关键词： 结直肠肿瘤/病理学   ATF3   CyclinD1   Maspin   免疫组织化学  

摘要： 目的:检测转录激活因子3(ATF3)及其靶基因Cyclin D1与Maspin在结直肠癌组织芯片中的表达,探讨ATF3表达在结直肠癌发生、发展中的意义。方法:构建含结直肠癌及癌旁相对正常肠黏膜的组织芯片,应用免疫组织化学检测ATF3、Cyclin D1及Maspin的表达情况。结果:ATF3、Cyclin D1与Maspin在结直肠癌中阳性表达率分别为70.3%、51.4%和59.5%,明显高于癌旁正常组织的21.6%、2.7%和13.5%,差异有统计学意义,χ2值分别为35.252、44.411和33.689,P值均为0.000;ATF3与结直肠癌患者的性别、年龄、肿瘤部位、肿瘤大小及肿瘤分化程度无关,而与浸润程度和淋巴结有无转移有关,浆膜层表达(83.3%)高于肌层(38.9%),有淋巴结转移(92.3%)高于无淋巴结转移(45.7%),χ2值分别为13.290和17.110,P值均为0.000;Cyclin D1与结直肠癌患者的性别、年龄、肿瘤部位及肿瘤大小无关,而与病理学分级、浸润程度和淋巴结有无转移有关,低分化组织表达(71.4%)高于高中分化组织(39.1%),浆膜层表达(61.1%)高于肌层(28.8%),有淋巴结转移(69.2%)高于无淋巴结转移(31.4%),χ2值分别为7.268、6.019和10.550,P值分别为0.007、0.014和0.001;Maspin与结直肠癌患者的性别、年龄、肿瘤部位、肿瘤大小、肿瘤分化程度、浸润深度及有无淋巴结转移均无关,P值均>0.05。ATF3、Cyclin D1与Maspin在结直肠癌中均高表达,ATF3与Cyc-lin D1在结直肠癌中表达呈正相关(r=0.362,P=0.000),与Maspin表达无明显相关(r=0.075,P=0.513)。结论:ATF3表达与结直肠癌的发生密切相关,ATF3可能通过调控Cyclin D1表达而促进结直肠癌的发生发展及侵袭转移。

关键词： GENE-EXPRESSION   RESPONSE GENE   ADENOCARCINOMA   IDENTIFICATION   STATISTICS   SUPPRESSOR   SIGNATURE   SELECTION   INVASION  

摘要： Biomarkers predicting metastatic capacity might assist the development of better therapeutic strategies for aggressive cancers such as lung cancer. In this study, we show that adenylate kinase-4 (AK4) is a progression-associated gene in human lung cancer that promotes metastasis. Analysis of published microarray data showed that AK4 was upregulated in lung adenocarcinoma compared with normal cells. High AK4 expression was associated with advanced stage, disease recurrence and poor prognosis. Loss of AK4 expression suppressed the invasive potential of lung cancer cell lines, whereas AK4 overexpression promoted invasion in vitro and in vivo. Mechanistically, the transcription factor ATF3 was identified as a pivotal regulatory target of AK4. Simultaneous reduction in AK4 and ATF3 expression abolished the inhibitory effects of ATF3 on invasion. ATF3 overexpression in AK4-overexpressing cells limits invasion activity. Furthermore, patients with high AK4 and low ATF3 expression showed unfavorable outcomes compared with patients with low AK4 and high ATF3 expression. Taken together, our findings indicated that AK4 promotes malignant progression and recurrence by promoting metastasis in an ATF3-dependent manner. Cancer Res; 72(19); 5119-29. (C)2012 AACR.

关键词： TRPV1   Pain   Capsaicin   Vanilloid   Nociception   Resiniferatoxin   ATF3   Dorsal root ganglion   MRS1477   Adelta fiber   CONCENTRATION CAPSAICIN PATCH   PRIMARY AFFERENT NEURONS   SENSORY NERVE-TERMINALS   PERIPHERAL AXOTOMY   INFLAMMATORY MEDIATORS   SPINAL-CORD   VANILLOID RECEPTOR-1   NEUROPATHIC PAIN   UNITED-STATES   SCIATIC-NERVE  

摘要： Background: The prevalence of long-term opiate use in treating chronic non-cancer pain is increasing, and prescription opioid abuse and dependence are a major public health concern. To explore alternatives to opioid-based analgesia, the present study investigates a novel allosteric pharmacological approach operating through the cation channel TRPV1. This channel is highly expressed in subpopulations of primary afferent unmyelinated C-and lightly-myelinated Ad-fibers that detect low and high rates of noxious heating, respectively, and it is also activated by vanilloid agonists and low pH. Sufficient doses of exogenous vanilloid agonists, such as capsaicin or resiniferatoxin, can inactivate/deactivate primary afferent endings due to calcium overload, and we hypothesized that positive allosteric modulation of agonist-activated TRPV1 could produce a selective, temporary inactivation of nociceptive nerve terminals in vivo. We previously identified MRS1477, a 1,4-dihydropyridine that potentiates vanilloid and pH activation of TRPV1 in vitro, but displays no detectable intrinsic agonist activity of its own. To study the in vivo effects of MRS1477, we injected the hind paws of rats with a non-deactivating dose of capsaicin, MRS1477, or the combination. An infrared diode laser was used to stimulate TRPV1-expressing nerve terminals and the latency and intensity of paw withdrawal responses were recorded. qRT-PCR and immunohistochemistry were performed on dorsal root ganglia to examine changes in gene expression and the cellular specificity of such changes following treatment. Results: Withdrawal responses of the capsaicin-only or MRS1477-only treated paws were not significantly different from the untreated, contralateral paws. However, rats treated with the combination of capsaicin and MRS1477 exhibited increased withdrawal latency and decreased response intensity consistent with agonist potentiation and inactivation or lesion of TRPV1-containing nerve terminals. The loss of n

关键词： ATF3   cerebral ischemia   inflammation   NF-kappa B   CREB   ADAPTIVE-RESPONSE GENE   NECROSIS-FACTOR-ALPHA   KAPPA-B   NEGATIVE REGULATOR   REPERFUSION INJURY   ARTERY OCCLUSION   CHEMOKINE CCL2   ATF3   STROKE   RECEPTOR  

摘要： Background and Purpose: Activating transcription factor 3 (ATF3) is a stress-induced transcription factor that has been shown to repress inflammatory gene expression in multiple cell types and diseases. This study was conducted to investigate the role of ATF3 in the pathological processes of cerebral ischemia and its influence on post-ischemic inflammation. Methods: Wild-type (WT) and ATF3 knockout (KO) mice were subjected to middle cerebral artery occlusion (45 min) followed by reperfusion. Infarct volume, brain edema, and neurological deficits were examined. Neural apoptosis, inflammatory gene expression, cellular inflammatory response and Matrix Metallo Proteinases 9 (MMP9) activity were assessed. Activity of the nuclear factor-kappa B (NF-kappa B) signaling pathway and cAMP-responsive element-binding protein (CREB) was studied. Results: Knockout of ATF3 significantly exacerbated the infarct volume and worsened neurological function after brain ischemia. Neural apoptosis, inflammatory gene expression and cellular inflammatory response were upregulated in ATF3 KO mice. The MMP9 mRNA expression and protein activity were increased in ATF3 KO mice. KO of ATF3 led to an elevation in the activity of the NF-kappa B signaling pathway and inhibition of CREB activity. Conclusions: Our study demonstrated that ATF3 was markedly induced by brain ischemia. ATF3 deficiency exacerbated the inflammatory response and brain injury after cerebral ischemia, potentially through further activation of the NF-kappa B signaling pathway. ATF3 is likely an important protective regulator in cerebral ischemic injury. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

关键词： ACTIVATING TRANSCRIPTION FACTOR-3   INDUCED CARDIOTOXICITY   SIGNALING PATHWAYS   INDUCED APOPTOSIS   GENE-EXPRESSION   TNF SUPERFAMILY   CELLS   AGENTS   KINASES   BIOLOGY  

摘要： Although doxorubicin is commonly used in the treatment of many cancer types, its use in chemotherapy has been limited, largely because of its severe side effects, including cardiotoxicity and nephrotoxicity. In this study, we aimed to identify the mechanism of doxorubicin-induced cytotoxicity by using the human kidney proximal tubule cell line HK-2. Furthermore, we investigated the role of activating transcription factor 3 (ATF3) as a mediator of doxorubicin-induced cytotoxicity by using wild-type mouse embryonic fibroblasts (MEF) cells and ATF3 knockout (KO) cells. In HK-2 cells, doxorubicin decreased cell viability in a dose-dependent manner and induced an increase in cells in the sub G1 and G2/M phases at all doses. Doxorubicin treatment showed the following dose-dependent effects: increase in the secretion of tumor necrosis factor alpha; decrease in the expression of phosphorylated protein kinase A and Bcl-2; and increase in the expression of phosphorylated signal transducer and activator of transcription 3, phosphorylated extracellular signal-regulated kinase (ERK), and ATF3. Based on these results, we suggest that doxorubicin induces cytotoxicity through an ERK-dependent pathway, and ATF3 plays a pivotal role as a transcriptional regulator in this process.

关键词： 5-HT1B/1D receptor activation   ATF3   c-Fos immunoreactive labeling   CGRP receptor blockade   IL-6   Neuropathic pain   Nociceptive tests   DORSAL-ROOT GANGLIA   TRIGEMINAL NEUROPATHIC PAIN   SPINAL-CORD   PERIPHERAL MONONEUROPATHY   PHARMACOLOGICAL-TREATMENT   ANTIMIGRAINE DRUG   VISCERAL PAIN   SUMATRIPTAN   MIGRAINE   MODEL  

摘要： Previous studies showed that 5-hydroxytryptamine (5-HT)(1B/1D) receptor stimulation by triptans alleviates neuropathic pain caused by chronic constriction injury to the infraorbital nerve (CCI-ION) but not the sciatic nerve (CCI-SN) in rats. To assess whether such differential effects in the cephalic vs extracephalic territories is a property shared by other antimigraine drugs, we used the same models to investigate the effects of olcegepant, which has an antimigraine action mediated through calcitonin gene-related peptide (CGRP) receptor blockade. Adult male rats underwent unilateral CCI to the ION or the SN, and subsequent allodynia and/or hyperalgesia were assessed in ipsilateral vibrissal territory or hindpaw, respectively, using von Frey filaments and validated nociceptive tests. c-Fos expression was quantified by immunohistochemistry and interleukin 6 and activating transcription factor 3 (ATF3) mRNAs by real-time quantitative reverse transcriptase-polymerase chain reaction. Like naratriptan (0.1 to 0.3 mg/kg, subcutaneously), olcegepant (0.3 to 0.9 mg/kg, intravenously) markedly reduced mechanical allodynia in CCI-ION rats. In contrast, in CCI-SN rats, mechanical allodynia was completely unaffected and hyperalgesia was only marginally reduced by these drugs. A supra-additive antiallodynic effect was observed in CCI-ION rats treated with olcegepant (0.3 mg/kg intravenously) plus naratriptan (0.1 mg/kg subcutaneously), whereas this drug combination remained inactive in CCI-SN rats. Olcegepant (0.6 mg/kg, intravenously) significantly reduced the number of c-Fos immunolabeled cells in spinal nucleus of the trigeminal nerve and upregulation of ATF3 transcript (a marker of neuron injury) but not that of interleukin-6 in trigeminal ganglion of CCI-ION rats. These findings suggest that CGRP receptor blockade might be of potential interest to alleviate trigeminal neuropathic pain. (C) 2012 International Association for the Study of Pain. Published by Elsevier B.V. All

关键词： Trigeminal ganglion neurons   Electrophysiology   ATF3   Na(v)1.3   Culture   DORSAL-ROOT GANGLION   SPINAL SENSORY NEURONS   SODIUM-CHANNEL   NEUROPATHIC PAIN   NERVE INJURY   C-JUN   MESSENGER-RNA   DRG NEURONS   EXPRESSION   NGF  

摘要： To clarify whether changes to the cellular properties of sensory neurons occur after a brief culture, we compared the electrophysiological and immunohistochemical properties of rat trigeminal ganglion neurons. We compared these neurons after acute dissociation and after a 1-day culture under serum-free and neurotrophin-free conditions. In whole-cell patch-clamp recordings. the 1-day cultured neurons required a lower current threshold to induce an action potential in both small- and medium-sized neurons. Furthermore, the input resistance was higher in the medium-sized neurons after a 1-day culture compared to the acutely dissociated medium-sized neurons. Immunofluorescent studies demonstrated that both the translocation of the activating transcription factor 3 (ATF3) into the nucleus and the expression of a low threshold Na+ channel (Na(v)1.3) were upregulated after 1-day of culture. However, in the acutely dissociated neurons, ATF3 translocation occurred at low levels, and Na(v)1.3 was not expressed. These electrophysiological and immunohistochemical changes after 1-day of culture were very similar to the reported changes that occur after nerve injury. Our study demonstrated that injury-like characteristics appear to be manifested in the 1-day cultured sensory neurons, which do not occur in acutely dissociated neurons. Overall, our results are relevant and will help when interpreting the results of studies examining dissociated sensory neurons in pain research. Crown Copyright (C) 2012 Published by Elsevier Ireland Ltd. All rights reserved.

关键词： ACTIVATING TRANSCRIPTION FACTOR-3   PROSTATE-SPECIFIC ANTIGEN   PROTEIN-PROTEIN INTERACTIONS   GENE-EXPRESSION   TERMINAL INTERACTION   OXIDATIVE STRESS   CANCER CELLS   DOMAIN   INSENSITIVITY   PROMOTER  

摘要： Activating transcription factor 3 (ATF3) is a common mediator of cellular stress response signaling and is often aberrantly expressed in prostate cancer. We report here that ATF3 can directly bind the androgen receptor (AR) and consequently repress AR-mediated gene expression. The ATF3-AR interaction requires the leucine zipper domain of ATF3 that independently binds the DNA-binding and ligand-binding domains of AR, and the interaction prevents AR from binding to cis-acting elements required for expression of androgen-dependent genes while inhibiting the AR N- and C-terminal interaction. The functional consequences of the loss of ATF3 expression include increased transcription of androgen-dependent genes in prostate cancer cells that correlates with increased ability to grow in low-androgen-containing medium and increased proliferative activity of the prostate epithelium in ATF3 knockout mice that is associated with prostatic hyperplasia. Our results thus demonstrate that ATF3 is a novel repressor of androgen signaling that can inhibit AR functions, allowing prostate cells to restore homeostasis and maintain integrity in the face of a broad spectrum of intrinsic and environmental insults.

关键词： NSCLC   ATF3   mutation   methylation   risk   ACTIVATING TRANSCRIPTION FACTOR-3   ADAPTIVE-RESPONSE GENE   EPITHELIAL-CELLS   DNA METHYLATION   PROSTATE-CANCER   EXPRESSION   PROMOTER   REPRESSION   CARCINOMA   APOPTOSIS  

摘要： Background: Non-small cell lung cancer (NSCLC) accounts for 85% of all cases of lung cancer and has a poor prognosis. Activating transcription factor 3 (ATF3), a member of the ATF/cyclic adenosine monophosphate response element binding (ATF/cyclic response element binding) family of transcription factors, has been implicated in the pathogenesis of several types of cancer. However, whether the expression of ATF3 is aberrant in NSCLC and genetic variants, or DNA methylation of the gene contributes to the tumorigenesis of NSCLC, are largely unknown. Methods: The expression of ATF3 in four NSCLC cell lines and normal human bronchial epithelial cell (HBEpiC) line was detected by Western blot analysis. The mutation of the 5'-flanking 1500-bp and coding sequence regions of the ATF3 gene were screened using DNA direct sequencing, and bisulfite-sodium modification sequencing was used to detect the promoter methylation status of the gene. Results: up-regulated expression of ATF3 was observed in NSCLC cell lines, and there was no difference in the sequence regions of the ATF3 gene between NSCLC cells and HBEpiC cells, which were validated in lung cancer tissues and their corresponding paracarcinoma tissues. Conclusion: Our findings suggest that the tumorigenesis of NSCLC may particularly attribute to increased expression of ATF3 but not the genetic variants of the gene.

关键词： actinic keratosis   ATF3   squamous cell carcinoma   ACTIVATING TRANSCRIPTION FACTOR-3   PROSTATE-CANCER   RESPONSE GENE   EXPRESSION   ROLES   P53   HOMEOSTASIS   FAMILY   GROWTH  

摘要： The histopathologic distinction between benign and malignant cutaneous keratinocytic proliferations can pose a difficult diagnostic challenge often with important clinical implications. Activating transcription factor 3 (ATF3) has emerged as a potential biomarker which may aid in the segregation of these lesions, and we hypothesize that ATF3 expression may be a specific marker of cutaneous squamous cell carcinoma (SCC). Using immunohistochemistry, we characterized ATF3 expression in a series of 126 cutaneous epithelial proliferations, including SCC (n?=?27), basal cell carcinomas (BCC, n?=?59), seborrheic keratoses with atypia (SK, n?=?16), hyperplastic actinic keratoses (AK, n?=?12) and prurigo nodularis cases (PN, n?=?12). We showed strong, nuclear and/or nucleolar expression of ATF3 in a statistically significant number of cases of SCC compared to BCC, SK and PN. We conclude that ATF3 expression is a surrogate of malignancy (or pre-malignancy) in keratinocytic epithelial proliferations and thus helps distinguish SCC from other cutaneous epithelial neoplasms.