, and UVRAG) associated with skin pigmentation, three of which already have been reported to be under selection. These selective sweeps point toward adaptations to the intense UV radiation of the Sahel.


Assuntos
Adaptação Fisiológica/genética , Variação Genética/genética , Seleção Genética/genética , Pigmentação da Pele/genética , Grupo com Ancestrais do Continente Africano/genética , Antiporters/genética , Gerenciamento de Dados , Etiópia/epidemiologia , Feminino , Genética Populacional , Genoma Humano/genética , Haplótipos/genética , Humanos , Masculino , Glicoproteínas de Membrana/genética , Oxirredutases/genética , Polimorfismo de Nucleotídeo Único/genética , Nexinas de Classificação/genética , Proteínas Supressoras de Tumor/genética , Uganda/epidemiologia
4.
PLoS One ; 15(8): e0237248, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790723

RESUMO

Despite enzalutamide's efficacy in delaying the progression of metastatic castration-resistant prostate cancer (CRPC), resistance to this anti-androgen inevitably occurs. Several studies have revealed that the signal transducer and activator of transcription (STAT) 5 plays a role in tumour progression and development of drug resistance such as enzalutamide. Data mining revealed heterogeneous expression of STAT5 in enzalutamide-treated mCRPC patients and enzalutamide-resistant prostate cancer (PCa). Isobologram analysis revealed that the STAT5 inhibitor pimozide combined with enzalutamide has? additive and synergistic inhibitory effects on cell viability in the used models. Functional analysis with siRNA-mediated STAT5 knockdown yielded divergent results. The LNCaP-derived cell line MR49F could be resensitised to enzalutamide by siRNA-mediated STAT5b-knock-down. In contrast, neither STAT5a nor STAT5b knockdown resensitised enzalutamide-resistant LAPC4-EnzaR cells to enzalutamide. In conclusion, our results indicate that STAT5 may be a possible target in a subgroup of enzalutamide-resistant PCa. However, based on the data presented here, a general role of STAT5 in enzalutamide-resistance and its potential as a therapeutic target could not be shown.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feniltioidantoína/análogos & derivados , Neoplasias da Próstata/tratamento farmacológico , Fator de Transcrição STAT5/genética , Proteínas Supressoras de Tumor/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Feniltioidantoína/farmacologia , Neoplasias da Próstata/genética
5.
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
6.
Medicine (Baltimore) ; 99(30): e21163, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791689

RESUMO

Autophagy, a major cause of cancer-related death, is correlated with the pathogenesis of various diseases including cancers. Our study aimed to develop an autophagy-related model for predicting prognosis of patients with laryngeal cancer.We analyzed the correlation between expression profiles of autophagy-related genes (ARGs) and clinical outcomes in 111 laryngeal cancer patients from The Cancer Genome Atlas (TCGA). Afterward, gene functional enrichment analyses of gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to find the major biological attributes. Univariate Cox regression analyses and multivariate Cox regression analyses were performed to screen ARGs whose expression profiles were significantly associated with laryngeal cancer patients overall survival (OS). Furthermore, to provide the doctors and patients with a quantitative method to perform an individualized survival prediction, we constructed a prognostic nomogram.Thirty eight differentially expressed ARGs were screened out in laryngeal cancer patients through the TCGA database. Related functional enrichments may act as tumor-suppressive roles in the tumorigenesis of laryngeal cancer. Subsequently, 4 key prognostic ARGs (IKBKB, ST13, TSC2, and MAP2K7) were identified from all ARGs by the Cox regression model, which significantly correlated with OS in laryngeal cancer. Furthermore, the risk score was constructed, which significantly divided laryngeal cancer patients into high- and low-risk groups. Integrated with clinical characteristics, gender, N and the risk score are very likely associated with patients OS. A prognostic nomogram of ARGs was constructed using the Cox regression model.Our study could provide a valuable prognostic model for predicting the prognosis of laryngeal cancer patients and a new understanding of autophagy in laryngeal cancer.


Assuntos
Autofagia/genética , Neoplasias Laríngeas/genética , Nomogramas , Fatores Etários , Proteínas de Transporte/genética , Perfilação da Expressão Gênica , Humanos , Quinase I-kappa B/genética , Neoplasias Laríngeas/patologia , MAP Quinase Quinase 7/genética , Modelos Biológicos , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores Sexuais , Taxa de Sobrevida , Transcriptoma , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética
7.
Ann Hematol ; 99(10): 2417-2427, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32862286

RESUMO

For most acute myeloid leukemia (AML) patients, an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of sustained remissions and long-term survival. At diagnosis, high expression of the AML-associated genes BAALC (brain and acute leukemia, cytoplasmic) and MN1 (meningioma-1) were repeatedly linked to inferior outcomes in patients consolidated with chemotherapy while data for patients receiving HSCT remain limited. Using clinically applicable digital droplet PCR assays, we analyzed the diagnostic BAALC/ABL1 and MN1/ABL1 copy numbers in 302 AML patients. High BAALC/ABL1 and MN1/ABL1 copy numbers associated with common adverse prognostic factors at diagnosis. However, while high diagnostic copy numbers of both genes associated with shorter event free survival (EFS) and overall survival (OS) in patients receiving chemotherapy, there was no prognostic impact in patients undergoing HSCT. Our data suggests that the adverse prognostic impact of high BAALC and MN1 expression are mitigated by allogeneic HSCT. But preHSCT BAALC/ABL1 and MN1/ABL1 assessed in remission prior to HSCT remained prognosticators for EFS and OS independent of the diagnostic expression status. Whether allogeneic HSCT may improve survival for AML patients with high diagnostic BAALC or MN1 expression should be investigated prospectively and may improve informed decisions towards individualized consolidation options in AML.


Assuntos
Medula Óssea/patologia , Leucemia Mieloide Aguda/terapia , Proteínas de Neoplasias/genética , Transplante de Células-Tronco de Sangue Periférico , Transativadores/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/química , Terapia Combinada , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Reação em Cadeia da Polimerase/métodos , Prognóstico , Proteínas Proto-Oncogênicas c-abl/genética , Transativadores/biossíntese , Resultado do Tratamento , Proteínas Supressoras de Tumor/biossíntese , Adulto Jovem
8.
Nat Commun ; 11(1): 3615, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32680986

RESUMO

Failure to preserve the integrity of the genome is a hallmark of cancer. Recent studies have revealed that loss of the capacity to repair DNA breaks via homologous recombination (HR) results in a mutational profile termed BRCAness. The enzymatic activity that repairs HR substrates in BRCA-deficient conditions to produce this profile is currently unknown. We here show that the mutational landscape of BRCA1 deficiency in C. elegans closely resembles that of BRCA1-deficient tumours. We identify polymerase theta-mediated end-joining (TMEJ) to be responsible: knocking out polq-1 suppresses the accumulation of deletions and tandem duplications in brc-1 and brd-1 animals. We find no additional back-up repair in HR and TMEJ compromised animals; non-homologous end-joining does not affect BRCAness. The notion that TMEJ acts as an alternative to HR, promoting the genome alteration of HR-deficient cells, supports the idea that polymerase theta is a promising therapeutic target for HR-deficient tumours.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , Reparo do DNA por Junção de Extremidades , DNA Polimerase Dirigida por DNA/metabolismo , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Animais , Animais Geneticamente Modificados , Análise Mutacional de DNA , DNA Polimerase Dirigida por DNA/genética , Técnicas de Inativação de Genes , Mutação
9.
Medicine (Baltimore) ; 99(27): e20995, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629717

RESUMO

RATIONAL: Intestinal lymphangiectasia (IL) is a rare disease characterized by dilatation and rupture of intestinal lymphatic channels leading to protein-losing enteropathy. IL is classified as primary and secondary types. PATIENT CONCERNS: A 3-month-old girl born at term from vaginal delivery with an APGAR score of 10/10 and birth weight of 4.310 g (>97° percentile) was admitted to our hospital because of increasing abdominal tenderness and diarrhea. At first examination, she presented an abdominal circumference of 60 cm, edema of the lower extremities and vulva, and facial dysmorphisms (hypertelorism, flat nasal bridge, flat mid-face). DIAGNOSIS: Once admitted, ultrasonography showed a large amount of ascites, while blood laboratory investigations revealed severe hypoproteinemia, hypoalbuminemia and hypogammaglobulinemia. Lymphoscintigraphy with 99m-Tc-nanocolloid demonstrated abnormal leakage of the tracer in the abdomen as evidence of IL. To detect a possible secondary, exams were performed and demonstrated positive antibody titres for CMV-IgM and IgG in blood and CMV-DNA positivity in blood, urine, saliva, maternal milk, and gastric and duodenal biopsies. Genetic investigations identified the genomic variant c.472C>T of the CCBE1 gene, coding for a protein variant (p.Arg158Cys), in homozygosity. INTERVENTIONS: Total parenteral nutrition was started and continued for a total of 18 days, then gradually bridged by enteral nutrition with a special formula. In addition, antiviral therapy for CMV infection was added first with intravenous ganciclovir for 14 days, resulting in the disappearance of blood viral load after 7 days of therapy and then with valganciclovir per os for another 30 days. OUTCOMES: The clinical course of the child gradually improved. A few days after starting treatments, lower extremities and vulvar edema disappeared, and abdominal circumference gradually decreased to a stable value of 38 cm, without any ultrasonographic signs of ascites left. Moreover, serum albumin and IgG rose to normal values after 3 months (4.3 g/dL and 501 mg/dL, respectively). LESSONS: This case suggests that in presence of IL both primary and secondary causes should be evaluated. On the other hand, genetic diagnosis is crucial not only for diagnosis but also for prognosis in HS. Life expectancy and quality could deeply vary among different gene mutations and protein variants of the same gene. Further studies and case reports are needed to better understand the clinical meaning of these genetic results and the role of CMV as trigger of IL.


Assuntos
Anormalidades Craniofaciais/genética , Linfangiectasia Intestinal/genética , Linfedema/genética , Proteínas de Ligação ao Cálcio/genética , Anormalidades Craniofaciais/diagnóstico , Feminino , Humanos , Lactente , Linfangiectasia Intestinal/diagnóstico , Linfedema/diagnóstico , Mutação , Proteínas Supressoras de Tumor/genética
10.
PLoS Pathog ; 16(6): e1008624, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32555725

RESUMO

Human papillomaviruses (HPV) are a major cause of malignancy worldwide. They are the aetiological agents of almost all cervical cancers as well as a sub-set of other anogenital and head and neck cancers. Hijacking of host cellular pathways is essential for virus pathogenesis; however, a major challenge remains to identify key host targets and to define their contribution to HPV-driven malignancy. The Hippo pathway regulates epithelial homeostasis by down-regulating the function of the transcription factor YAP. Increased YAP expression has been observed in cervical cancer but the mechanisms driving this increase remain unclear. We found significant down-regulation of the master Hippo regulatory kinase STK4 (also termed MST1) in cervical disease samples and cervical cancer cell lines compared with healthy controls. Re-introduction of STK4 inhibited the proliferation of HPV positive cervical cells and this corresponded with decreased YAP nuclear localization and decreased YAP-dependent gene expression. The HPV E6 and E7 oncoproteins maintained low STK4 expression in cervical cancer cells by upregulating the oncomiR miR-18a, which directly targeted the STK4 mRNA 3'UTR. Interestingly, miR-18a knockdown increased STK4 expression and activated the Hippo pathway, significantly reducing cervical cancer cell proliferation. Our results identify STK4 as a key cervical cancer tumour suppressor, which is targeted via miR-18a in HPV positive tumours. Our study indicates that activation of the Hippo pathway may offer a therapeutically beneficial option for cervical cancer treatment.


Assuntos
Transformação Celular Viral , MicroRNAs/metabolismo , Papillomaviridae/metabolismo , Infecções por Papillomavirus/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , RNA Neoplásico/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo , Neoplasias do Colo do Útero/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Papillomaviridae/genética , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Proteínas Serina-Treonina Quinases/genética , RNA Neoplásico/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia
11.
Life Sci ; 256: 117955, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32534038

RESUMO

AIMS: Cancer associated fibroblasts (CAFs) play a crucial role in lung tumor development, but the underlying mechanism is still not fully understood. MAIN METHODS: SCRIB expression in the CAFs of human lung cancer tissues was examined by immunohistochemistry (IHC). A coculture of mouse Lewis lung cancer cells (LLC) and fibroblasts was used to investigate SCRIB expression in cocultured fibroblasts. Proliferation, scratch wound, and transwell assays were used to examine the proliferation, migration and invasion ability of SCRIB knockdown fibroblasts and their effects on LLC. A 3D-coculture system and co-injection xenograft model were used to examine LLC invasion. RNA sequencing and transwell experiments were used to explore the molecules that may participate in LLC invasion. KEY FINDINGS: Herein, we found that the low expression of SCRIB in CAFs is correlated with advanced tumor stages and poor survival for human lung squamous cell carcinoma. SCRIB expression in fibroblasts is drastically downregulated by LLC cells. SCRIB knockdown fibroblasts not only enhance invasion but also facilitate LLC invasion in a 3D-coculture system and in an in vivo subcutaneous transplantation model. The upregulation of asporin in SCRIB knockdown fibroblasts is involved in LLC invasion in vitro. SIGNIFICANCE: Collectively, the results indicate that fibroblasts with low SCRIB expression promote lung cancer cell invasion, which suggests that the downregulated expression of SCRIB may represent one of the important characteristics of tumor-promoting CAFs in lung squamous cell cancer.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas de Membrana/genética , Proteínas Supressoras de Tumor/genética , Animais , Fibroblastos Associados a Câncer/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Regulação para Baixo/genética , Proteínas da Matriz Extracelular/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Modelos Biológicos , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Supressoras de Tumor/metabolismo
12.
PLoS Genet ; 16(6): e1008841, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32544203

RESUMO

Hypomyelination, a neurological condition characterized by decreased production of myelin sheets by glial cells, often has no known etiology. Elucidating the genetic causes of hypomyelination provides a better understanding of myelination, as well as means to diagnose, council, and treat patients. Here, we present evidence that YIPPEE LIKE 3 (YPEL3), a gene whose developmental role was previously unknown, is required for central and peripheral glial cell development. We identified a child with a constellation of clinical features including cerebral hypomyelination, abnormal peripheral nerve conduction, hypotonia, areflexia, and hypertrophic peripheral nerves. Exome and genome sequencing revealed a de novo mutation that creates a frameshift in the open reading frame of YPEL3, leading to an early stop codon. We used zebrafish as a model system to validate that YPEL3 mutations are causative of neuropathy. We found that ypel3 is expressed in the zebrafish central and peripheral nervous system. Using CRISPR/Cas9 technology, we created zebrafish mutants carrying a genomic lesion similar to that of the patient. Our analysis revealed that Ypel3 is required for development of oligodendrocyte precursor cells, timely exit of the perineurial glial precursors from the central nervous system (CNS), formation of the perineurium, and Schwann cell maturation. Consistent with these observations, zebrafish ypel3 mutants have metabolomic signatures characteristic of oligodendrocyte and Schwann cell differentiation defects, show decreased levels of Myelin basic protein in the central and peripheral nervous system, and develop defasciculated peripheral nerves. Locomotion defects were observed in adult zebrafish ypel3 mutants. These studies demonstrate that Ypel3 is a novel gene required for perineurial cell development and glial myelination.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Bainha de Mielina/patologia , Neurogênese/genética , Proteínas Supressoras de Tumor/genética , Animais , Plexo Braquial/diagnóstico por imagem , Criança , Análise Mutacional de DNA , Modelos Animais de Doenças , Embrião não Mamífero , Feminino , Mutação da Fase de Leitura , Substância Cinzenta/diagnóstico por imagem , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico por imagem , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Humanos , Imagem por Ressonância Magnética , Neuroglia/patologia , Oligodendroglia , Nervo Isquiático/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Sequenciamento Completo do Exoma , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
13.
Proc Natl Acad Sci U S A ; 117(24): 13447-13456, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32482854

RESUMO

Precisely controlling the activation of transcription factors is crucial for physiology. After a transcription factor is activated and carries out its transcriptional activity, it also needs to be properly deactivated. Here, we report a deactivation mechanism of HIF-1 and several other oncogenic transcription factors. HIF-1 promotes the transcription of an ADP ribosyltransferase, TiPARP, which serves to deactivate HIF-1. Mechanistically, TiPARP forms distinct nuclear condensates or nuclear bodies in an ADP ribosylation-dependent manner. The TiPARP nuclear bodies recruit both HIF-1α and an E3 ubiquitin ligase HUWE1, which promotes the ubiquitination and degradation of HIF-1α. Similarly, TiPARP promotes the degradation of c-Myc and estrogen receptor. By suppressing HIF-1α and other oncogenic transcription factors, TiPARP exerts strong antitumor effects both in cell culture and in mouse xenograft models. Our work reveals TiPARP as a negative-feedback regulator for multiple oncogenic transcription factors, provides insights into the functions of protein ADP-ribosylation, and suggests activating TiPARP as an anticancer strategy.


Assuntos
Núcleo Celular/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , ADP-Ribosilação , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Receptor alfa de Estrogênio/metabolismo , Retroalimentação Fisiológica , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos , Poli(ADP-Ribose) Polimerases/química , Poli(ADP-Ribose) Polimerases/genética , Domínios e Motivos de Interação entre Proteínas , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
14.
Nat Commun ; 11(1): 3018, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32541668

RESUMO

Chronic pancreatitis represents a risk factor for the development of pancreatic cancer. We find that heterozygous loss of histone H2A lysine 119 deubiquitinase BAP1 (BRCA1 Associated Protein-1) associates with a history of chronic pancreatitis and occurs in 25% of pancreatic ductal adenocarcinomas and 40% of acinar cell carcinomas. Deletion or heterozygous loss of Bap1 in murine pancreata causes genomic instability, tissue damage, and pancreatitis with full penetrance. Concomitant expression of KrasG12D leads to predominantly intraductal papillary mucinous neoplasms and mucinous cystic neoplasms, while pancreatic intraepithelial neoplasias are rarely detected. These lesions progress to metastatic pancreatic cancer with high frequency. Lesions with histological features mimicking Acinar Cell Carcinomas are also observed in some tumors. Heterozygous mice also develop pancreatic cancer suggesting a haploinsufficient tumor suppressor role for BAP1. Mechanistically, BAP1 regulates genomic stability, in a catalytic independent manner, and its loss confers sensitivity to irradiation and platinum-based chemotherapy in pancreatic cancer.


Assuntos
Neoplasias Pancreáticas/metabolismo , Pancreatite Crônica/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Animais , Estudos de Coortes , Regulação Neoplásica da Expressão Gênica , Haploinsuficiência , Humanos , Camundongos , Neoplasias Pancreáticas/genética , Pancreatite Crônica/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética
15.
BMC Infect Dis ; 20(1): 403, 2020 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-32517725

RESUMO

BACKGROUND: Current tools for diagnosing latent TB infection (LTBI) detect immunological memory of past exposure but are unable to determine whether exposure is recent. We sought to identify a whole-blood transcriptome signature of recent TB exposure. METHODS: We studied household contacts of TB patients; healthy volunteers without recent history of TB exposure; and patients with active TB. We performed whole-blood RNA sequencing (in all), an interferon gamma release assay (IGRA; in contacts and healthy controls) and PET/MRI lung scans (in contacts only). We evaluated differentially-expressed genes in household contacts (log2 fold change ≥1 versus healthy controls; false-discovery rate < 0.05); compared these to differentially-expressed genes seen in the active TB group; and assessed the association of a composite gene expression score to independent exposure/treatment/immunological variables. RESULTS: There were 186 differentially-expressed genes in household contacts (n = 26, age 22-66, 46% male) compared with healthy controls (n = 5, age 29-38, 100% male). Of these genes, 141 (76%) were also differentially expressed in active TB (n = 14, age 27-69, 71% male). The exposure signature included genes from inflammatory response, type I interferon signalling and neutrophil-mediated immunity pathways; and genes such as BATF2 and SCARF1 known to be associated with incipient TB. The composite gene-expression score was higher in IGRA-positive contacts (P = 0.04) but not related to time from exposure, isoniazid prophylaxis, or abnormalities on PET/MRI (all P > 0.19). CONCLUSIONS: Transcriptomics can detect TB exposure and, with further development, may be an approach of value for epidemiological research and targeting public health interventions.


Assuntos
Tuberculose Latente/diagnóstico , RNA/sangue , Adulto , Idoso , Fatores de Transcrição de Zíper de Leucina Básica/genética , Estudos de Casos e Controles , Busca de Comunicante , Feminino , Humanos , Interferon Tipo I/metabolismo , Tuberculose Latente/microbiologia , Tuberculose Latente/transmissão , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/metabolismo , Mapas de Interação de Proteínas/genética , RNA/química , RNA/metabolismo , Receptores Depuradores Classe F/genética , Proteínas Supressoras de Tumor/genética , Adulto Jovem
16.
Respir Med ; 168: 105995, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32469710

RESUMO

INTRODUCTION: Brit-Hogg-Dubé syndrome (BHD) is a rare disorder that is estimated to affects about 600 families in the World. The disease-causing mutations is on FLCN gene which codes for folliculin. This protein has a role in different organs as skin, kidney and lung, thanks to the interaction with type I and II cadherins, RhoA activity and the regulation of AMPK, mTORC1 pathways and cell adhesion. The aim of our study is to focus on the manifestation of the syndrome, especially the pulmonary involvement, then on genetical analysis and on the available treatments. MATERIAL AND METHODS: We collected 15 previous studies where we found medical history information, clinical manifestations, radiological and histological diagnosis and genetical analysis. RESULTS: The prevalence of pneumothorax in patients with BHD syndrome was about 65%, but the lung involvement with multiple small cysts, localized especially in the lower part, was 85%. The prevalence of renal involvement in BHD patients ranged from 6.5% to 34%, while skin lesions ranged from 11% to 50%. More than 150 FLCN germline has been described, though the mutation in exon 11 is the most frequently detected, especially among Caucasian population. CONCLUSIONS: BHD syndrome is rare and usually the first manifestations appear in early age. In patients with these clinical and radiological characteristics we suggest taking a careful medical history, though the diagnosis of BHD syndrome should be confirmed with the analysis of FLCN gene.


Assuntos
Síndrome de Birt-Hogg-Dubé/genética , Cistos/etiologia , Pneumopatias/etiologia , Pneumotórax/etiologia , Proteínas Proto-Oncogênicas/genética , Proteínas Supressoras de Tumor/genética , Síndrome de Birt-Hogg-Dubé/complicações , Cistos/epidemiologia , Feminino , Humanos , Pneumopatias/epidemiologia , Masculino , Mutação , Pneumotórax/epidemiologia , Prevalência
17.
Nat Commun ; 11(1): 2380, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404936

RESUMO

YAP1 gene fusions have been observed in a subset of paediatric ependymomas. Here we show that, ectopic expression of active nuclear YAP1 (nlsYAP5SA) in ventricular zone neural progenitor cells using conditionally-induced NEX/NeuroD6-Cre is sufficient to drive brain tumour formation in mice. Neuronal differentiation is inhibited in the hippocampus. Deletion of YAP1's negative regulators LATS1 and LATS2 kinases in NEX-Cre lineage in double conditional knockout mice also generates similar tumours, which are rescued by deletion of YAP1 and its paralog TAZ. YAP1/TAZ-induced mouse tumours display molecular and ultrastructural characteristics of human ependymoma. RNA sequencing and quantitative proteomics of mouse tumours demonstrate similarities to YAP1-fusion induced supratentorial ependymoma. Finally, we find that transcriptional cofactor HOPX is upregulated in mouse models and in human YAP1-fusion induced ependymoma, supporting their similarity. Our results show that uncontrolled YAP1/TAZ activity in neuronal precursor cells leads to ependymoma-like tumours in mice.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Encefálicas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Ependimoma/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/ultraestrutura , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Proteínas de Ciclo Celular/genética , Criança , Ependimoma/genética , Ependimoma/patologia , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Camundongos Knockout , Camundongos Transgênicos , Microscopia Eletrônica de Varredura , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transativadores/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
18.
PLoS Genet ; 16(5): e1008757, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32379754

RESUMO

In the last decades in vitro studies highlighted the potential for crosstalk between Hypoxia-Inducible Factor-(HIF) and glucocorticoid-(GC) signalling pathways. However, how this interplay precisely occurs in vivo is still debated. Here, we use zebrafish larvae (Danio rerio) to elucidate how and to what degree hypoxic signalling affects the endogenous glucocorticoid pathway and vice versa, in vivo. Firstly, our results demonstrate that in the presence of upregulated HIF signalling, both glucocorticoid receptor (Gr) responsiveness and endogenous cortisol levels are repressed in 5 days post fertilisation larvae. In addition, despite HIF activity being low at normoxia, our data show that it already impedes both glucocorticoid activity and levels. Secondly, we further analysed the in vivo contribution of glucocorticoids to HIF activity. Interestingly, our results show that both glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) play a key role in enhancing it. Finally, we found indications that glucocorticoids promote HIF signalling via multiple routes. Cumulatively, our findings allowed us to suggest a model for how this crosstalk occurs in vivo.


Assuntos
Glucocorticoides/farmacologia , Fator 1 Induzível por Hipóxia/fisiologia , Receptor Cross-Talk/fisiologia , Peixe-Zebra , Animais , Animais Geneticamente Modificados , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Embrião não Mamífero , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/genética , Glucocorticoides/metabolismo , Fator 1 Induzível por Hipóxia/metabolismo , Larva/genética , Larva/metabolismo , Receptor Cross-Talk/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteínas Supressoras de Tumor/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética
19.
Nat Med ; 26(6): 909-918, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32472114

RESUMO

PD-1 blockade has transformed the management of advanced clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of the PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors from patients with advanced ccRCC enrolled in prospective clinical trials of treatment with PD-1 blockade by whole-exome and RNA sequencing, integrated with immunofluorescence analysis, to uncover the immunogenomic determinants of the therapeutic response. Although conventional genomic markers (such as tumor mutation burden and neoantigen load) and the degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations associated with response or resistance to PD-1 blockade. These advanced ccRCC tumors were highly CD8+ T cell infiltrated, with only 27% having a non-infiltrated phenotype. Our analysis revealed that infiltrated tumors are depleted of favorable PBRM1 mutations and enriched for unfavorable chromosomal losses of 9p21.3, as compared with non-infiltrated tumors, demonstrating how the potential interplay of immunophenotypes with somatic alterations impacts therapeutic efficacy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Nivolumabe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Apresentação do Antígeno/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Deleção Cromossômica , Cromossomos Humanos Par 6 , Cromossomos Humanos Par 9/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteínas de Ligação a DNA/genética , Feminino , Imunofluorescência , Deleção de Genes , Genômica , Antígenos de Histocompatibilidade Classe II/genética , Histona Desmetilases/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Mutação , PTEN Fosfo-Hidrolase/genética , Prognóstico , Complexo de Endopeptidases do Proteassoma/genética , Análise de Sequência de RNA , Serina-Treonina Quinases TOR/genética , Fatores de Transcrição/genética , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Sequenciamento Completo do Exoma
20.
Mol Biol (Mosk) ; 54(2): 204-211, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32392189

RESUMO

DNA hypermethylation and mutations are key mechanisms for the downregulation of tumor suppressor genes. NotI-microarrays allowed us to detect hypermethylation and/or deletions in 180 NotI sites associated with 188 genes of human chromosome 3, in 24 paired (tumor/normal) colon samples. The most frequent aberrations (in more than 20% of tumor samples) were detected in the promoter regions of 20 genes. Expression and promoter methylation of these genes were analyzed using the data for paired colon samples from The Cancer Genome Atlas project. Three genes - ALDH1L1, PLCL2, and PPP2R3A - revealed a more than two-fold average decrease in expression and a negative correlation between mRNA level and promoter hypermethylation. The expression of these three genes was then evaluated in 30 paired colon samples by quantitative PCR. Frequent (in more than 60% of cases) and significant (5-9-fold on average) mRNA level decrease was found for each of the genes in the tumor samples. The results indicate a suppressor role of the ALDH1L1, PLCL2, and PPP2R3A genes in colon cancer, as well as functional significance of hypermethylation in the downregulation of these genes.


Assuntos
Neoplasias do Colo/genética , Metilação de DNA , Peptídeos e Proteínas de Sinalização Intracelular/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Proteína Fosfatase 2/genética , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/genética
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