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1.
Am J Hum Genet ; 105(3): 509-525, 2019 Sep 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.

2.
Methods Mol Biol ; 1922: 407-452, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30838594

RESUMO

Rare genetic disorders are often challenging to diagnose. Anomalies of tooth number, shape, size, mineralized tissue structure, eruption, and resorption may exist as isolated symptoms or diseases but are often part of the clinical synopsis of numerous syndromes (Bloch-Zupan A, Sedano H, Scully C. Dento/oro/craniofacial anomalies and genetics, 1st edn. Elsevier, Boston, MA, 2012). Concerning amelogenesis imperfecta (AI), for example, mutations in a number of genes have been reported to cause isolated AI, including AMELX, ENAM, KLK4, MMP20, FAM83H, WDR72, C4orf26, SLC24A4, and LAMB3. In addition, many other genes such as DLX3, CNNM4, ROGDI, FAM20A, STIM1, ORAI1, and LTBP3 have been shown to be involved in developmental syndromes with enamel defects. The clinical presentation of the enamel phenotype (hypoplastic, hypomineralized, hypomature, or a combination of severities) alone does not allow a reliable prediction of possible causative genetic mutations. Understanding the potential genetic cause(s) of rare diseases is critical for overall health management of affected patient. One effective strategy to reach a genetic diagnosis is to sequence a selected gene panel chosen for a determined range of phenotypes. Here we describe a laboratory protocol to set up a specific gene panel for orodental diseases.


Assuntos
Anormalidades Craniofaciais/genética , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Doenças Raras/genética , Anormalidades Dentárias/genética , Amelogênese Imperfeita/diagnóstico , Amelogênese Imperfeita/genética , Anormalidades Craniofaciais/diagnóstico , DNA/genética , Desenho de Equipamento , Sequenciamento de Nucleotídeos em Larga Escala/instrumentação , Humanos , Doenças Raras/diagnóstico , Anormalidades Dentárias/diagnóstico
3.
EMBO Mol Med ; 8(12): 1390-1408, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27861123

RESUMO

Genetic causes of many familial arrhythmia syndromes remain elusive. In this study, whole-exome sequencing (WES) was carried out on patients from three different families that presented with life-threatening arrhythmias and high risk of sudden cardiac death (SCD). Two French Canadian probands carried identical homozygous rare variant in TECRL gene (p.Arg196Gln), which encodes the trans-2,3-enoyl-CoA reductase-like protein. Both patients had cardiac arrest, stress-induced atrial and ventricular tachycardia, and QT prolongation on adrenergic stimulation. A third patient from a consanguineous Sudanese family diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) had a homozygous splice site mutation (c.331+1G>A) in TECRL Analysis of intracellular calcium ([Ca2+]i) dynamics in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from this individual (TECRLHom-hiPSCs), his heterozygous but clinically asymptomatic father (TECRLHet-hiPSCs), and a healthy individual (CTRL-hiPSCs) from the same Sudanese family, revealed smaller [Ca2+]i transient amplitudes as well as elevated diastolic [Ca2+]i in TECRLHom-hiPSC-CMs compared with CTRL-hiPSC-CMs. The [Ca2+]i transient also rose markedly slower and contained lower sarcoplasmic reticulum (SR) calcium stores, evidenced by the decreased magnitude of caffeine-induced [Ca2+]i transients. In addition, the decay phase of the [Ca2+]i transient was slower in TECRLHom-hiPSC-CMs due to decreased SERCA and NCX activities. Furthermore, TECRLHom-hiPSC-CMs showed prolonged action potentials (APs) compared with CTRL-hiPSC-CMs. TECRL knockdown in control human embryonic stem cell-derived CMs (hESC-CMs) also resulted in significantly longer APs. Moreover, stimulation by noradrenaline (NA) significantly increased the propensity for triggered activity based on delayed afterdepolarizations (DADs) in TECRLHom-hiPSC-CMs and treatment with flecainide, a class Ic antiarrhythmic drug, significantly reduced the triggered activity in these cells. In summary, we report that mutations in TECRL are associated with inherited arrhythmias characterized by clinical features of both LQTS and CPVT Patient-specific hiPSC-CMs recapitulated salient features of the clinical phenotype and provide a platform for drug screening evidenced by initial identification of flecainide as a potential therapeutic. These findings have implications for diagnosis and treatment of inherited cardiac arrhythmias.


Assuntos
Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Predisposição Genética para Doença , Mutação , Oxirredutases/genética , Adolescente , Adulto , Células Cultivadas , Exoma , Feminino , Genoma Humano , Humanos , Masculino , Análise de Sequência de DNA , Adulto Jovem
4.
Am J Med Genet A ; 164A(5): 1175-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24648384

RESUMO

Metaphyseal dysplasia, Spahr type (MDST; OMIM 250400) was described in 1961 based on the observation of four children in one family who had rickets-like metaphyseal changes but normal blood chemistry and moderate short stature. Its molecular basis and nosologic status remained unknown. We followed up on those individuals and diagnosed the disorder in an additional member of the family. We used exome sequencing to ascertain the underlying mutation and explored its consequences on three-dimensional models of the affected protein. The MDST phenotype is associated with moderate short stature and knee pain in adults, while extra-skeletal complications are not observed. The sequencing showed that MDST segregated with a c.619T>G single nucleotide transversion in MMP13. The predicted non-conservative amino acid substitution, p.Trp207Gly, disrupts a crucial hydrogen bond in the calcium-binding region of the catalytic domain of the matrix metalloproteinase, MMP13. The MDST phenotype is associated with recessive MMP13 mutations, confirming the importance of this metalloproteinase in the metaphyseal growth plate. Dominant MMP13 mutations have been associated with metaphyseal anadysplasia (OMIM 602111), while a single child homozygous for a MMP13 mutation had been previously diagnosed as "recessive metaphyseal anadysplasia," that we conclude is the same nosologic entity as MDST. Molecular confirmation of MDST allows distinction of it from dominant conditions (e.g., metaphyseal dysplasia, Schmid type; OMIM # 156500) and from more severe multi-system conditions (such as cartilage-hair hypoplasia; OMIM # 250250) and to give precise recurrence risks and prognosis.


Assuntos
Genes Recessivos , Cabelo/anormalidades , Doença de Hirschsprung/diagnóstico , Doença de Hirschsprung/genética , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Metaloproteinase 13 da Matriz/genética , Mutação , Osteocondrodisplasias/congênito , Adolescente , Adulto , Alelos , Domínio Catalítico , Criança , Colágeno Tipo XI/genética , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Metaloproteinase 13 da Matriz/química , Modelos Moleculares , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Linhagem , Conformação Proteica , RNA Longo não Codificante/genética , Adulto Jovem
5.
Sci Rep ; 3: 3151, 2013 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-24193225

RESUMO

Using an in vivo cycling strategy, we selected metastatic cancer cells from the lymph nodes (LN) of mice bearing orthotopic DU145 human prostate tumors. Repeated rounds of metastatic selection (LN1-LN4) progressively increased the epithelial phenotype, resulting in a new model of tumor cell mesenchymal-epithelial transition (MET). DU145-LN4 showed increased cell-cell adhesions, higher expression of multiple epithelial markers, such as E-cadherin, EpCAM and cytokeratin 18, and reduced expression of mesenchymal markers such as vimentin. The MET in DU145-LN4 cells was accompanied by increased expression of the miR-200 family, and antimiRs to miR-200c and miR-141 induced an EMT. MET also correlated with the loss of miR-424. Ectopic transient and stable miR-424 expression induced EMT, with reduced epithelial marker expression and increased cell scattering. Our model provides evidence for spontaneous MET in vivo. We show that this cellular plasticity can be mediated through the combined action of miR-424 and the miR-200 family.


Assuntos
MicroRNAs/metabolismo , Neoplasias da Próstata/patologia , Animais , Antígenos de Neoplasias/metabolismo , Caderinas/metabolismo , Adesão Celular , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Molécula de Adesão da Célula Epitelial , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Queratina-18/metabolismo , Metástase Linfática , Masculino , Camundongos , Camundongos Nus , MicroRNAs/antagonistas & inibidores , Oligonucleotídeos Antissenso/metabolismo , Neoplasias da Próstata/genética , Transplante Heterólogo , Vimentina/metabolismo
6.
Am J Hum Genet ; 92(6): 990-5, 2013 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-23684011

RESUMO

Kenny-Caffey syndrome (KCS) and the similar but more severe osteocraniostenosis (OCS) are genetic conditions characterized by impaired skeletal development with small and dense bones, short stature, and primary hypoparathyroidism with hypocalcemia. We studied five individuals with KCS and five with OCS and found that all of them had heterozygous mutations in FAM111A. One mutation was identified in four unrelated individuals with KCS, and another one was identified in two unrelated individuals with OCS; all occurred de novo. Thus, OCS and KCS are allelic disorders of different severity. FAM111A codes for a 611 amino acid protein with homology to trypsin-like peptidases. Although FAM111A has been found to bind to the large T-antigen of SV40 and restrict viral replication, its native function is unknown. Molecular modeling of FAM111A shows that residues affected by KCS and OCS mutations do not map close to the active site but are clustered on a segment of the protein and are at, or close to, its outer surface, suggesting that the pathogenesis involves the interaction with as yet unidentified partner proteins rather than impaired catalysis. FAM111A appears to be crucial to a pathway that governs parathyroid hormone production, calcium homeostasis, and skeletal development and growth.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Craniofaciais/genética , Nanismo/genética , Hiperostose Cortical Congênita/genética , Hipocalcemia/genética , Hipoparatireoidismo/genética , Receptores Virais/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/mortalidade , Doenças do Desenvolvimento Ósseo/patologia , Criança , Anormalidades Craniofaciais/mortalidade , Anormalidades Craniofaciais/patologia , Nanismo/diagnóstico por imagem , Nanismo/mortalidade , Estudos de Associação Genética , Heterozigoto , Humanos , Hiperostose Cortical Congênita/diagnóstico por imagem , Hiperostose Cortical Congênita/mortalidade , Hipocalcemia/diagnóstico por imagem , Hipocalcemia/mortalidade , Hipoparatireoidismo/diagnóstico por imagem , Hipoparatireoidismo/mortalidade , Lactente , Recém-Nascido , Masculino , Mutação de Sentido Incorreto , Hormônio Paratireóideo/deficiência , Radiografia
7.
Nucleic Acids Res ; 41(1): e8, 2013 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-22941654

RESUMO

The development of new high-throughput technologies enables us to measure genome-wide transcription levels, protein abundance, metabolite concentration, etc. Nevertheless, these experimental data are often noisy and incomplete, which hinders data analysis, modeling and prediction. Here, we propose a method to predict expression values of genes involved in stable cellular phenotypes from the expression values of the remaining genes in a literature-based gene regulatory network. The consistency between predicted and known stable states from experimental data is used to guide an iterative network pruning that contextualizes the network to the biological conditions under which the expression data were obtained. Using the contextualized network and the property of network stability we predict gene expression values missing from experimental data. The prediction method assumes a Boolean model to compute steady states of networks and an evolutionary algorithm to iteratively prune the networks. The evolutionary algorithm samples the probability distribution of positive feedback loops or positive circuits and individual interactions within the subpopulation of the best-pruned networks at each iteration. The resulting expression inference is based not only on previous knowledge about local connectivity but also on a global network property (stability), providing robustness in the predictions.


Assuntos
Algoritmos , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Diferenciação Celular/genética , Interpretação Estatística de Dados , Transição Epitelial-Mesenquimal/genética , Células HL-60 , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Células-Tronco/metabolismo
8.
PLoS One ; 7(4): e35440, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22514743

RESUMO

BACKGROUND: The majority of human cancer deaths are caused by metastasis. The metastatic dissemination is initiated by the breakdown of epithelial cell homeostasis. During this phenomenon, referred to as epithelial to mesenchymal transition (EMT), cells change their genetic and trancriptomic program leading to phenotypic and functional alterations. The challenge of understanding this dynamic process resides in unraveling regulatory networks involving master transcription factors (e.g. SNAI1/2, ZEB1/2 and TWIST1) and microRNAs. Here we investigated microRNAs regulated by SNAI1 and their potential role in the regulatory networks underlying epithelial plasticity. RESULTS: By a large-scale analysis on epithelial plasticity, we highlighted miR-203 and its molecular link with SNAI1 and the miR-200 family, key regulators of epithelial homeostasis. During SNAI1-induced EMT in MCF7 breast cancer cells, miR-203 and miR-200 family members were repressed in a timely correlated manner. Importantly, miR-203 repressed endogenous SNAI1, forming a double negative miR203/SNAI1 feedback loop. We integrated this novel miR203/SNAI1 with the known miR200/ZEB feedback loops to construct an a priori EMT core network. Dynamic simulations revealed stable epithelial and mesenchymal states, and underscored the crucial role of the miR203/SNAI1 feedback loop in state transitions underlying epithelial plasticity. CONCLUSION: By combining computational biology and experimental approaches, we propose a novel EMT core network integrating two fundamental negative feedback loops, miR203/SNAI1 and miR200/ZEB. Altogether our analysis implies that this novel EMT core network could function as a switch controlling epithelial cell plasticity during differentiation and cancer progression.


Assuntos
Transição Epitelial-Mesenquimal/fisiologia , MicroRNAs/metabolismo , Fatores de Transcrição/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/fisiologia , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , MicroRNAs/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição da Família Snail , Fatores de Transcrição/genética , Proteína 1 Relacionada a Twist/genética , Proteína 1 Relacionada a Twist/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco , Homeobox 1 de Ligação a E-box em Dedo de Zinco
9.
BMC Bioinformatics ; 12: 67, 2011 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-21375730

RESUMO

BACKGROUND: To understand biological processes and diseases, it is crucial to unravel the concerted interplay of transcription factors (TFs), microRNAs (miRNAs) and their targets within regulatory networks and fundamental sub-networks. An integrative computational resource generating a comprehensive view of these regulatory molecular interactions at a genome-wide scale would be of great interest to biologists, but is not available to date. RESULTS: To identify and analyze molecular interaction networks, we developed MIR@NT@N, an integrative approach based on a meta-regulation network model and a large-scale database. MIR@NT@N uses a graph-based approach to predict novel molecular actors across multiple regulatory processes (i.e. TFs acting on protein-coding or miRNA genes, or miRNAs acting on messenger RNAs). Exploiting these predictions, the user can generate networks and further analyze them to identify sub-networks, including motifs such as feedback and feedforward loops (FBL and FFL). In addition, networks can be built from lists of molecular actors with an a priori role in a given biological process to predict novel and unanticipated interactions. Analyses can be contextualized and filtered by integrating additional information such as microarray expression data. All results, including generated graphs, can be visualized, saved and exported into various formats. MIR@NT@N performances have been evaluated using published data and then applied to the regulatory program underlying epithelium to mesenchyme transition (EMT), an evolutionary-conserved process which is implicated in embryonic development and disease. CONCLUSIONS: MIR@NT@N is an effective computational approach to identify novel molecular regulations and to predict gene regulatory networks and sub-networks including conserved motifs within a given biological context. Taking advantage of the M@IA environment, MIR@NT@N is a user-friendly web resource freely available at http://mironton.uni.lu which will be updated on a regular basis.


Assuntos
Bases de Dados Genéticas , Redes Reguladoras de Genes , MicroRNAs/genética , Fatores de Transcrição/genética , Motivos de Aminoácidos/genética , Biologia Computacional/métodos , Regulação da Expressão Gênica , Humanos , Internet , MicroRNAs/metabolismo , RNA Mensageiro/genética , Fatores de Transcrição/metabolismo
10.
BMC Bioinformatics ; 9: 273, 2008 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-18544157

RESUMO

BACKGROUND: Misfolding and aggregation of proteins into ordered fibrillar structures is associated with a number of severe pathologies, including Alzheimer's disease, prion diseases, and type II diabetes. The rapid accumulation of knowledge about the sequences and structures of these proteins allows using of in silico methods to investigate the molecular mechanisms of their abnormal conformational changes and assembly. However, such an approach requires the collection of accurate data, which are inconveniently dispersed among several generalist databases. RESULTS: We therefore created a free online knowledge database (AMYPdb) dedicated to amyloid precursor proteins and we have performed large scale sequence analysis of the included data. Currently, AMYPdb integrates data on 31 families, including 1,705 proteins from nearly 600 organisms. It displays links to more than 2,300 bibliographic references and 1,200 3D-structures. A Wiki system is available to insert data into the database, providing a sharing and collaboration environment. We generated and analyzed 3,621 amino acid sequence patterns, reporting highly specific patterns for each amyloid family, along with patterns likely to be involved in protein misfolding and aggregation. CONCLUSION: AMYPdb is a comprehensive online database aiming at the centralization of bioinformatic data regarding all amyloid proteins and their precursors. Our sequence pattern discovery and analysis approach unveiled protein regions of significant interest. AMYPdb is freely accessible 1.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Bases de Dados de Proteínas , Sequência de Aminoácidos , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Doenças do Sistema Nervoso Central/metabolismo , Complicações do Diabetes , Humanos , Dados de Sequência Molecular , Dobramento de Proteína , Homologia de Sequência de Aminoácidos
11.
In Silico Biol ; 8(1): 63-9, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18430991

RESUMO

Microarray technology is a widely used approach to gene expression analysis. Many tools for microarray management and data analysis have been developed, and recently new methods have been proposed for deciphering biological pathways by integrating microarray data with other data sources. However, to improve microarray analysis and provide meaningful gene interaction networks, integrated software solutions are still needed. Therefore, we developed M@IA, an environment for DNA microarray data analysis allowing gene network reconstruction. M@IA is a microarray integrated application which includes all of the steps of a microarray study, from MIAME-compliant raw data storage and processing gene expression analysis. Furthermore, M@IA allows automatic gene annotation based on ontology, metabolic/signalling pathways, protein interaction, miRNA and transcriptional factor associations, as well as integrative analysis of gene interaction networks. Statistical and graphical methods facilitate analysis, yielding new hypotheses on gene expression data. To illustrate our approach, we applied M@IA modules to microarray data taken from an experiment on liver tissue. We integrated differentially expressed genes with additional biological information, thus identifying new molecular interaction networks that are associated with fibrogenesis. M@IA is a new application for microarray management and data analysis, offering functional insights into microarray data by the combination of gene expression data and biological knowledge annotation based on interactive graphs. M@IA is an interactive multi-user interface based on a flexible modular architecture and it is freely available for academic users at http://maia.genouest.org.


Assuntos
Perfilação da Expressão Gênica , Análise de Sequência com Séries de Oligonucleotídeos , Software , Interface Usuário-Computador , Simulação por Computador , Bases de Dados Genéticas , Regulação da Expressão Gênica
12.
Hepatology ; 44(5): 1296-307, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17058241

RESUMO

The molecular mechanisms underlying the progression of cirrhosis toward hepatocellular carcinoma were investigated by a combination of DNA microarray analysis and literature data mining. By using a microarray screening of suppression subtractive hybridization cDNA libraries, we first analyzed genes differentially expressed in tumor and nontumor livers with cirrhosis from 15 patients with hepatocellular carcinomas. Seventy-four genes were similarly recovered in tumor (57.8% of differentially expressed genes) and adjacent nontumor tissues (64% of differentially expressed genes) compared with histologically normal livers. Gene ontology analyses revealed that downregulated genes (n = 35) were mostly associated with hepatic functions. Upregulated genes (n = 39) included both known genes associated with extracellular matrix remodeling, cell communication, metabolism, and post-transcriptional regulation gene (e.g., ZFP36L1), as well as the tumor suppressor gene menin (multiple endocrine neoplasia type 1; MEN1). MEN1 was further identified as an important node of a regulatory network graph that integrated array data with array-independent literature mining. Upregulation of MEN1 in tumor was confirmed in an independent set of samples and associated with tumor size (P = .016). In the underlying liver with cirrhosis, increased steady-state MEN1 mRNA levels were correlated with those of collagen alpha2(I) mRNA (P < .01). In addition, MEN1 expression was associated with hepatic stellate cell activation during fibrogenesis and involved in transforming growth factor beta (TGF-beta)-dependent collagen alpha2(I) regulation. In conclusion, menin is a key regulator of gene networks that are activated in fibrogenesis associated with hepatocellular carcinoma through the modulation of TGF-beta response.


Assuntos
Carcinoma Hepatocelular/genética , Colágeno Tipo I/metabolismo , Hepatócitos/fisiologia , Cirrose Hepática/metabolismo , Proteínas Proto-Oncogênicas/genética , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/metabolismo , Biblioteca Gênica , Genes Supressores de Tumor , Humanos , Cirrose Hepática/complicações , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas/biossíntese , RNA Mensageiro/biossíntese , Transfecção , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima
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