RESUMO
Mutations in RanBP2 (also known as Nup358), one of the main components of the cytoplasmic filaments of the nuclear pore complex, contribute to the overproduction of acute necrotizing encephalopathy (ANE1)-associated cytokines. Here we report that RanBP2 represses the translation of the interleukin 6 (IL6) mRNA, which encodes a cytokine that is aberrantly up-regulated in ANE1. Our data indicates that soon after its production, the IL6 messenger ribonucleoprotein (mRNP) recruits Argonautes bound to let-7 microRNA. After this mRNP is exported to the cytosol, RanBP2 sumoylates mRNP-associated Argonautes, thereby stabilizing them and enforcing mRNA silencing. Collectively, these results support a model whereby RanBP2 promotes an mRNP remodelling event that is critical for the miRNA-mediated suppression of clinically relevant mRNAs, such as IL6.
Assuntos
Proteínas Argonautas/genética , Fatores de Iniciação em Eucariotos/genética , Regulação da Expressão Gênica , MicroRNAs/genética , Chaperonas Moleculares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Regiões 3' não Traduzidas/genética , Proteínas Argonautas/metabolismo , Linhagem Celular Tumoral , Fatores de Iniciação em Eucariotos/metabolismo , Células HEK293 , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , MicroRNAs/metabolismo , Chaperonas Moleculares/metabolismo , Mutação , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Pancreatite Necrosante Aguda/genética , Pancreatite Necrosante Aguda/metabolismo , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , SumoilaçãoRESUMO
PURPOSE: The goal of this study was to determine the predictive value of prostate-specific antigen density (PSAD) plus Prostate Imaging Reporting and Data System (PI-RADS) category for the detection of clinically significant prostate cancer. MATERIALS AND METHODS: This retrospective study included 526 men without known prostate cancer (initial diagnosis group) and 133 men with prostate cancer grade group 1 (active surveillance group) who underwent magnetic resonance imaging-guided and/or systematic prostate biopsy procedures between August 2014 and October 2018. Prostate specific antigen (PSA), PSAD, and PI-RADS category were entered into logistic regression models for predicting clinically significant prostate cancer (grade group ≥2) at biopsy. Receiver operating characteristic curve analysis was performed to assess model accuracy. RESULTS: The area under the curve (AUC) increased when PSAD was combined with PI-RADS in the initial diagnosis group (difference in AUCâ¯=â¯0.031; 95% confidence interval: 0.012, 0.050; Pâ¯=â¯0.002) but not in the active surveillance group (difference in AUCâ¯=â¯0.016; 95% confidence interval: -0.040, 0.071; Pâ¯=â¯0.579). When a PSAD threshold of 0.15 was applied, the frequency of clinically significant prostate cancer in patients with a PI-RADS score of 3 or lower decreased from 9.8% to 5.6% in the initial diagnosis group and from 10.7% to 2.7% in the active surveillance group. CONCLUSIONS: The addition of PSAD improves the predictive performance of PI-RADS in men without known prostate cancer. A PSAD threshold of 0.15 can help to minimize the number of missed clinically significant prostate cancer cases in men with a PI-RADS score of 3 or lower who decide to defer biopsy.
Assuntos
Antígeno Prostático Específico/sangue , Próstata/patologia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico por imagem , Idoso , Sistemas de Dados , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Valor Preditivo dos Testes , Neoplasias da Próstata/patologia , Estudos RetrospectivosRESUMO
BACKGROUND/AIM: Carbonic anhydrase IX (CA9) catalyses the interconversion of carbon dioxide to carbonic acid and bicarbonate and is considered a putative biomarker of tumour hypoxia. We set out to evaluate the prognostic significance of CA9 in prostate cancer. PATIENTS AND METHODS: Plasma samples were assessed from 68 men with high-risk localised prostate cancer treated with radical prostatectomy (RP) or radiotherapy (RT), and 20 men with castration-resistant prostate cancer (CRPC) treated with docetaxel chemotherapy between 2010 and 2012 at the Princess Margaret Cancer Centre, Canada. RESULTS: Of the 68 patients with high-risk localised prostate cancer, 57 underwent RP and 11 underwent RT. Baseline CA9 was not associated with recurrence or prostate-specific antigen in either group (p=0.98 and 0.20, respectively). CA9 levels before chemotherapy correlated with overall survival (r=-0.37; two-sided p=0.11). CONCLUSION: Baseline CA9 in men with CRPC may portend a more aggressive prostate cancer phenotype with poorer survival.
Assuntos
Antígenos de Neoplasias/sangue , Anidrase Carbônica IX/sangue , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/diagnóstico , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Idoso , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Docetaxel , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Fenótipo , Prognóstico , Antígeno Prostático Específico/sangue , Prostatectomia , Neoplasias da Próstata/mortalidade , Neoplasias de Próstata Resistentes à Castração/mortalidade , Taxoides/uso terapêutico , Resultado do TratamentoRESUMO
Six years ago, the Singer lab published a landmark paper which described how individual mRNA particles cross the nuclear pore complex in mammalian tissue culture cells. This involved the simultaneous imaging of mRNAs, each labeled by a large number of tethered fluorescent proteins and fluorescently tagged nuclear pore components. Now two groups have applied this technique to the budding yeast Saccharomyces cerevisiae. Their results indicate that in the course of nuclear export, mRNAs likely engage complexes that are present on either side of the pore and that these interactions are modulated by proteins present in the messenger ribonucleoprotein (mRNP) complex. These findings lend support to the notion that just before and/or after the completion of nuclear export, mRNPs undergo one or more maturation steps that prepare the packaged mRNAs for translation. These results represent new and exciting insights into the mechanism of mRNA nuclear export.