RESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) has a high mortality rate, and the mechanisms underlying tumor development and progression remain unclear. However, inactivated tumor suppressor genes might play key roles. DNA methylation is a critical regulatory mechanism for inactivating tumor suppressor genes in HCC. Therefore, this study investigated methylation-related tumor suppressors in HCC to identify potential biomarkers and therapeutic targets. METHODS: We assessed genome-wide DNA methylation in HCC using whole genome bisulfite sequencing (WGBS) and RNA sequencing, respectively, and identified the differential expression of methylation-related genes, and finally screened phosphodiesterase 7B (PDE7B) for the study. The correlation between PDE7B expression and clinical features was then assessed. We then analyzed the changes of PDE7B expression in HCC cells before and after DNA methyltransferase inhibitor treatment by MassArray nucleic acid mass spectrometry. Furthermore, HCC cell lines overexpressing PDE7B were constructed to investigate its effect on HCC cell function. Finally, GO and KEGG were applied for the enrichment analysis of PDE7B-related pathways, and their effects on the expression of pathway proteins and EMT-related factors in HCC cells were preliminarily explored. RESULTS: HCC exhibited a genome-wide hypomethylation pattern. We screened 713 hypomethylated and 362 hypermethylated mCG regions in HCC and adjacent normal tissues. GO analysis showed that the main molecular functions of hypermethylation and hypomethylation were "DNA-binding transcriptional activator activity" and "structural component of ribosomes", respectively, whereas KEGG analysis showed that they were enriched in "bile secretion" and "Ras-associated protein-1 (Rap1) signaling pathway", respectively. PDE7B expression was significantly down-regulated in HCC tissues, and this low expression was negatively correlated with recurrence and prognosis of HCC. In addition, DNA methylation regulates PDE7B expression in HCC. On the contrary, overexpression of PDE7B inhibited tumor proliferation and metastasis in vitro. In addition, PDE7B-related genes were mainly enriched in the PI3K/ATK signaling pathway, and PDE7B overexpression inhibited the progression of PI3K/ATK signaling pathway-related proteins and EMT. CONCLUSION: PDE7B expression in HCC may be regulated by promoter methylation. PDE7B can regulate the EMT process in HCC cells through the PI3K/AKT pathway, which in turn affects HCC metastasis and invasion.
Asunto(s)
Carcinoma Hepatocelular , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7 , Neoplasias Hepáticas , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Femenino , Humanos , Masculino , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/metabolismo , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Invasividad Neoplásica/genética , Metástasis de la Neoplasia , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/genéticaRESUMEN
BACKGROUND: PDEs regulate cAMP levels which is critical for PKA activity-dependent activation of CREB-mediated transcription in learning and memory. Inhibitors of PDEs like PDE4 and Pde7 improve learning and memory in rodents. However, the role of PDE7 in cognition or learning and memory has not been reported yet. METHODS: Therefore, we aimed to explore the cognitive effects of a PDE7 subtype, PDE7a, using combined pharmacological and genetic approaches. RESULTS: PDE7a-nko mice showed deficient working memory, impaired novel object recognition, deficient spatial learning & memory, and contextual fear memory, contrary to enhanced cued fear memory, highlighting the potential opposite role of PDE7a in the hippocampal neurons. Further, pharmacological inhibition of PDE7 by AGF2.20 selectively strengthens cued fear memory in C57BL/6 J mice, decreasing its extinction but did not affect cognitive processes assessed in other behavioral tests. The further biochemical analysis detected deficient cAMP in neural cell culture with genetic excision of the PDE7a gene, as well as in the hippocampus of PDE7a-nko mice in vivo. Importantly, we found overexpression of PKA-R and the reduced level of pPKA-C in the hippocampus of PDE7a-nko mice, suggesting a novel mechanism of the cAMP regulation by PDE7a. Consequently, the decreased phosphorylation of CREB, CAMKII, eif2a, ERK, and AMPK, and reduced total level of NR2A have been found in the brain of PDE7a-nko animals. Notably, genetic excision of PDE7a in neurons was not able to change the expression of NR2B, BDNF, synapsin1, synaptophysin, or snap25. CONCLUSION: Altogether, our current findings demonstrated, for the first time, the role of PDE7a in cognitive processes. Future studies will untangle PDE7a-dependent neurobiological and molecular-cellular mechanisms related to cAMP-associated disorders.
Asunto(s)
Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7 , Memoria a Corto Plazo , Aprendizaje Espacial , Animales , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Miedo , Hipocampo/metabolismo , Ratones Endogámicos C57BL , Sinaptofisina/metabolismo , Memoria , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/metabolismoRESUMEN
Neurodegenerative illness develops as a result of genetic defects that cause changes at numerous levels, including genomic products and biological processes. It entails the degradation of cyclic nucleotides, cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP). PDE7 modulates intracellular cAMP signalling, which is involved in numerous essential physiological and pathological processes. For the therapy of neurodegenerative illnesses, the normalization of cyclic nucleotide signalling through PDE inhibition remains intriguing. In this article, we shall examine the role of PDEs in neurodegenerative diseases. Alzheimer's disease, Multiple sclerosis, Huntington's disease, Parkinson's disease, Stroke, and Epilepsy are related to alterations in PDE7 expression in the brain. Earlier, animal models of neurological illnesses including Alzheimer's disease, Parkinson's disease, and multiple sclerosis have had significant results to PDE7 inhibitors, i.e., VP3.15; VP1.14. In addition, modulation of CAMP/CREB/GSK/PKA signalling pathways involving PDE7 in neurodegenerative diseases has been addressed. To understand the etiology, treatment options of these disorders mediated by PDE7 and its subtypes can be the focus of future research.
Asunto(s)
Enfermedad de Alzheimer , Esclerosis Múltiple , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Esclerosis Múltiple/tratamiento farmacológicoRESUMEN
Phosphodiesterase 7 (PDE7), one of the 11 phosphodiesterase (PDE) families, specifically hydrolyzes cyclic 3', 5'-adenosine monophosphate (cAMP). PDE7 is involved in many important functional processes in physiology and pathology by regulating intracellular cAMP signaling. Studies have demonstrated that PDE7 is widely expressed in the central nervous system (CNS) and potentially related to pathogenesis of many CNS diseases. Here, we summarized the classification and distribution of PDE7 in the brain and its functional roles in the mediation of CNS diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and schizophrenia. It is expected that the findings collected here will not only lead to a better understanding of the mechanisms by which PDE7 mediates CNS function and diseases, but also aid in the development of novel drugs targeting PDE7 for treatment of CNS diseases.
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Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/metabolismo , Esclerosis Múltiple/metabolismo , Enfermedad de Parkinson/metabolismo , Esquizofrenia/metabolismo , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/antagonistas & inhibidores , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/genética , Humanos , Terapia Molecular Dirigida , Esclerosis Múltiple/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/uso terapéutico , Isoformas de ProteínasRESUMEN
Circular RNA plays an important role in the progression of sepsis. Circ_0091702 has been found to be an important regulator of sepsis progression, so its role and mechanism in sepsis progression deserve to be further explored. Lipopolysaccharide (LPS) could suppress cell viability, while enhance cell apoptosis and inflammation to induce cell injury. Circ_0091702 was downregulated in LPS-induced HK2 cells, and its overexpression alleviated LPS-induced cell injury. MiR-182 could be sponged by circ_0091702. Moreover, miR-182 inhibitor could relieve LPS-induced cell injury, and its overexpression also reversed the inhibition of circ_0091702 on LPS-induced cell injury. PDE7A was a target of miR-182, and its expression was reduced in LPS-induced HK2 cells. Additionally, silencing of PDE7A reversed the suppressive effect of circ_0091702 on LPS-induced cell injury. Our data suggested that circ_0091702 sponged miR-182 to regulate PDE7A, thereby alleviating LPS-induced cell injury in sepsis.
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Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/metabolismo , Lipopolisacáridos/farmacología , MicroARNs/metabolismo , ARN Circular/fisiología , Línea Celular , Biología Computacional/métodos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/genética , Técnicas de Silenciamiento del Gen , HumanosRESUMEN
Phosphodiesterase 7 (PDE7), a cAMP-specific PDE family, insensitive to rolipram, is present in many immune cells, including T lymphocytes. Two genes of PDE7 have been identified: PDE7A and PDE7B with three or four splice variants, respectively. Both PDE7A and PDE7B are expressed in T cells, and the predominant splice variant in these cells is PDE7A1. PDE7 is one of several PDE families that terminates biological functions of cAMP-a major regulating intracellular factor. However, the precise role of PDE7 in T cell activation and function is still ambiguous. Some authors reported its crucial role in T cell activation, while according to other studies PDE7 activity was not pivotal to T cells. Several studies showed that inhibition of PDE7 by its selective or dual PDE4/7 inhibitors suppresses T cell activity, and consequently T-mediated immune response. Taken together, it seems quite likely that simultaneous inhibition of PDE4 and PDE7 by dual PDE4/7 inhibitors or a combination of selective PDE4 and PDE7 remains the most interesting therapeutic target for the treatment of some immune-related disorders, such as autoimmune diseases, or selected respiratory diseases. An interesting direction of future studies could also be using a combination of selective PDE7 and PDE3 inhibitors.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/metabolismo , Inhibidores de Fosfodiesterasa/farmacología , Enfermedades Respiratorias/inmunología , Linfocitos T/metabolismo , Empalme Alternativo , Animales , Enfermedades Autoinmunes/tratamiento farmacológico , División Celular , AMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/genética , Humanos , Activación de Linfocitos , Inhibidores de Fosfodiesterasa 4/farmacología , Inhibidores de Fosfodiesterasa/uso terapéutico , Enfermedades Respiratorias/tratamiento farmacológico , Linfocitos T/efectos de los fármacosRESUMEN
BACKGROUND: This study investigated the relationship between smoking and hearing loss and deafness (HLD) and whether the relationship is modified by genetic variation. Data for these analyses was from the subset of Japanese American families collected as part of the American Diabetes Association Genetics of Non-insulin Dependent Diabetes Mellitus study. Logistic regression with generalized estimating equations assessed the relationship between HLD and smoking. Nonparametric linkage analysis identified genetic regions harboring HLD susceptibility genes and ordered subset analysis was used to identify regions showing evidence for gene-smoking interactions. Genetic variants within these candidate regions were then each tested for interaction with smoking using logistic regression models. RESULTS: After adjusting for age, sex, diabetes status and smoking duration, for each pack of cigarettes smoked per day, risk of HLD increased 4.58 times (odds ratio (OR)â¯=â¯4.58; 95% Confidence Interval (CI): (1.40,15.03)), and ever smokers were over 5 times more likely than nonsmokers to report HLD (ORâ¯=â¯5.22; 95% CI: (1.24, 22.03)). Suggestive evidence for linkage for HLD was observed in multiple genomic regions (Chromosomes 5p15, 8p23 and 17q21), and additional suggestive regions were identified when considering interactions with smoking status (Chromosomes 7p21, 11q23, 12q32, 15q26, and 20q13) and packs-per-day (Chromosome 8q21). CONCLUSIONS: To our knowledge this was the first report of possible gene-by-smoking interactions in HLD using family data. Additional work, including independent replication, is needed to understand the basis of these findings. HLD are important public health issues and understanding the contributions of genetic and environmental factors may inform public health messages and policies.
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Asiático/genética , Sordera/genética , Interacción Gen-Ambiente , Audición/genética , Polimorfismo de Nucleótido Simple , Fumar/efectos adversos , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Anciano , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/genética , Sordera/etnología , Sordera/fisiopatología , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Japón/etnología , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Fenotipo , Prevalencia , Proteínas Represoras/genética , Medición de Riesgo , Factores de Riesgo , Fumar/etnología , Estados Unidos/epidemiologíaRESUMEN
Parkinson's disease is characterized by a loss of dopaminergic neurons in the ventral midbrain. This disease is diagnosed when around 50% of these neurons have already died; consequently, therapeutic treatments start too late. Therefore, an urgent need exists to find new targets involved in the onset and progression of the disease. Phosphodiesterase 7 (PDE7) is a key enzyme involved in the degradation of intracellular levels of cyclic adenosine 3', 5'-monophosphate in different cell types; however, little is known regarding its role in neurodegenerative diseases, and specifically in Parkinson's disease. We have previously shown that chemical as well as genetic inhibition of this enzyme results in neuroprotection and anti-inflammatory activity in different models of neurodegenerative disorders, including Parkinson's disease. Here, we have used in vitro and in vivo models of Parkinson's disease to study the regulation of PDE7 protein levels. Our results show that PDE7 is upregulated after an injury both in the human dopaminergic cell line SH-SY5Y and in primary rat mesencephalic cultures and after lipopolysaccharide or 6-hidroxydopamine injection in the Substantia nigra pars compacta of adult mice. PDE7 increase takes place mainly in degenerating dopaminergic neurons and in microglia cells. This enhanced expression appears to be direct since 6-hydroxydopamine and lipopolysaccharide increase the expression of a 962-bp fragment of its promoter. Taking together, these results reveal an essential function for PDE7 in the pathways leading to neurodegeneration and inflammatory-mediated brain damage and suggest novel roles for PDE7 in neurodegenerative diseases, specifically in PD, opening the door for new therapeutic interventions.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/metabolismo , Enfermedad de Parkinson/enzimología , Enfermedad de Parkinson/patología , Animales , Apoptosis , Línea Celular , Células Cultivadas , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/genética , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/enzimología , Neuronas Dopaminérgicas/patología , Embrión de Mamíferos/enzimología , Humanos , Masculino , Mesencéfalo/enzimología , Mesencéfalo/patología , Neuroglía/enzimología , Neuroglía/patología , Oxidopamina , Regiones Promotoras Genéticas/genética , Ratas Wistar , Sustancia Negra/enzimología , Sustancia Negra/patologíaRESUMEN
Acute myeloid leukemia (AML) is a malignant hematological disease in which nearly half have normal cytogenetics. We have tried to find some significant molecular markers for this part of the cytogenetic normal AML, which hopes to provide a benefit for the diagnosis, molecular typing and prognosis prediction of AML patients. In the present study, we calculated and compared the gene expression profiles of cytogenetically normal acute myeloid leukemia (CN-AML) patients in database of The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and dataset Vizome (a total of 632 CN-AML samples), and we have demonstrated a correlation between PDE7B gene and CN-AML. Then we proceeded to a survival analysis and prognostic risk analysis between the expression levels of PDE7B gene and CN-AML patients. The result showed that the event-free survival (EFS) and overall survival (OS) were significantly shorter in CN-AML patients with high PDE7B levels in each dataset. And we detected a significantly higher expression level of PDE7B in the leukemia stem cell (LSC) positive group. The Cox proportional hazards regression model showed that PDE7B is an independent risk predictor for CN-AML. All results indicate that PDE7B is an unfavorable prognostic factor for CN-AML.
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Biomarcadores de Tumor/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/genética , Análisis Citogenético/métodos , Perfilación de la Expresión Génica/métodos , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide/genética , Enfermedad Aguda , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide/diagnóstico , Masculino , Persona de Mediana Edad , Análisis Multivariante , PronósticoRESUMEN
Members of microRNA-200 (miRNA-200) family have a regulatory role in epithelial to mesenchymal transition (EMT) by suppressing Zeb1 and Zeb2 expression. Consistent with its role in suppressing EMT, Hsa-miR-200c-3p (miR-200c), a member of miR-200 family is poorly expressed in mesenchymal-like triple-negative breast cancer (TNBC) cells and ectopic miR-200c expression suppresses cell migration. In this study, we demonstrated that miR-200c potently inhibited TNBC cell growth and tumor development in a mechanism distinct from its ability to downregulate Zeb1 and Zeb2 expression, because silencing them only marginally affected TNBC cell growth. We identified phosphodiesterase 7B (PDE7B) as a bona fide miR-200c target. Importantly, miR-200c-led inhibition in cell growth and tumor development was prevented by forcing PDE7B transgene expression, while knockdown of PDE7B effectively inhibited cell growth. These results suggest that miR-200c inhibits cell growth by targeting PDE7B mRNA. To elucidate mechanism underlying miR-200c/PDE7B regulation of TNBC cell growth, we showed that cAMP concentration was lower in TNBC cells compared with estrogen receptor-positive (ER + ) cells, and that both miR-200c and PDE7B siRNAs were able to increase cAMP concentration in TNBC cells. High level of cellular cAMP has been shown to induce cell cycle arrest and apoptosis in TNBC cells. Our observation that ectopic expression of miR-200c triggered apoptosis indicates that it does so by elevating level of cellular cAMP. Analysis of breast tumor gene expression datasets revealed an inverse association between miR-200c and PDE7B expression. Especially, both low miR-200c and high PDE7B expression were correlated with poor survival of breast cancer patients. Our study supports a critical role of miR-200c/PDE7B relationship in TNBC tumorigenesis.
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Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/biosíntesis , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , MicroARNs/biosíntesis , Proteínas de Neoplasias/biosíntesis , ARN Neoplásico/biosíntesis , Neoplasias de la Mama Triple Negativas/metabolismo , Línea Celular Tumoral , AMP Cíclico/genética , AMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/genética , Femenino , Humanos , MicroARNs/genética , Proteínas de Neoplasias/genética , ARN Neoplásico/genética , Neoplasias de la Mama Triple Negativas/mortalidad , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Adrenal cortex steroids are essential for body homeostasis, and adrenal insufficiency is a life-threatening condition. Adrenal endocrine activity is maintained through recruitment of subcapsular progenitor cells that follow a unidirectional differentiation path from zona glomerulosa to zona fasciculata (zF). Here, we show that this unidirectionality is ensured by the histone methyltransferase EZH2. Indeed, we demonstrate that EZH2 maintains adrenal steroidogenic cell differentiation by preventing expression of GATA4 and WT1 that cause abnormal dedifferentiation to a progenitor-like state in Ezh2 KO adrenals. EZH2 further ensures normal cortical differentiation by programming cells for optimal response to adrenocorticotrophic hormone (ACTH)/PKA signaling. This is achieved by repression of phosphodiesterases PDE1B, 3A, and 7A and of PRKAR1B. Consequently, EZH2 ablation results in blunted zF differentiation and primary glucocorticoid insufficiency. These data demonstrate an all-encompassing role for EZH2 in programming steroidogenic cells for optimal response to differentiation signals and in maintaining their differentiated state.
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Corteza Suprarrenal/enzimología , Subunidad RIbeta de la Proteína Quinasa Dependiente de AMP Cíclico/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Transducción de Señal , Corteza Suprarrenal/metabolismo , Animales , Diferenciación Celular , Subunidad RIbeta de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Femenino , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Esteroides/metabolismo , Zona Fascicular/citología , Zona Fascicular/enzimología , Zona Fascicular/metabolismo , Zona Glomerular/citología , Zona Glomerular/enzimología , Zona Glomerular/metabolismoRESUMEN
"BRCAX" refers breast cancers occurring in women with a family history predictive of being a BRCA1/2 mutation carrier, but BRCA1/2 genetic screening has failed to find causal mutations. In this study, we report the findings of the genetic architecture of BRCAX with novel and redefined candidate loci and their potential impacts on preventive strategy. We performed a genome-wide association study involving 1,469 BRCAX cases from the Korean Hereditary Breast Cancer study, and high-risk breast cancer cases (1,482 Asians and 9,902 Europeans) from the Breast Cancer Association Consortium. We also evaluated the previously reported susceptibility loci for their roles in the high-risk breast cancers. We have identified three novel loci (PDE7B, UBL3, and a new independent marker in CDKN2B-AS1) associated with BRCAX, and replicated previously reported SNPs (24 of 92) and moderate/high-penetrance (seven of 23) genes for Korean BRCAX. For the novel candidate loci, evidence supported their roles in regulatory function. We estimated that the common low-penetrance loci might explain a substantial part of high-risk breast cancer (39.4% for Koreans and 24.0% for Europeans). Our study findings suggest that common genetic markers with lower penetrance constitute a part of susceptibility to high-risk breast cancers, with potential implications for a more comprehensive genetic screening test.
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Neoplasias de la Mama/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/genética , ARN Largo no Codificante/genética , Ubiquitinas/genética , Adulto , Pueblo Asiatico/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Mama/patología , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Persona de Mediana Edad , Mutación , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
The Leydig cell physiology displays a circadian rhythm driven by a complex interaction of the reproductive axis hormones and circadian system. The final output of this regulatory process is circadian pattern of steroidogenic genes expression and testosterone production. Aging gradually decreases robustness of rhythmic testosterone secretion without change in pattern of LH secretion. Here, we analyzed effect of aging on circadian variation of cAMP and cGMP signaling in Leydig cells. Results showed opposite effect of aging on cAMP and cGMP daily variation. Reduced amplitude of cAMP circadian oscillation was probably associated with changed expression of genes involved in cAMP production (increased circadian pattern of Adcy7, Adcy9, Adcy10 and decreased Adcy3); cAMP degradation (increased Pde4a, decreased Pde8b, canceled rhythm of Pde4d, completely reversed circadian pattern of Pde7b and Pde8a); and circadian expression of protein kinase A subunits (Prkac/PRKAC and Prkar2a). Aging stimulates expression of genes responsible for cGMP production (Nos2, Gucy1a3 and Gucy1b3/GUCYB3) and degradation (Pde5a, Pde6a and Pde6h) but the overall net effect is elevation of cGMP circadian oscillations in Leydig cells. In addition, the expression of cGMP-dependent kinase, Prkg1/PRKG1 is up-regulated. It seems that aging potentiate cGMP- and reduce cAMP-signaling in Leydig cells. Since both signaling pathways affect testosterone production and clockwork in the cells, further insights into these signaling pathways will help to unravel disorders linked to the circadian timing system, aging and reproduction.
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Envejecimiento/fisiología , Ritmo Circadiano/fisiología , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Células Intersticiales del Testículo/metabolismo , Adenilil Ciclasas/genética , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/genética , Regulación de la Expresión Génica , Células Intersticiales del Testículo/fisiología , Masculino , Óxido Nítrico/metabolismo , Ratas Wistar , Testosterona/metabolismoRESUMEN
BACKGROUND: We investigated phosphodiesterase 7B (PDE7B), neuromedin B receptor (NMBR) and epilepsy progressive myoclonus type 2A (EPM2A) genes in schizophrenia (SCZ). To the best of our knowledge, these genes have been poorly investigated in studies of SCZ. METHODS: Five hundred and seventy-three SCZ inpatients of Korean ethnicity and 560 healthy controls were genotyped for 2 PDE7B, 3 NMBR and 3 EPM2A polymorphisms. Differences in the allelic and genetic frequencies among healthy subjects and patients were calculated using the x03C7;2 statistics. Repeated-measure ANOVA was used to test possible influences of single-nucleotide polymorphisms on treatment efficacy. In case of positive findings, clinical and demographic variables were added as covariates, in order to investigate possible stratixFB01;cation bias. RESULTS: The rs2717 and rs6926279 within the NMBR gene and rs702304 and rs2235481 within the EPM2A gene were associated with SCZ liability. rs1415744 was also associated with Positive and Negative Symptom Scale negative clinical improvement. The results remained the same after inclusion of the covariates and were partially confirmed in the allelic and haplotype analyses. CONCLUSION: Our preliminary findings suggest a possible role of NMBR and EPM2A genes in SCZ susceptibility and, for the second one, also in antipsychotic pharmacogenetics. Nonetheless, further research is needed to conxFB01;rm our findings.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/genética , Proteínas Tirosina Fosfatasas no Receptoras/genética , Receptores de Bombesina/genética , Esquizofrenia/genética , Adulto , Antipsicóticos/uso terapéutico , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Variantes Farmacogenómicas/genética , Esquizofrenia/tratamiento farmacológico , Adulto JovenRESUMEN
In developed countries, endometrial cancer (EC) is the most common malignancy among women. Unopposed estrogen therapy, obesity, nulliparity, diabetes mellitus and arterial hypertension have been linked to an increased risk of EC. However, the molecular mechanisms of EC oncogenesis and metastasis have not yet been fully elucidated. Our recent studies of microRNA (miRNA) expression signatures revealed that the microRNA-1/133a (miR1/133a) cluster is frequently downregulated in various types of human cancers. However, the functional role of the miR1/133a cluster in EC cells is still unknown. Thus, the aim of this study was to investigate the functional significance of the miR1/133a cluster and its regulated molecular targets, with an emphasis on the contributions of miR1/133a to EC oncogenesis and metastasis. We found that the expression levels of miR1 and miR133a were significantly reduced in EC tissues. Moreover, restoration of mature miR1 or miR133a miRNAs significantly inhibited cancer cell migration and invasion, suggesting that these clustered miRNAs act as tumor suppressors. Prediction of miRNA targets revealed that phosphodiesterase 7A (PDE7A) was a potential target gene regulated by both miR1 and miR133a. PDE7A was confirmed to be overexpressed in EC clinical specimens and silencing of PDE7A significantly inhibited cancer cell migration and invasion. Our data demonstrated that downregulation of the miR1/133a cluster promoted cancer cell migration and invasion via overexpression of PDE7A in EC cells. Elucidation of the molecular networks regulated by tumor-suppressive miRNAs will provide insights into the molecular mechanisms of EC oncogenesis and metastasis.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/genética , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , MicroARNs/genética , Regiones no Traducidas 3' , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Movimiento Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Familia de Multigenes , Invasividad NeoplásicaRESUMEN
Different studies have suggested that the nucleotide cyclic adenosine 3', 5'-monophosphate can actively play an important role as a neuroprotective and anti-inflammatory agent after a brain injury. The phosphodiesterase 7 (PDE7) enzyme is one of the enzymes responsible for controlling specifically the intracellular levels of cyclic adenosine 3', 5'-monophosphate in the immune and central nervous systems. Therefore, this enzyme could play an important role in brain inflammation and neurodegeneration. In this regard, using different chemical inhibitors of PDE7 we have demonstrated their neuroprotective and anti-inflammatory activity in different models of neurodegenerative disorders, including Parkinson's disease (PD). In the present study, we have used the toxin 6-hydroxydopamine and lipopolysaccharide to model PD and explore the protective effects of PDE7B deficiency in dopaminergic neurons cell death. Lentivirus-mediated PDE7B deprivation conferred marked in vitro and in vivo neuroprotection against 6-hydroxydopamine and lipopolysaccharide toxicity in dopaminergic neurons and preserved motor function involving the dopamine system in mouse. Our results substantiate previous data and provide a validation of PDE7B enzyme as a valuable new target for therapeutic development in the treatment of PD.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/antagonistas & inhibidores , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/genética , Silenciador del Gen , Lentivirus/genética , Actividad Motora/genética , Degeneración Nerviosa/genética , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/terapia , Interferencia de ARN , ARN Interferente Pequeño/genética , Animales , Células Cultivadas , Sistema Nervioso Central/metabolismo , AMP Cíclico/metabolismo , AMP Cíclico/fisiología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/deficiencia , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/fisiología , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/fisiología , Encefalitis/genética , Humanos , Sistema Inmunológico/metabolismo , Masculino , Ratones Endogámicos C57BL , Terapia Molecular Dirigida , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatologíaRESUMEN
In order to determine the relationship between expression of cyclic nucleotide phosphodiesterase isoform 7B (PDE7B) and mantle cell lymphoma (MCL) progression, PDE7B mRNA expression was measured by qRT-PCR in 21 untreated MCL patients with bone marrow involvement and 20 healthy donors. The expression level of PDE7B was markedly higher in MCL patients compared with normal controls (P=0.001), and the higher level of PDE7B expression was associated with unfavorable cytogenetic characteristics in MCL. It was showed that higher expression of PDE7B might be a novel unfavorable prognostic indicator in MCL, which possess important clinical significance.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/biosíntesis , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Linfoma de Células del Manto/enzimología , Linfoma de Células del Manto/mortalidad , Proteínas de Neoplasias/biosíntesis , ARN Mensajero/biosíntesis , ARN Neoplásico/biosíntesis , Adulto , Anciano , Médula Ósea/enzimología , Médula Ósea/patología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/genética , Supervivencia sin Enfermedad , Femenino , Humanos , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/patología , Linfoma de Células del Manto/terapia , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Valor Predictivo de las Pruebas , ARN Mensajero/genética , ARN Neoplásico/genética , Estudios Retrospectivos , Tasa de SupervivenciaAsunto(s)
Andrógenos/metabolismo , Doping en los Deportes , Técnicas de Genotipaje , Testosterona/metabolismo , Andrógenos/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/metabolismo , Doping en los Deportes/etnología , Epitestosterona/genética , Epitestosterona/metabolismo , Epitestosterona/orina , Genotipo , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Humanos , Antígenos de Histocompatibilidad Menor , Sensibilidad y Especificidad , Esteroide 17-alfa-Hidroxilasa/genética , Esteroide 17-alfa-Hidroxilasa/metabolismo , Testosterona/genética , Testosterona/orinaRESUMEN
There are eleven families of phosphodiesterases that regulate cellular levels of cyclic nucleotides by degradation of cAMP or cGMP. Knowledge of the expression sites of different PDE genes in brain is of special importance for studies on development of specific inhibitors considering that, for example, PDE4 inhibitor treatments exhibit profound anti-inflammatory effects. To address possible species differences we examined the expression of mRNAs coding for the cAMP specific PDE4 and PDE7 families since inhibitors have been used in clinic for schizophrenia, mood disorders, cognition and inflammatory diseases treatment. We have compared the expression of these PDEs in mouse brain by in situ hybridization histochemistry in comparison with rat brain and found that their neuroanatomical distribution differs in a few areas.
Asunto(s)
Encéfalo/enzimología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/metabolismo , ARN Mensajero/metabolismo , Animales , Encéfalo/anatomía & histología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/genética , Hibridación in Situ , Isoenzimas/genética , Isoenzimas/metabolismo , Ratones , Ratas , Especificidad de la EspecieRESUMEN
Type 7 phosphodiesterases (PDE7) are responsible for the decrease of intracellular cyclic AMP (cAMP) in many cells involved in allergic asthma by suppressing their potential to respond to many activating stimuli. The elevation of intracellular cAMP has been associated with immunosuppressive and anti-inflammatory activities and represents a potential treatment of asthma. Our aim was to evaluate the impact of the deletion of the murine phosphodiesterase (PDE)7B gene and then to evaluate the efficacy of a newly described selective PDE7A and -B inhibitor on an ovalbumin (OVA)-induced airway inflammation and airway hyperreactivity (AHR) model in mice. Inflammation was determined 72 h after single OVA challenge or 24 h after multiple challenges by the relative cell influx and cytokine content in bronchoalveolar lavage fluid. AHR and immunoglobulin E levels in serum were determined after multiple challenges. For the first time, we have demonstrated that the deletion of the PDE7B gene or the pharmacological inhibition of PDE7A and -B had no effect on all the parameters looked at in this model. These results highlight the absence of any implication of the PDE7 enzyme in our model.