Cell survival is dicey without Dicer.
Ontology highlight
ABSTRACT:
SUBMITTER: Adams CM
PROVIDER: S-EPMC4279215 | biostudies-other | 2014 Jun
REPOSITORIES: biostudies-other
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Project description:The RNaseIII enzyme Dicer is required for mature microRNA production. Although extensive investigation has been carried out to determine the role of Dicer/miRNAs in the immune system, their function in mature CD8(+) T cells has not been examined. We deleted Dicer in mature polyclonal and TCR transgenic CD8(+) T cells using either tat-cre or the distal lck promoter, which drives cre expression after the stage of positive selection. Following antigenic challenge by a pathogen infection in vivo, Dicer-deleted CD8(+) T cells failed to accumulate at the usual peak of the response. Surprisingly however, we found that deletion of Dicer in mature CD8(+) T cells allowed them to respond more rapidly than control cells to TCR stimuli in vitro. In response to anti-CD3 plus anti-CD28 stimulation, Dicer-deleted T cells up-regulated CD69 faster and entered the first mitosis earlier than control T cells. In addition, activated Dicer(-/-) cells failed to rapidly down-regulate CD69 when removed from the TCR stimulus. As a probable consequence of this sustained CD69 expression, Dicer(-/-) T cells showed defective migration out of the central lymphoid organs in vivo. We identify miR-130/301, which are dramatically up-regulated following T-cell activation, as able to down-regulate CD69 expression via binding to a conserved site in the 3'UTR of CD69 mRNA. Thus, cellular functions dependent on Dicer expression are not required for the early steps in CD8(+) T-cell activation, but are essential for their survival and accumulation.
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Project description:Dicer, an endonuclease in RNase III family, is essential for the RNA interference (RNAi) pathway. Aberrant expression of Dicer has been shown in various cancers including some subtypes of T cell lymphoma (TCL), which influences patient prognosis. A single-nucleotide polymorphism (SNP) rs3742330A>G has been identified in the Dicer gene, located in the 3' untranslated region (3' UTR) that is important for mRNA transcript stability. We investigated whether rs3742330 is associated with the survival in 163 TCL patients. Significant association between Dicer rs3742330 and TCL survival were found. Patients carrying the GG genotype (n = 12) had a significantly increased overall survival (OS) compared with those carrying the GA and AA genotypes (n = 70 and n = 81, respectively; p = 0.031). Moreover, the significant association was maintained for patients with mature T type (n = 134; p = 0.026). In multivariate Cox-regression analysis, rs3742330 proved to be an independent predictor for OS, together with the commonly used International Prognostic Index (IPI) and BAFF rs9514828, another SNP we have previously reported to be associated with TCL survival, with hazard ratios (HRs) for patient death rate of 8.956 (95% CI, 1.210 to 66.318; p = 0.032) for the GA genotype and 10.145 (95% CI, 1.371 to 75.084; p = 0.023) for the AA genotype. Furthermore, we observed cumulative effects of Dicer rs3742330 and BAFF rs9514828 on TCL survival. Compared with patients carrying zero unfavorable genotype, those carrying one and two unfavorable genotypes had an increased risk of death with a HR of 7.104 (95% CI, 0.969-53.086; p = 0.054) and 14.932 (95% CI, 1.950-114.354; p = 0.009), respectively, with a significant dose-response trend (p(trend) = 0.004). In conclusion, Dicer rs3742330 is associated with TCL survival, suggesting that genetic variation might play a role in predicting prognosis of TCL patients.
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Project description:Inactivation of p53, the master regulator of cellular stress and damage signals, often allows cells that should die or senesce to live. Loss of Dicer, an RNase III-like enzyme critical in microRNA biogenesis, causes embryonic lethality and activation of the p53 pathway. Several nonhematopoietic cell types that contain inactivated p53 have been shown to survive Dicer deletion, suggesting that p53 loss may protect cells from the negative consequences of Dicer deletion. However, here, we report that loss of p53 did not provide a survival advantage to B cells, as they underwent rapid apoptosis upon Dicer deletion. Moreover, a deficiency in p53 neither rescued the Dicer deletion-induced delay in Myc-driven B-cell lymphomagenesis, nor allowed a single B-cell lymphoma to develop with biallelic deletion of Dicer. A p53 deficiency did, however, restore the pre-B/B-cell phenotype and CD19 surface expression of the lymphomas that emerged in conditional Dicer knockout Eμ-myc transgenic mice. Moreover, p53 loss in transformed B cells did not confer protection from apoptosis, as Dicer deletion in established p53-null B-cell lymphomas induced apoptosis, and all of the 1,260 B-cell lymphoma clones analyzed that survived Cre-mediated Dicer deletion retained at least one allele of Dicer. Moreover, Dicer deletion in lymphomas in vivo reduced tumor burden and prolonged survival. Therefore, inactivation of p53 is insufficient to allow untransformed B cells and B-cell lymphomas to survive without Dicer, presenting a potential therapeutic opportunity for the treatment of B-cell lymphomas.
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Project description:Clinical trials on cancer treatments frequently exclude patients with prior cancer, but more evidence is needed to understand their possible effects on outcomes. This study analyzed the prognostic impact of prior cancer in newly diagnosed non-small cell lung cancer (NSCLC) patients while accounting for various patient and cancer characteristics. Using population-based cancer registry data linked with administrative claims data, this retrospective cohort study examined patients aged 15-84 years diagnosed with NSCLC between 2010 and 2015 in Japan. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause mortality in patients with versus without prior cancer. The analysis was stratified according to NSCLC stage and diagnostic time intervals between prior cancers and the index NSCLC. We analyzed 9103 patients (prior cancer: 1416 [15.6%]; no prior cancer: 7687 [84.4%]). Overall, prior cancer had a non-significant mortality HR of 1.07 (95% CI: 0.97-1.17). Furthermore, prior cancer had a significantly higher mortality hazard for diagnostic time intervals of 3 years (HR: 1.23, 95% CI: 1.06-1.43) and 5 years (1.18, 1.04-1.33), but not for longer intervals. However, prior cancer in patients with more advanced NSCLC did not show a higher mortality risk for any diagnostic time interval. Smoking-related prior cancers and prior cancers with poorer prognosis were associated with poorer survival. NSCLC patients with prior cancer do not have an invariably higher risk of mortality, and should be considered for inclusion in clinical trials depending on their cancer stage.
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2007-10-31 | GSE9306 | GEO
Project description:Single-nucleotide polymorphisms (SNPs) in microRNA machinery genes might affect microRNA processing and subsequently impact tumorigenesis. The aim of this study was to investigate the associations between SNPs in microRNA machinery genes and hepatocellular carcinoma (HCC) in a Korean population. Genotyping of six SNPs in microRNA machinery genes was performed using blood samples from 147 patients with HCC and 209 healthy control subjects. None of the six SNPs in microRNA machinery genes were significantly associated with HCC development. However, among the models for six polymorphic loci-DICER (rs3742330 and rs13078), DROSHA (rs10719 and rs6877842), RAN (rs14035) and XPO5 (rs11077)-one allele combination (A-A-T-C-C-C) showed synergistic effects in terms of an increased risk of HCC development (odds ratio = 8.881, 95% confidence interval [CI] = 1.889-41.750; P = 0.002). Multivariate Cox proportional hazard regression analysis showed a significant survival benefit for the DICER rs3742330 GG compared with the AA type (hazard ratio [HR], 0.314; 95% CI, 0.135-0.730; P = 0.007) and for the RAN rs14035 CT compared with the CC genotype (HR, 0.587; 95% CI, 0.349-0.987; P = 0.044). Although we found no direct association between DICER (rs3742330 and rs13078), DROSHA (rs10719 and rs6877842), RAN (rs14035) or XPO5 (rs11077) polymorphisms and HCC risk, we demonstrated that DICER (rs3742330) and RAN (rs14035) were associated with the survival of HCC patients. Future studies with larger samples are needed to determine associations of SNPs in microRNA machinery genes with HCC risk and prognosis.
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