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1.
Medicine (Baltimore) ; 98(36): e17028, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31490389

RESUMO

Vasculogenic mimicry (VM) involves a tubular structure with a basement membrane that is similar to and communicates with vessels but functions independent of blood vessels to nourish tumor cells, promote tumor progression, invasion, and metastasis, with reduced 5-year survival rates. Tumor cell proliferation, invasion, and metastasis are promoted by the epithelial-mesenchymal transition (EMT). Paired-related homeobox 1 (PRRX1), a newly discovered EMT inducer, has been shown to correlate with metastasis and prognosis in diverse cancer types. Cancerous inhibitor of protein phosphatase 2A (CIP2A) was initially recognized as an oncoprotein. In this study, we aimed to investigate the expression and clinical significance of the EMT markers PRRX1, CIP2A and VM in clear cell renal cell carcinoma (CCRCC) and their respective associations with clinicopathological parameters and survival.Expression of PRRX1, CIP2A and VM in whole CCRCC tissues from 110 patients was analyzed by immunohistochemical and histochemical staining. Fisher's exact test or the chi square test was used to assess associations with positive or negative staining of these markers and clinicopathological characteristics.Positive expression of CIP2A and VM presence was significantly higher and that of PRRX1 was significantly lower in CCRCC tissues than in corresponding normal tissues. Furthermore, positive expression of CIP2A and VM was significantly associated with tumor grade, size, lymph node metastasis (LNM) stage, and tumor node metastasis (TNM) stage and inversely associated with overall survival time (OST). Moreover, levels of PRRX1 were negatively associated with tumor grade, size, LNM stage, and TNM stage. The PRRX1 subgroup had a significantly longer OST time than did the PRRX1 subgroup. In multivariate analysis, high VM and CIP2A, tumor grade, LNM stage, TNM stage, and low PRRX1 levels were identified as potential independent prognostic factors for OST in CCRCC patients.VM and expression of CIP2A and PRRX1 represent promising biomarkers for metastasis and prognosis and potential therapeutic targets in CCRCC.


Assuntos
Autoantígenos/metabolismo , Carcinoma de Células Renais/metabolismo , Proteínas de Homeodomínio/metabolismo , Neoplasias Renais/metabolismo , Proteínas de Membrana/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/patologia , Feminino , Humanos , Rim/patologia , Neoplasias Renais/diagnóstico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico
2.
Gene ; 718: 144048, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31421189

RESUMO

Main conclusion Among 247 RsAP2/ERF identified, the majority of the 21 representatives were preferably expressed under drought and heat while suppressed under heavy metals, indicating their potential roles in abiotic stress responses and tolerance. APETALA2/Ethylene-Responsive factor (AP2/ERF) transcription factor (TF) is one of the largest gene families in plants that play a fundamental role in growth and development as well as biotic and/or abiotic stresses responses. Although AP2/ERFs have been extensively characterized in many plant species, little is known about this family in radish, which is an important root vegetable with various medicinal properties. The available genome provides valuable opportunity to identify and characterize the global information on AP2/ERF TFs in radish. In this study, a total of 247 ERF family genes were identified from the radish genome, and sequence alignment and phylogenetic analyses classified the AP2/ERF superfamily into five groups (AP2, ERF, DREB, RAV and soloist). Motif analysis showed that other than AP2/ERF domains, other conserved regions were selectively distributed among different clades in the phylogenetic tree. Chromosome location analysis showed that tandem duplication may result in the expansion of RsAP2/ERF gene family. The RT-qPCR analysis confirmed that a proportion of AP2/ERF genes were preferably expressed under drought and heat stresses, whereas they were suppressed under the ABA and heavy metal stresses. These results provided valuable information for further evolutionary and functional characterization of RsAP2/ERF genes, and contributed to genetic improvement of stress tolerances in radish and other root vegetable crops.


Assuntos
Evolução Molecular , Proteínas de Homeodomínio , Metais Pesados/toxicidade , Família Multigênica , Proteínas Nucleares , Filogenia , Proteínas de Plantas , Raphanus , Estresse Fisiológico/efeitos dos fármacos , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Raphanus/genética , Raphanus/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
3.
Medicine (Baltimore) ; 98(26): e15954, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261501

RESUMO

Early diagnosis of pancreatic cancer (PC) is based on endoscopic ultrasound (EUS). However, EUS is invasive and requires a high level of technical skill. Recently, liquid biopsies have achieved the same sensitivity and specificity for the diagnosis of numerous pathologies, including cancer. Insulin-promoting factor 1 (PDX1) and Msh-homeobox 2 (MSX2), 2 homeotic genes, have been confirmed to be related to pancreatic oncogenesis.The aim of this study is to establish the diagnostic utility of circulating serum levels of MSX2 and PDX1 expression in patients with PC.A prospective study was conducted from January 2014 to February 2017. Patients with a suspected diagnosis of PC who underwent fine needle aspiration biopsy guided by EUS (EUS-FNA) were included in the study, in addition to non-PC control subjects. Both tissue and blood serum samples were submitted to histopathological analysis and measurement of PDX1 and MSX2 gene expression by means of qRT-PCR.Patients were divided into non-PC, malignant pathology (MP), or benign pathology (BP) groups. Significant differences in both MSX2 [2.05 (1.66-4.60) vs 0.83 (0.49-1.60), P = .006] and PDX1 [2.59 (1.28-10.12) vs 1.02 (0.81-1.17), P = .036] gene expression were found in blood samples of PC compared with non-PC subjects. We also observed a significant increase in MSX2 transcripts in tissue biopsy samples of patients diagnosed with MP compared with those with BP [1.98 (1.44-4.61) and 0.66 (0.45-1.54), respectively, P = .012]. The ROC curves indicate a sensitivity and specificity of 80% for PDX1 and 86% for MSX2.Gene expression of MSX2 in tissue samples obtained by EUS-FNA and serum expression of MSX2 and PDX1 were higher in patients with PC.


Assuntos
Proteínas de Homeodomínio/metabolismo , Neoplasias Pancreáticas/metabolismo , Transativadores/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Biópsia por Agulha Fina , Estudos de Casos e Controles , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Estudos Prospectivos , Sensibilidade e Especificidade
4.
Nat Commun ; 10(1): 2913, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266935

RESUMO

Mechanistic studies in human cancer have relied heavily on cell lines and mouse models, but are limited by in vitro adaptation and species context issues, respectively. More recent efforts have utilized patient-derived xenografts; however, these are hampered by variable genetic background, inability to study early events, and practical issues with availability/reproducibility. We report here an efficient, reproducible model of T-cell leukemia in which lentiviral transduction of normal human cord blood yields aggressive leukemia that appears indistinguishable from natural disease. We utilize this synthetic model to uncover a role for oncogene-induced HOXB activation which is operative in leukemia cells-of-origin and persists in established tumors where it defines a novel subset of patients distinct from other known genetic subtypes and with poor clinical outcome. We show further that anterior HOXB genes are specifically activated in human T-ALL by an epigenetic mechanism and confer growth advantage in both pre-leukemia cells and established clones.


Assuntos
Proteínas de Homeodomínio/metabolismo , Leucemia/metabolismo , Família Multigênica , Animais , Proliferação de Células , Epigênese Genética , Feminino , Xenoenxertos , Proteínas de Homeodomínio/genética , Humanos , Leucemia/genética , Leucemia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Modelos Genéticos , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo
5.
Hum Genet ; 138(8-9): 937-955, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31359131

RESUMO

Ocular developmental anomalies are among the most common causes of severe visual impairment in newborns (combined incidence 1-2:10,000). They comprise a wide range of inborn errors of eye development with a spectrum of overlapping phenotypes and they are frequently associated with extraocular malformations, neuropsychomotor developmental delay and/or intellectual disabilities. Many studies from model organisms have demonstrated the role of retinoic acid (RA) during organogenesis, including eye development, and have revealed the wide spectrum of malformations that can arise from defective RA signaling. However, genes coding for homeobox proteins and morphogenetic factors were implicated in anomalies of ocular development long before genes coding for RA-signaling proteins. The purpose of this review is to discuss current knowledge about the highly complex genetic architecture of RA-signaling-associated ocular developmental anomalies in humans. Despite less than a dozen genes identified thus far, all steps of RA-signaling, from vitamin A transport to target cells to transcriptional activation of RA targets, have been implicated. Furthermore, the majority of these genetic disorders are associated with both dominant and recessive inheritance patterns and a wide spectrum of ocular malformations, which can dominate the phenotype or represent one of many features. Although some genotype-phenotype correlations are described, in many cases, the variability of clinical expression cannot be accounted for by the genotype alone. This observation and the large number of unsolved cases suggest that the relationship between RA signaling and eye development deserves further investigation.


Assuntos
Olho/metabolismo , Transdução de Sinais/fisiologia , Tretinoína/metabolismo , Animais , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Genótipo , Proteínas de Homeodomínio/metabolismo , Humanos , Fenótipo
6.
Cell Physiol Biochem ; 53(2): 323-336, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31359737

RESUMO

BACKGROUND/AIMS: Vascular calcification represents a huge clinical problem contributing to adverse cardiovascular events, with no effective treatment currently available. Upregulation of hepatocyte growth factor has been linked with vascular calcification, and thus, represent a potential target in the development of a novel therapeutic strategy. Glycomimetics have been shown to interrupt HGF-receptor signalling, therefore this study investigated the effect of novel glycomimetics on osteogenic signalling and vascular calcification in vitro. METHODS: Primary human vascular smooth muscle cells (HVSMCs) were induced by ß-glycerophosphate (ß-GP) and treated with 4 glycomimetic compounds (C1-C4). The effect of ß-GP and C1-C4 on alkaline phosphatase (ALP), osteogenic markers and c-Met/Notch3/HES1 signalling was determined using colorimetric assays, qRT-PCR and western blotting respectively. RESULTS: C1-C4 significantly attenuated ß-GP-induced calcification, as shown by Alizarin Red S staining and calcium content by day 14. In addition, C1-C4 reduced ALP activity and prevented upregulation of the osteogenic markers, BMP-2, Runx2, Msx2 and OPN. Furthermore, ß-GP increased c-Met phosphorylation at day 21, an effect ameliorated by C2 and C4 and the c-Met inhibitor, crizotinib. We next interrogated the effects of the Notch inhibitor DAPT and confirmed an inhibition of ß-GP up-regulated Notch3 protein by C2, DAPT and crizotinib compared to controls. Hes-1 protein upregulation by ß-GP, was also significantly downregulated by C2 and DAPT. GOLD docking analysis identified a potential binding interaction of C1-C4 to HGF which will be investigated further. CONCLUSION: These findings demonstrate that glycomimetics have potent anti-calcification properties acting via HGF/c-Met and Notch signalling.


Assuntos
Músculo Liso Vascular/citologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptor Notch3/metabolismo , Fatores de Transcrição HES-1/metabolismo , Calcificação Vascular/metabolismo , Materiais Biomiméticos/farmacologia , Proteína Morfogenética Óssea 2/metabolismo , Linhagem Celular , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Glicerofosfatos/farmacologia , Proteínas de Homeodomínio/metabolismo , Humanos , Miócitos de Músculo Liso/metabolismo , Proteínas Recombinantes/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo
7.
J Agric Food Chem ; 67(28): 7898-7907, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31282664

RESUMO

This study aimed to explore the effects of silencing HB12 and TT8 genes on protein utilization characteristics of alfalfa. Ground samples of 11 HB12-silenced (HB12i), 5 TT8-silenced (TT8i) and 4 wild type (WT) were incubated in a Daisy II incubator with N15 labeled ammonium sulfate for 0, 4, 8, 12, and 24 h. CP degradation and degradational kinetics, microbial nitrogen fractions, and protein metabolic profiles were determined. Moreover, relationships between protein profiles and FTIR spectral parameters were estimated. Results showed that transgenic alfalfa had lower CP degradation, microbial protein, and total available protein compared with WT, especially for HB12i. In addition, CP degradation and protein metabolic profiles were closely correlated with FTIR spectral parameters and thereby could be predicted from spectral parameters. In conclusion, silencing of HB12 and TT8 genes in alfalfa decreased protein degradational and metabolic profiles, which were predictable with FTIR spectral parameters.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Inativação Gênica , Proteínas de Homeodomínio/genética , Medicago sativa/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Rúmen/metabolismo , Ração Animal/análise , Animais , Bactérias/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Bovinos , Digestão , Proteínas de Homeodomínio/metabolismo , Cinética , Medicago sativa/química , Medicago sativa/metabolismo , Proteínas de Plantas/química , Plantas Geneticamente Modificadas/química , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Proteólise , Rúmen/química , Rúmen/microbiologia
8.
Nature ; 571(7764): 211-218, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31207603

RESUMO

Exhausted CD8+ T (Tex) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (Teff) or memory (Tmem) CD8+ T cells. Tex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, Tex cells are a distinct immune subset, with a unique chromatin landscape compared with Teff and Tmem cells. However, the mechanisms that govern the transcriptional and epigenetic development of Tex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of Tex cells in mice. TOX is largely dispensable for the formation of Teff and Tmem cells, but it is critical for exhaustion: in the absence of TOX, Tex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in Tex cells. Robust expression of TOX therefore results in commitment to Tex cells by translating persistent stimulation into a distinct Tex cell transcriptional and epigenetic developmental program.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Epistasia Genética , Proteínas de Homeodomínio/metabolismo , Transcrição Genética , Animais , Calcineurina/metabolismo , Sinalização do Cálcio , Retroalimentação Fisiológica , Feminino , Regulação da Expressão Gênica/imunologia , Genótipo , Memória Imunológica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/metabolismo , Evasão Tumoral
9.
Nature ; 571(7764): 265-269, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31207605

RESUMO

Cytotoxic T cells are essential mediators of protective immunity to viral infection and malignant tumours and are a key target of immunotherapy approaches. However, prolonged exposure to cognate antigens often attenuates the effector capacity of T cells and limits their therapeutic potential1-4. This process, known as T cell exhaustion or dysfunction1, is manifested by epigenetically enforced changes in gene regulation that reduce the expression of cytokines and effector molecules and upregulate the expression of inhibitory receptors such as programmed cell-death 1 (PD-1)5-8. The underlying molecular mechanisms that induce and stabilize the phenotypic and functional features of exhausted T cells remain poorly understood9-12. Here we report that the development and maintenance of populations of exhausted T cells in mice requires the thymocyte selection-associated high mobility group box (TOX) protein13-15. TOX is induced by high antigen stimulation of the T cell receptor and correlates with the presence of an exhausted phenotype during chronic infections with lymphocytic choriomeningitis virus in mice and hepatitis C virus in humans. Removal of its DNA-binding domain reduces the expression of PD-1 at the mRNA and protein level, augments the production of cytokines and results in a more polyfunctional T cell phenotype. T cells with this deletion initially mediate increased effector function and cause more severe immunopathology, but ultimately undergo a massive decline in their quantity, notably among the subset of TCF-1+ self-renewing T cells. Altogether, we show that TOX is a critical factor for the normal progression of T cell dysfunction and the maintenance of exhausted T cells during chronic infection, and provide a link between the suppression of effector function intrinsic to CD8 T cells and protection against immunopathology.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Proteínas de Grupo de Alta Mobilidade/metabolismo , Proteínas de Homeodomínio/metabolismo , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Animais , Proliferação de Células , Doença Crônica , Citocinas/imunologia , Citocinas/metabolismo , Epigênese Genética , Feminino , Regulação da Expressão Gênica/imunologia , Hepacivirus/imunologia , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Humanos , Memória Imunológica , Vírus da Coriomeningite Linfocítica/imunologia , Masculino , Camundongos , Fenótipo , Timócitos/citologia , Timócitos/imunologia , Transcrição Genética
10.
Nature ; 571(7764): 270-274, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31207604

RESUMO

Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states1-6. Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox-deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1, Entpd1, Havcr2, Cd244 and Tigit), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, 'non-exhausted' immunophenotype, Tox-deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox-deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Diferenciação Celular/imunologia , Proteínas de Grupo de Alta Mobilidade/metabolismo , Proteínas de Homeodomínio/metabolismo , Neoplasias/imunologia , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Grupo de Alta Mobilidade/deficiência , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Homeodomínio/genética , Humanos , Memória Imunológica , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Camundongos , Neoplasias/patologia , Fenótipo , Receptores de Antígenos de Linfócitos T/imunologia , Transcrição Genética
11.
Genome Biol ; 20(1): 115, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31159833

RESUMO

BACKGROUND: Hox transcription factors specify segmental diversity along the anterior-posterior body axis in metazoans. While the different Hox family members show clear functional specificity in vivo, they all show similar binding specificity in vitro and a satisfactory understanding of in vivo Hox target selectivity is still lacking. RESULTS: Using transient transfection in Kc167 cells, we systematically analyze the binding of all eight Drosophila Hox proteins. We find that Hox proteins show considerable binding selectivity in vivo even in the absence of canonical Hox cofactors Extradenticle and Homothorax. Hox binding selectivity is strongly associated with chromatin accessibility, being highest in less accessible chromatin. Individual Hox proteins exhibit different propensities to bind less accessible chromatin, and high binding selectivity is associated with high-affinity binding regions, leading to a model where Hox proteins derive binding selectivity through affinity-based competition with nucleosomes. Extradenticle/Homothorax cofactors generally facilitate Hox binding, promoting binding to regions in less accessible chromatin but with little effect on the overall selectivity of Hox targeting. These cofactors collaborate with Hox proteins in opening chromatin, in contrast to the pioneer factor, Glial cells missing, which facilitates Hox binding by independently generating accessible chromatin regions. CONCLUSIONS: These studies indicate that chromatin accessibility plays a key role in Hox selectivity. We propose that relative chromatin accessibility provides a basis for subtle differences in binding specificity and affinity to generate significantly different sets of in vivo genomic targets for different Hox proteins.


Assuntos
Montagem e Desmontagem da Cromatina , Cromatina/metabolismo , Proteínas de Homeodomínio/metabolismo , Motivos de Aminoácidos , Animais , Linhagem Celular , Drosophila , Proteínas de Drosophila/metabolismo , Fatores de Transcrição/metabolismo
12.
DNA Cell Biol ; 38(7): 678-687, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31188017

RESUMO

Staging and pathological grading systems are convenient, but imperfect predictors of recurrence of head and neck squamous cell carcinoma. Therefore, to identify potential alternative prognostic markers, we investigated the methylation status of the promoter of Sal-like protein 2 (SALL2). SALL2 mRNA expression was absent in 8/9 (88.9%) University of Michigan squamous cell carcinoma cell lines, whereas two nonmalignant cell lines had stable expression. The normalized methylation value of SALL2 in cancer cell lines was significantly higher than in normal cell lines. SALL2 methylation found in 74 of 233 (31.8%) tumor specimens was correlated with the methylation status of both SALL1 and SALL3. SALL2 methylation was not associated with any difference in disease-free survival (DFS). Therefore, the presence of SALL2 methylation was statistically correlated with a decrease in DFS in patients with oral cancer (log-rank test, p = 0.032). Furthermore, it was associated with disease recurrence in 36.2% of oral cancer cases, with an odds ratio of 2.922 (95% confidence interval = 1.198-7.130; p = 0.018) by multivariate Cox proportional hazard regression analysis. This study suggests that cytosine-phosphate- guanosine (CpG) hypermethylation is a likely mechanism of SALL2 inactivation and supports the hypothesis that SALL2 could serve as an important clinical risk assessment.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Metilação de DNA , Neoplasias Bucais/genética , Fatores de Transcrição/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Fatores de Transcrição/metabolismo
13.
Nat Commun ; 10(1): 2789, 2019 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-31243274

RESUMO

IGH@ proto-oncogene translocation is a common oncogenic event in lymphoid lineage cancers such as B-ALL, lymphoma and multiple myeloma. Here, to investigate the interplay between IGH@ proto-oncogene translocation and IGH allelic exclusion, we perform long-read whole-genome and transcriptome sequencing along with epigenetic and 3D genome profiling of Nalm6, an IGH-DUX4 positive B-ALL cell line. We detect significant allelic imbalance on the wild-type over the IGH-DUX4 haplotype in expression and epigenetic data, showing IGH-DUX4 translocation occurs on the silenced IGH allele. In vitro, this reduces the oncogenic stress of DUX4 high-level expression. Moreover, patient samples of IGH-DUX4 B-ALL have similar expression profile and IGH breakpoints as Nalm6, suggesting a common mechanism to allow optimal dosage of non-toxic DUX4 expression.


Assuntos
Proteínas de Homeodomínio/metabolismo , Cadeias Pesadas de Imunoglobulinas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Animais , Apoptose , DNA/genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Genômica , Histonas , Humanos , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Sequenciamento Completo do Genoma
14.
Eur J Med Chem ; 178: 168-176, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31181481

RESUMO

The androgen receptor (AR) is a steroid hormone receptor and its high expression and disruption of its regulation are strongly implicated in prostate cancer (PCa) development. One of the current therapies includes application of steroidal antiandrogens leading to blockade of the AR action by the abrogation of AR-mediated signaling. We introduced here novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused steroidal compounds, described their synthesis based on [8π+2π] cycloaddition reactions of diazafulvenium methides with different steroidal scaffolds and showed their biological evaluation in different prostate cancer cell lines in vitro. Our results showed the ability of novel compounds to suppress the expression of known androgen receptor targets, Nkx3.1 and PSA in two prostate cell lines, 22Rv1 and VCaP. Candidate compound diminished the transcription of AR-regulated genes in the reporter cell line in a concentration-dependent manner. Antiproliferative activity of the most promising steroid was studied by clonogenic assay and induction of apoptosis in treated cells was documented by immunoblot detection of cleaved PARP.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Pirazóis/farmacologia , Piridinas/farmacologia , Esteroides/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Simulação de Acoplamento Molecular , Pirazóis/síntese química , Pirazóis/metabolismo , Piridinas/síntese química , Piridinas/metabolismo , Receptores Androgênicos/metabolismo , Esteroides/síntese química , Esteroides/metabolismo , Fatores de Transcrição/metabolismo
15.
Nat Immunol ; 20(7): 890-901, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209400

RESUMO

Progenitor-like CD8+ T cells mediate long-term immunity to chronic infection and cancer and respond potently to immune checkpoint blockade. These cells share transcriptional regulators with memory precursor cells, including T cell-specific transcription factor 1 (TCF1), but it is unclear whether they adopt distinct programs to adapt to the immunosuppressive environment. By comparing the single-cell transcriptomes and epigenetic profiles of CD8+ T cells responding to acute and chronic viral infections, we found that progenitor-like CD8+ T cells became distinct from memory precursor cells before the peak of the T cell response. We discovered a coexpression gene module containing Tox that exhibited higher transcriptional activity associated with more abundant active histone marks in progenitor-like cells than memory precursor cells. Moreover, thymocyte selection-associated high mobility group box protein TOX (TOX) promoted the persistence of antiviral CD8+ T cells and was required for the programming of progenitor-like CD8+ T cells. Thus, long-term CD8+ T cell immunity to chronic viral infection requires unique transcriptional and epigenetic programs associated with the transcription factor TOX.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Regulação da Expressão Gênica , Proteínas de Homeodomínio/genética , Infecção/etiologia , Análise de Célula Única , Animais , Biomarcadores , Imunoprecipitação da Cromatina , Epigênese Genética , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Homeodomínio/metabolismo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Memória Imunológica , Infecção/metabolismo , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Fatores de Tempo , Transcriptoma
16.
Mol Biol (Mosk) ; 53(3): 497-501, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31184615

RESUMO

Homeodomain transcription factors play a significant role in adipocyte differentiation. The role of Pbx1 and Prep1, proteins of the TALE family (the three amino acid loop extension), was previously established in adipocyte differentiation of mesenchymal stromal cells and 3T3-L1 cell line. In this study, with the use of RNA interference technology we show that another transcription factor from the same family, Meis1, which is a core protein of mature cardiomyocytes, represses adipogenesis to a greater degree than its paralog Meis2. A number of Meis target genes, markers of adipocytes, are identified. This may indicate the transcriptional mechanism of the effect of Meis1 on the adipocyte differentiation of mouse preadipocytes.


Assuntos
Adipócitos/citologia , Diferenciação Celular , Proteína Meis1/metabolismo , Miócitos Cardíacos/metabolismo , Adipócitos/metabolismo , Animais , Diferenciação Celular/genética , Proteínas de Homeodomínio/metabolismo , Camundongos , Células-Tronco/citologia , Células-Tronco/metabolismo
17.
J Photochem Photobiol B ; 195: 33-38, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31060031

RESUMO

Dysfunctional or death of retinal photoreceptors is an irreversible phenomenon that is closely associated with a broad range of retinal degenerative diseases, such as retinitis pigmentosa and age-related macular degeneration (AMD), resulting in successive loss of visual function and blindness. In search for viable treatment for retinal degenerative diseases, mesenchymal stem cells (MSCs) has demonstrated promising therapeutic capabilities to repair and replace damaged photoreceptor cells in both in vitro and in vivo conditions. Nevertheless, the dearth of MSC differentiation capacity into photoreceptors has limited its use in cell replacement therapy. Erythropoietin (EPO) has vital role in early neural retinal cell differentiation and demonstrated rescue potential on dying photoreceptor cells. Hence, we aimed to evaluate the differentiation capacity of MSCs into photoreceptor cells in the presence of human EPO protein. We derived the MSC from human Wharton's jelly of umbilical cord and transduced the cells with lentivirus particles encoding EPO and green fluorescent protein (GFP) as reporter gene. The transduced cells were selectively cultured and induced to differentiate into photoreceptors by exposing to photoreceptor differentiation cocktail. Our preliminary results showed that transduced cells exposed to induction medium had an enhanced differentiation capacity when compared to non-transduced cells. Our results demonstrated a novel strategy to increase the yield of in vitro photoreceptor differentiation and may be potentially useful in improving the efficiency of stem cell transplantation for ocular disorders.


Assuntos
Eritropoetina/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células Fotorreceptoras de Vertebrados/metabolismo , Diferenciação Celular , Células Cultivadas , Eritropoetina/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Células-Tronco Mesenquimais/citologia , Células Fotorreceptoras de Vertebrados/citologia , Rodopsina/metabolismo , Transativadores/metabolismo , Geleia de Wharton/citologia
18.
Nat Immunol ; 20(6): 687-700, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31061528

RESUMO

Most tissue-resident macrophage populations develop during embryogenesis, self-renew in the steady state and expand during type 2 immunity. Whether shared mechanisms regulate the proliferation of macrophages in homeostasis and disease is unclear. Here we found that the transcription factor Bhlhe40 was required in a cell-intrinsic manner for the self-renewal and maintenance of large peritoneal macrophages (LPMs), but not that of other tissue-resident macrophages. Bhlhe40 was necessary for the proliferation, but not the polarization, of LPMs in response to the cytokine IL-4. During infection with the helminth Heligmosomoides polygyrus bakeri, Bhlhe40 was required for cell cycling of LPMs. Bhlhe40 repressed the expression of genes encoding the transcription factors c-Maf and Mafb and directly promoted expression of transcripts encoding cell cycle-related proteins to enable the proliferation of LPMs. In LPMs, Bhlhe40 bound to genomic sites co-bound by the macrophage lineage-determining factor PU.1 and to unique sites, including Maf and loci encoding cell-cycle-related proteins. Our findings demonstrate a tissue-specific control mechanism that regulates the proliferation of resident macrophages in homeostasis and type 2 immunity.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Homeodomínio/genética , Homeostase/genética , Homeostase/imunologia , Imunidade/genética , Macrófagos/imunologia , Macrófagos/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Biomarcadores , Ciclo Celular/genética , Ciclo Celular/imunologia , Proliferação de Células , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Infecções por Helicobacter/genética , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Proteínas de Homeodomínio/metabolismo , Imunofenotipagem , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Transgênicos , Monócitos/imunologia , Monócitos/metabolismo , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Transcriptoma
19.
DNA Cell Biol ; 38(7): 700-707, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31090452

RESUMO

Substantial research has revealed that peroxisome proliferator-activated receptor-gamma (PPARG) plays a critical role in glucose homeostasis and lipid metabolism, and recent studies have shown different effects in the progression of different tumors. However, the role of PPARG and its target gene in clear cell renal cell carcinoma (ccRCC) are incompletely understood. Clinical data revealed abnormal glucolipid metabolism in primary ccRCC samples. In addition, transcriptional profiling indicated that PPARG expression was positively correlated, whereas Six2 expression was negatively correlated with the overall survival of ccRCC patients. Staining showed that PPARG was mainly expressed in tumor cell cytoplasm, and Six2 was localized to the nuclei. In a ccRCC cell line, PPARG activation promoted cell apoptosis, inhibited cell migration and proliferation, and reduced Six2 expression. Mechanistically, overexpressing Six2 downregulated E-cadherin expression and cell apoptosis, but PPARG activation reversed those effects. Taken together, PPARG promotes apoptosis and suppresses the migration and proliferation of ccRCC cells by inhibiting Six2. These findings reveal that the PPARG/Six2 axis acts as a central pathobiological mediator of ccRCC formation and as a potential therapeutic target for the treatment of patients with ccRCC.


Assuntos
Carcinoma de Células Renais/metabolismo , Proteínas de Homeodomínio/genética , Neoplasias Renais/metabolismo , Proteínas do Tecido Nervoso/genética , PPAR gama/genética , Apoptose , Caderinas/genética , Caderinas/metabolismo , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Feminino , Células HEK293 , Proteínas de Homeodomínio/metabolismo , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , PPAR gama/metabolismo
20.
Plant Mol Biol ; 100(4-5): 561-569, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31053987

RESUMO

KEY MESSAGE: Plant defensin AtPDF2.6 is not secreted to the apoplast and localized in cytoplasm. AtPDF2.6 is mainly expressed in root vascular bundles of xylem parenchyma cell, and significantly induced by Cd stress. AtPDF2.6 detoxicate cytoplasmic Cd via chelation, thus enhanced Cd tolerance in Arabidopsis. In order to detoxify the heavy metal cadmium (Cd), plants have evolved several mechanisms, among which chelation represents the major Cd-detoxification mechanism. In this study, we aimed to identify a new defensin protein involved in cytoplasmic Cd detoxification by using plant molecular genetics and physiological methods. The results of bioinformatic analysis showed that the Arabidopsis thaliana defensin gene AtPDF2.6 has a signal peptide that may mediate its secretion to the cell wall. Subcellular localization analysis revealed that AtPDF2.6 is localized to the cytoplasm and is not secreted to the apoplast, whereas histochemical analysis indicated that AtPDF2.6 is mainly expressed in the root xylem parenchyma cells and that its expression is significantly induced by Cd. An in vitro Cd-binding assay revealed that AtPDF2.6 has Cd-chelating activity. Heterologous overexpression of AtPDF2.6 increased Cd tolerance in Escherichia coli and yeast, and AtPDF2.6 overexpression significantly enhanced Cd tolerance in Arabidopsis, whereas functional disruption of AtPDF2.6 decreased Cd tolerance. These data suggest that AtPDF2.6 detoxifies cytoplasmic Cd via chelation and thereby enhances Cd tolerance in Arabidopsis. Our findings accordingly challenge the commonly accepted view of defensins as secreted proteins.


Assuntos
Proteínas de Arabidopsis/fisiologia , Arabidopsis/metabolismo , Cádmio/metabolismo , Proteínas de Homeodomínio/fisiologia , Poluentes do Solo/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Cádmio/farmacologia , Citoplasma/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Raízes de Plantas/metabolismo , Estresse Fisiológico , Regulação para Cima , Xilema/metabolismo
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