关键词： beta-catenin   noncoding RNA   ASBEL   colorectal tumorigenesis   ATF3  

摘要： Wnt/beta-catenin signaling plays a key role in the tumorigenicity of colon cancer. Furthermore, it has been reported that lncRNAs are dysregulated in several steps of cancer development. Here we show that beta-catenin directly activates the transcription of the long noncoding RNA (lncRNA) ASBEL [antisense ncRNA in the ANA (Abundant in neuroepithelium area)/BTG3 (B-cell translocation gene 3) locus] and transcription factor 3 (TCF3), both of which are required for the survival and tumorigenicity of colorectal cancer cells. ASBEL interacts with and recruits TCF3 to the activating transcription factor 3 (ATF3) locus, where it represses the expression of ATF3. Furthermore, we demonstrate that ASBEL-TCF3-mediated down-regulation of ATF3 expression is required for the proliferation and tumorigenicity of colon tumor cells. ATF3, in turn, represses the expression of ASBEL. Our results reveal a pathway involving an lncRNA and two transcription factors that plays a key role in Wnt/beta-catenin-mediated tumorigenesis. These results may provide insights into the variety of biological and pathological processes regulated by Wnt/beta-catenin signaling.

关键词： ATF3   Human labour   Inflammation   Infection   Fetal membranes  

摘要： Introduction: Infection and inflammation stimulate pro-inflammatory cytokines, prostaglandins and matrix metalloproteinase (MMP)-9, which play a central role in myometrial contractions and rupture of fetal membranes. In human and mouse immune cells, activating transcription factor 3 (ATF3) is a negative regulator of inflammation. No studies have examined the role of ATF3 in human labour. Methods: Primary amnion cells were used to determine the effect of interleukin (IL)-1 beta and the bacterial product fibroblast-stimulating lipopeptide (fsl-1) on ATF3 expression, and the effect of ATF3 siRNA on pro-labour mediators. ATF3 expression was assessed in fetal membranes from non-labouring and labouring women at term and preterm, and after preterm pre-labour rupture of membranes (PPROM). Results: IL-1 beta and fsl-1 significantly increased ATF3 expression. Silencing ATF3 significantly increased IL-1 beta- or fsl-1-induced expression of pro-inflammatory cytokines (TNF-alpha, IL-1 alpha, IL-1 beta, IL-6) and chemokines (IL-8 and monocyte chemoattractant protein-1 (MCP-1));cyclooxygenase-2 (COX-2) mRNA expression and prostaglandin PGF(2 alpha) release;and MMP-9 expression. ATF3 expression was decreased in fetal membranes with term labour. There was no effect of preterm labour or PPROM on ATF3 expression. Discussion: ATF3 is a negative regulator of inflammation in human fetal membranes;in primary amnion cells, ATF3 expression is induced by IL-1 beta and fsl-1, and ATF3 silencing further exacerbates the inflammatory response when stimulated with these factors. Subsequently, ATF3 expression is decreased in fetal membranes after term labour and with preterm chorioamnionitis, conditions closely associated with inflammation and infection. Our data suggest that ATF3 may play a role in the terminal processes of human labour and delivery. (C) 2016 Elsevier Ltd. All rights reserved.

关键词： cAMP response element-binding protein   glucocorticoid   immunosuppression   liver metabolism   S100 proteins  

摘要： Glucocorticoids (GCs) used as inflammation suppressors have harmful side effects, including induction of hepatic steatosis. The underlying mechanisms of GC-promoted dysregulation of lipid metabolism, however, are not fully understood. GCs could facilitate the accumulation of myeloid-derived suppressor cells (MDSC) in the liver of animals, and the potential role of MDSCs in GC-induced hepatic steatosis was therefore investigated in this study. We demonstrated that granulocytic (G)-MDSC accumulation mediated the effects of GCs on the fatty liver, in which activating transcription factor 3 (ATF3)/S100A9 signaling plays an important role. ATF3-deficient mice developed hepatic steatosis and displayed expansion of G-MDSCs in the liver and multiple immune organs, which shared high similarity with the phenotype observed in GC-treated wild-type littermates. Adoptive transfer of GC-induced or ATF3-deficient G-MDSCs promoted lipid accumulation in the liver, whereas depletion of G-MDSCs alleviated these effects. Mechanistic studies showed that in MDSCs, ATF3 was transrepressed by the GC receptor GR through direct binding to the negative GR-response element. S100A9 is the major transcriptional target of ATF3 in G-MDSCs. Silencing S100A9 clearly alleviated G-MDSCs expansion and hepatic steatosis caused by ATF3 deficiency or GC treatment. Our study uncovers an important role of G-MDSCs in GC-induced hepatic steatosis, in which ATF3 may have potential therapeutic implications.

关键词： 子宫颈鳞癌   鳞状细胞癌抗原   激活转录因子3   相关性  

摘要： 目的：研究子宫颈鳞癌患者血清SCC-Ag 及组织ATF3表达与临床分期及肿瘤直径的相关性，为临床治疗提供参考。方法选取我院2014年1月～2016年6月收治的81例宫颈癌患者为观察对象，检测血清SCC-Ag和组织ATF3表达水平，并采用Logistic回归性分析来分析血清SCC-Ag 及组织ATF3的表达与子宫颈鳞癌临床分期及肿瘤直径的相关性。结果患者血清SCC-Ag及组织ATF3检测显示，临床分期从玉到郁期阳性率逐渐递增；肿瘤直径小于或等于4cm的患者SCC-Ag及ATF3表达阳性率明显小于肿瘤直径大于4cm的患者；Logistic回归性分析显示，SCC-Ag及ATF3升高均是子宫颈鳞癌的危险因素。结论血清SCC-Ag、组织ATF3表达均与子宫颈鳞癌的癌变程度相关，患者从玉期到郁期SCC-Ag和ATF3水平均呈上升趋势；肿瘤直径越大，SCC-Ag和ATF3水平越高，联合监测有助于评估患者病情。

关键词： Pterostilbene   ATF3   Apoptosis   Colon cancer   Chemoprevention   ER stress  

摘要： Pterostilbene (Ptero), a major active compound of blue berries, is a natural antioxidant phytochemical which has a strong potential for cancer prevention and intervention. However, it has not been shown the detailed anti-cancer mechanism of action for Ptero which has not fully elucidated. In present study, we report that Ptero treatment in human colon cancer cells inhibits the cell cycle via the suppression of Cyclin D1 expression. This inhibition of Cyclin D1 was associated with changes in the TCF4 expression and activation of PARP cleavage. The induction of apoptotic cells by Ptero was observed by Hoechst staining. We also observed that Ptero promotes to delay S phase into G2/M phase cell cycle transition in colon cancer cells. Analysis of the gene expression profiles by western blotting revealed that Ptero increased the expression of GRP78 protein related to the unfolded protein response. This induction was associated with the activation of the eIF2 alpha-ATF3 cascade of endoplasmic reticulum (ER) stress. Moreover, our result showed that p38MAPK is essential factor for Ptero-induced ATF3 expression. The current study shows that Ptero stimulates GPR78-eIF2 alpha-ATF3 cascade and subsequently induces apoptosis. Our results therefore provide new insights into the molecular mechanisms of Ptero-induced cell death in human colon cancer cells and suggest Ptero might be a potential chemotherapeutic agent which is able to intervene and prevent the human colon cancer. (C) 2016 Elsevier Ltd. All rights reserved.

关键词： FORKHEAD transcription factors   PROLACTIN   ENDOMETRIUM   EMBRYO transplantation   STROMAL cells   OVEREXPRESSION (Genetics)   IMMUNOFLUORESCENCE  

摘要： P-282

关键词： Experimental allergic encephalomyelitis   Demyelination   ATF3   Dorsal root ganglion   Spinal cord   Myelin oligodendrocyte glycoprotein   Pertussis toxin  

摘要： Experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis produced by immunization with myelin oligodendrocyte glycoprotein (MOG) and adjuvants, results from profound T-cell mediated CNS demyelination. EAE is characterized by progressive, ascending motor dysfunction and symptoms of ongoing pain and hypersensitivity, in some cases preceding or concomitant with the motor deficits. In this regard, the EAE model mimics major features of multiple sclerosis, where a central neuropathic pain state is common. Although the latter condition is presumed to arise from a CNS loss of inhibitory controls secondary to the demyelination, dysfunction of sensory neurons may also contribute. Based on our previous studies that demonstrated the utility of monitoring expression of activating transcription factor 3 (ATF3), a sensitive marker of injured sensory neurons, here we followed both ATF3 and CD4 + T cells invasion of sensory ganglia (as well as the CNS) at different stages of the EAE model. We found that ATF3 is induced in peripheral sensory ganglia and brainstem well before the appearance of motor deficits. Unexpectedly, the ATF3 induction always preceded T cell infiltration, typically in adjacent, but non-overlapping regions. Surprisingly, control administration of the pertussis toxin and/or Complete Freund's adjuvants, without MOG, induced ATF3 in sensory neurons. In contrast, T cell infiltration only occurred with MOG. Taken together, our results suggest that the clinical manifestations in the EAE result not only from central demyelination but also from neuronal stress and subsequent pathophysiology of sensory neurons. (C) 2016 Published by Elsevier Inc.

关键词： DDIT3 gene   Erbium   Transcription Factors   ATF4 gene   Activating Transcription Factor 4   Death Domain Receptors   PC12 Cells  

摘要： Tetrachlorobenzoquinone (TCBQ) is a downstream metabolite of pentachlorophenol (PCP). Previously, we demonstrated that TCBQ caused cytotoxicity due to mitochondrial-related apoptosis. Here, we confirmed the upregulation of death receptor 5 (DR5) followed by the construction of the death-inducing signaling complex (DISC). We also detected the activation of the caspase cascade, which was correlated with TCBQ-induced apoptotic cell death in PC12 cells. The upregulation of DR5 included transcriptional activation and de novo protein synthesis in response to TCBQ, We also identified the endoplasmic reticulum (ER) as a new target for the TCBQ challenge in PC12 cells. The protein kinase R-like ER kinase/eukaryotic translation initiation factor 2 alpha (PERK/eIF2 alpha)-mediated activating transcription factor 4 (ATF4)-ATF3-C/EBP homologous protein (CHOP) signaling pathway contributed to the process of TCBQ-induced ER stress. Blocking ATF4, ATF3, or CHOP signaling by gene silencing technology resulted in decreased cell apoptosis after exposure to TCBQ Finally, NAC ameliorated TCBQ-induced apoptosis and ER stress, which illustrated that TCBQ-induced apoptosis is somehow ROS-dependent. In summary, this study provided important mechanistic insight into how TCBQ utilizes ER stress-related signaling to exhibit pro-apoptotic activity in PC12 cells.

关键词： esophageal squamous cell carcinoma   activating transcription factor 3   inhibitor of DNA binding 1   proliferation   metastasis  

摘要： Esophageal cancer is one of the most prevalent forms of cancer and has a particularly high mortality rate due to early metastasis;however, the underlying mechanisms of its formation and progression remain unclear. The present study performed immunohistochemical analysis and observed that the expression of activating transcription factor 3 (ATF3) was reduced in esophageal squamous cell carcinoma (ESCC) in comparison with non-tumor adjacent tissues. By contrast, inhibitor of DNA binding 1 (ID1) was overexpressed in ESCC tissues, demonstrating an inverse correlation with ATF3 (P<0.01). In ESCC EC109 and KYSE450 cells lines, transfection with an ATF3-overexpression plasmid resulted in the inhibition of cell proliferation, motility and migration, which was associated with the induction of E-cadherin expression and inhibition of cyclin D1 and Twist. Notably, ATF3 exerted an inverse regulatory interaction with ID1. The results of the present study provide additional evidence of the tumor suppressive features of ATF3 and demonstrate a novel mechanism of ATF3-mediated inhibition of cancer metastasis in esophageal cancer.

关键词： Ras   scribble   Hippo pathway   Drosophila   tumor   invasion   AP-1   Fos   Kayak   Atf3   Pdp-1   CG6272   CEBPG   Myc   Taiman   Ftz-f1   Mef-2   Cropped   STAT   JNK signaling  

摘要： Cancer cells have abnormal gene expression profiles;however, to what degree these are chaotic or driven by structured gene regulatory networks is often not known. Here we studied a model of Ras-driven invasive tumorigenesis in Drosophila epithelial tissues and combined in vivo genetics with next-generation sequencing and computational modeling to decipher the regulatory logic of tumor cells. Surprisingly, we discovered that the bulk of the tumor-specific gene expression is controlled by an ectopic network of a few transcription factors that are overexpressed and/or hyperactivated in tumor cells. These factors are Stat, AP-1, the bHLH proteins Myc and AP-4, the nuclear hormone receptor Ftz-f1, the nuclear receptor coactivator Taiman/SRC3, and Mef2. Notably, many of these transcription factors also are hyperactivated in human tumors. Bioinformatic analysis predicted that these factors directly regulate the majority of the tumor-specific gene expression, that they are interconnected by extensive cross-regulation, and that they show a high degree of co-regulation of target genes. Indeed, the factors of this network were required in multiple epithelia for tumor growth and invasiveness, and knockdown of several factors caused a reversion of the tumor-specific expression profile but had no observable effect on normal tissues. We further found that the Hippo pathway effector Yorkie was strongly activated in tumor cells and initiated cellular reprogramming by activating several transcription factors of this network. Thus, modeling regulatory networks identified an ectopic and ordered network of master regulators that control a large part of tumor cell-specific gene expression.