XIAP mRNA levels but not XAF1 or XIAP/XAF1 mRNA levels predict pathological response in bladder cancer patients treated with neoadjuvant chemotherapy

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 20030-20030
Author(s):  
M. B. Pinho ◽  
J. Sellos ◽  
F. Costas ◽  
D. Herchenhorn ◽  
F. A. Peixoto ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Mrna Expression ◽  
Cancer Patients ◽  
Pathological Response ◽  
Negative Regulator ◽  
Inhibitor Of Apoptosis ◽  
Mrna Levels ◽  
Bivariate Correlation ◽  
Xiap Expression

20030 Background: The relation between apoptosis-related molecules and chemosensitivity has been extensively studied. In recent years, attention has shifted to a new family of inhibitor of apoptosis proteins (IAPs). XIAP (X- linked inhibitor of apoptosis) is the most versatile and potent member of the IAP family. To date, the overexpression of XIAP has been detected in various cancers. XAF1 (X-linked inhibitor of apoptosis associated factor 1) is a new protein identified for its ability to interact with XIAP. Neither XIAP nor XAF1 or XIAP/XAF1 mRNA expression have been studied in bladder cancer patients. Methods: The expression of XIAP and XAF1 mRNA was analyzed by a real time quantitative fluorogenic PCR method in a group of 17 patients with locally advanced bladder cancer treated with a combination of neoadjuvant Gemcitabine and Cisplatin. The prognostic significance of XIAP and XAF1 mRNA expression and the correlation with several clinicopathological variables was evaluated. Results: XIAP and XAF1 mRNA expression was detected in all 17 (100%) case samples. The levels of XIAP mRNA expression showed a moderate variation among samples. In contrast, XAF1 and XIAP/XAF1 mRNA levels showed significant variation among samples. Bivariate correlation analyses revealed a significant positive Spearman direct correlation coefficient between the XIAP expression and the pathological response. No significant correlation was found for XAF1 expression as well as for the XIAP/XAF1 ratio and clinical and pathological response. Conclusions: This is first study to address the role of XIAP, its negative regulator XAF1, and the XIAP/XAF1 ratio in bladder cancer patients. The positive correlation between the XIAP mRNA expression and the pathological response is in line with a previous study from our group in which a correlation was found between XIAP expression and survival. All these observations point to a complex role of XIAP in tumor biology. XAF1 mRNA expression in bladder carcinomas did not achieve significance as an independent predictive and prognostic factor in a bivariate analysis. Further studies are necessary in order to better assess a possible clinical value for XIAP and XAF1 as predictive and prognostic markers in cancer patients. No significant financial relationships to disclose.

DDR1 methylation is associated with bipolar disorder and the isoform expression and methylation of myelin genes

Epigenomics ◽  
2021 ◽  
Author(s):  
Beatriz Garcia-Ruiz ◽  
Manuel Castro de Moura ◽  
Gerard Muntané ◽  
Lourdes Martorell ◽  
Elena Bosch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Bipolar Disorder ◽  
Mrna Expression ◽  
Gene Expression Analysis ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Genome Wide ◽  
Isoform Expression

Aim: To investigate DDR1 methylation in the brains of bipolar disorder (BD) patients and its association with DDR1 mRNA levels and comethylation with myelin genes. Materials & methods: Genome-wide profiling of DNA methylation (Infinium MethylationEPIC BeadChip) corrected for glial composition and DDR1 gene expression analysis in the occipital cortices of individuals with BD (n = 15) and healthy controls (n = 15) were conducted. Results: DDR1 5-methylcytosine levels were increased and directly associated with DDR1b mRNA expression in the brains of BD patients. We also observed that DDR1 was comethylated with a group of myelin genes. Conclusion: DDR1 is hypermethylated in BD brain tissue and is associated with isoform expression. Additionally, DDR1 comethylation with myelin genes supports the role of this receptor in myelination.

High mRNA expression of LMO4, a BRCA1 downregulator, correlates with better prognosis in erlotinib-treated non-small cell lung cancer (NSCLC) patients (p) with EGFR mutations.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18137-e18137
Author(s):  
Santiago Viteri Ramirez ◽  
Carlota Costa ◽  
Ana Gimenez Capitan ◽  
Susana Benlloch ◽  
Miquel Taron ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Negative Regulator ◽  
Egfr Mutations ◽  
Mrna Levels ◽  
Breast Cancers ◽  
T790m Mutation ◽  
Low Levels ◽  
The Impact

e18137 Background: Advanced NSCLC p with EGFR activating mutations show an impressive progression-free survival (PFS) to erlotinib. The co-existence of the EGFR T790M mutation, in conjunction with high BRCA1 mRNA levels, affected PFS to erlotinib (Rosell et al. CCR 2011). LMO4 is a negative regulator of BRCA1 function in sporadic breast cancers, and CtIP can bind to BRCA1 and LMO4. We have assessed the expression of CtIP, LMO4 and BRCA1 and examined the impact of CtIP and LMO4 levels on outcome. Methods: mRNA expression of LMO4 and CtIP was examined by RT-PCR in the original pretreatment tumor biopsies of 81 NSCLC p with sensitive EGFR mutations. Results: Expression of BRCA1 and LMO4 was successfully assessed in 55 p: median age, 68; 61.8% female; 98.2% Caucasian; 63.6% never-smokers; 81.8% ECOG PS <2; 80% adenocarcinoma; 14.5% BAC; 4.5% LCC; 94.5% stage IV; 63.6% exon 19 deletion; 36.4% L858R mutation; 36.4% T790M; 83.1% showed clinical benefit to erlotinib (CR/PR/SD). BRCA1 expression was correlated with that of CtIP (r=0.31; P=0.01) and LMO4 (r=0.32; P=0.02). There was no correlation between CtIP and LMO4 (r=0.09; P=0.49). PFS for p with high LMO4 levels was not reached while it was 13 months (m) for p with low levels (P=0.006). Overall survival (OS) was not reached for p with high levels of LMO4 and was 31 m for p with low levels (P=0.17). No differences in PFS or OS were observed according to CtIP levels. When BRCA1 and LMO4 expression was analyzed together, PFS was not reached for p with low BRCA1 and high LMO4 levels and was 19 m for p with low levels of both genes (P=0.04). PFS was 8 m for p with high BRCA1 and low LMO4 levels and 18 m for p with high levels of both genes (P=0.03). In the multivariate analysis, BRCA1 and LMO4 expression emerged as markers of PFS (Table). Conclusions: BRCA1 and LMO4 mRNA expression can predict PFS to erlotinib in p with EGFR mutations and could be useful in the development of new therapeutic strategies. [Table: see text]

scholarly journals Regulation of the C/EBP-related gene gadd153 by glucose deprivation.

1993 ◽  
Vol 13 (8) ◽  
pp. 4736-4744 ◽  
Author(s):  
S G Carlson ◽  
T W Fawcett ◽  
J D Bartlett ◽  
M Bernier ◽  
N J Holbrook
Keyword(s):  
Glucose Utilization ◽  
Glucose Deprivation ◽  
Negative Regulator ◽  
Mrna Levels ◽  
Hormonal Stimulation ◽  
Differentiation Protocol ◽  
Enhancer Binding Protein ◽  
Functional Dna ◽  
Gadd153 Expression

gadd153 encodes a CCAAT/enhancer-binding protein (C/EBP)-related protein that lacks a functional DNA-binding domain. Since the gadd153 protein is capable of heterodimerizing with other C/EBPs, gadd153 may function as a negative regulator of these transcription factors. Here we examined the role of glucose in regulating gadd153 expression. We found that glucose deprivation markedly induces gadd153 mRNA levels in both HeLa and 3T3-L1 cells and that addition of D-(+)-glucose resulted in a rapid decrease of gadd153 mRNA. Similar induction and reversal of gadd153 expression were observed at the protein level. Because C/EBP alpha appears to play an important role in regulating genes involved in adipogenesis and energy metabolism, we examined gadd153 expression during the differentiation of 3T3-L1 preadipocytes and as a function of glucose utilization in differentiated adipocytes. Using a standard differentiation protocol that consisted of hormonal stimulation for 2 days followed by medium changes every 2 days thereafter, we observed that both C/EBP alpha and gadd153 mRNAs were elevated. However, C/EBP alpha induction occurred on day 3, while gadd153 expression was not seen until day 4, when the cells were fully differentiated. Frequent addition of fresh medium to the cells during the differentiation process, as well as supplementation of medium with glucose, reduced gadd153 expression without preventing C/EBP alpha expression or interfering with cellular differentiation. Thus, gadd153 expression is not essential for the process of adipocyte differentiation but is significantly influenced by the availability of glucose to the cell.

scholarly journals A Novel Role of Numb as A Regulator of Pro-inflammatory Cytokine Production in Macrophages in Response to Toll-like Receptor 4

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Patipark Kueanjinda ◽  
Sittiruk Roytrakul ◽  
Tanapat Palaga
Keyword(s):  
Notch Signaling ◽  
P38 Mapk ◽  
Inflammatory Responses ◽  
Notch Signaling Pathway ◽  
Negative Regulator ◽  
Mrna Levels ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Murine Bone Marrow

Abstract Activation of macrophages triggers the release of pro-inflammatory cytokines leading to inflammation. Numb is a negative regulator of Notch signaling, but the role of Numb in macrophages is not fully understood. In this study, the role of Numb as a regulator of inflammatory responses in macrophages was investigated. Murine bone marrow-derived macrophages, in which expression of Numb was silenced, secreted significantly less TNFα, IL-6 and IL-12 and more IL-10 upon activation by lipopolysaccharide (LPS), a ligand for Toll-like receptor 4 (TLR4), despite increased Notch signaling. The Tnfα mRNA levels both in Numb-deficient and wild-type macrophages were not significantly different, unlike those of Il6 and Il12-p40. In Numb-deficient macrophages, the Tnfα mRNAs were degraded at faster rate, compared to those in control macrophages. Activation of p38 MAPK and NF-κΒ p65 were compromised in activated Numb deficient macrophages. Numb was found to interact with the E3 ubiquitin ligase, Itch, which reportedly regulates p38 MAPK. In addition, blocking the Notch signaling pathway in activated, Numb-deficient macrophages did not further reduce TNFα levels, suggesting a Notch-independent role for Numb. A proteomics approach revealed a novel funciton for Numb in regulating complex signaling cascades downstream of TLRs, partially involving Akt/NF-κB p65/p38 MAPK in macrophages.

scholarly journals Interleukin 2 induction of pore-forming protein gene expression in human peripheral blood CD8+ T cells.

1990 ◽  
Vol 171 (4) ◽  
pp. 1269-1281 ◽  
Author(s):  
M J Smyth ◽  
J R Ortaldo ◽  
Y Shinkai ◽  
H Yagita ◽  
M Nakata ◽  
...  
Keyword(s):  
T Cells ◽  
Mrna Expression ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Human Peripheral Blood ◽  
Interleukin 2 ◽  
Cytotoxic Lymphocytes ◽  
Mrna Levels ◽  
Cytotoxic Potential

Our studies have analyzed pore-forming protein (PFP) mRNA expression in resting and stimulated human peripheral blood CD3- large granular lymphocytes (LGL), CD3+ T cells, and their CD4+ or CD8+ subsets. Signals that stimulate T cells to develop cytotoxic activity (i.e., IL-2 or OKT-3 mAb) led to the induction of PFP mRNA in T cells. The data indicated that IL-2 directly increased PFP mRNA in the CD8+ subset of T cells, in the absence of new DNA or protein synthesis. Abrogation of IL-2-induced PFP mRNA expression and cytotoxic potential of T cells by the anti-p75 IL-2 receptor mAb suggested that low numbers of p75 IL-2 receptors on CD8+ T cells were capable of transducing signals responsible for these IL-2-induced effects. The induction of T cell PFP mRNA via CD3, using OKT-3 mAb, was less rapid but greater than that caused by IL-2; however, a combination of PMA and ionomycin, which bypasses crosslinking of the TCR/CD3 complex, could not mimic this increase in PFP mRNA levels in T cells. The role of second messenger systems in regulating PFP mRNA expression remains to be determined. In contrast, high constitutive PFP mRNA expression was observed in CD3- LGL and these mRNA levels could not be enhanced by stimulation with IL-2. The cytotoxic potential of peripheral blood T cells and LGL induced in response to IL-2 correlated with IL-2-induced PFP mRNA levels in these cells and was consistent with PFP being one of several important molecules involved in the effector function of cytotoxic lymphocytes.

scholarly journals A novel function of Tis11b/BRF1 as a regulator of Dll4 mRNA 3′-end processing

2011 ◽  
Vol 22 (19) ◽  
pp. 3625-3633 ◽  
Author(s):  
Agnès Desroches-Castan ◽  
Nadia Cherradi ◽  
Jean-Jacques Feige ◽  
Delphine Ciais
Keyword(s):  
Endothelial Cells ◽  
Mrna Expression ◽  
Binding Site ◽  
Mammalian Cell ◽  
Mrna Stability ◽  
Untranslated Region ◽  
Vascular Network ◽  
Mrna Levels ◽  
Angiogenic Gene

Tis11b/BRF1 belongs to the tristetraprolin family, the members of which are involved in AU-rich-dependent regulation of mRNA stability/degradation. Mouse inactivation of the Tis11b gene has revealed disorganization of the vascular network and up-regulation of the proangiogenic factor VEGF. However, the VEGF deregulation alone cannot explain the phenotype of Tis11b knockouts. Therefore we investigated the role of Tis11b in expression of Dll4, another angiogenic gene for which haploinsufficiency is lethal. In this paper, we show that Tis11b silencing in endothelial cells leads to up-regulation of Dll4 protein and mRNA expressions, indicating that Dll4 is a physiological target of Tis11b. Tis11b protein binds to endogenous Dll4 mRNA, and represses mRNA expression without affecting its stability. In the Dll4 mRNA 3′ untranslated region, we identified one particular AUUUA motif embedded in a weak noncanonical polyadenylation (poly(A)) signal as the major Tis11b-binding site. Moreover, we observed that inhibition of Tis11b expression changes the ratio between mRNAs that are cleaved or read through at the poly(A) signal position, suggesting that Tis11b can interfere with mRNA cleavage and poly(A) efficiency. Last, we report that this Tis11b-mediated mechanism is used by endothelial cells under hypoxia for controlling Dll4 mRNA levels. This work constitutes the first description of a new function for Tis11b in mammalian cell mRNA 3′-end maturation.

scholarly journals Silencing the Honey Bee (Apis mellifera) Naked Cuticle Gene (nkd) Improves Host Immune Function and Reduces Nosema ceranae Infections

2016 ◽  
Vol 82 (22) ◽  
pp. 6779-6787 ◽  
Author(s):  
Wenfeng Li ◽  
Jay D. Evans ◽  
Qiang Huang ◽  
Cristina Rodríguez-García ◽  
Jie Liu ◽  
...  
Keyword(s):  
Apis Mellifera ◽  
Immune Function ◽  
Honey Bee ◽  
Honey Bees ◽  
Nosema Ceranae ◽  
Negative Regulator ◽  
Mrna Levels ◽  
Content Type ◽  
Bee Disease

ABSTRACTNosema ceranaeis a new and emerging microsporidian parasite of European honey bees,Apis mellifera, that has been implicated in colony losses worldwide. RNA interference (RNAi), a posttranscriptional gene silencing mechanism, has emerged as a potent and specific strategy for controlling infections of parasites and pathogens in honey bees. While previous studies have focused on the silencing of parasite/pathogen virulence factors, we explore here the possibility of silencing a host factor as a mechanism for reducing parasite load. Specifically, we used an RNAi strategy to reduce the expression of a honey bee gene,naked cuticle(nkd), which is a negative regulator of host immune function. Our studies found thatnkdmRNA levels in adult bees were upregulated byN. ceranaeinfection (and thus, the parasite may use this mechanism to suppress host immune function) and that ingestion of double-stranded RNA (dsRNA) specific tonkdefficiently silenced its expression. Furthermore, we found that RNAi-mediated knockdown ofnkdtranscripts inNosema-infected bees resulted in upregulation of the expression of several immune genes (Abaecin,Apidaecin,Defensin-1, andPGRP-S2), reduction ofNosemaspore loads, and extension of honey bee life span. The results of our studies clearly indicate that silencing the hostnkdgene can activate honey bee immune responses, suppress the reproduction ofN. ceranae, and improve the overall health of honey bees. This study represents a novel host-derived therapeutic for honey bee disease treatment that merits further exploration.IMPORTANCEGiven the critical role of honey bees in the pollination of agricultural crops, it is urgent to develop strategies to prevent the colony decline induced by the infection of parasites/pathogens. Targeting parasites and pathogens directly by RNAi has been proven to be useful for controlling infections in honey bees, but little is known about the disease impacts of RNAi silencing of host factors. Here, we demonstrate that knocking down the honey bee immune repressor-encodingnkdgene can suppress the reproduction ofN. ceranaeand improve the overall health of honey bees, which highlights the potential role of host-derived and RNAi-based therapeutics in controlling the infections in honey bees. The information obtained from this study will have positive implications for honey bee disease management practices.

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