关键词： chemotherapy   breast cancer metastasis   stress response   adaptive-response network   ATF3   seed and soil theory   cancer-host interaction   tumor microenvironment   immune modulation   tumor immune environment  

摘要： An emerging picture in cancer biology is that, paradoxically, chemotherapy can actively induce changes that favor cancer progression. These pro-cancer changes can be either inside (intrinsic) or outside (extrinsic) the cancer cells. In this review, we will discuss the extrinsic pro-cancer effect of chemotherapy;that is, the effect of chemotherapy on the non-cancer host cells to promote cancer progression. We will focus on metastasis, and will first discuss recent data from mouse models of breast cancer. Despite reducing the size of primary tumors, chemotherapy changes the tumor microenvironment, resulting in an increased escape of cancer cells into the blood stream. Furthermore, chemotherapry changes the tissue microenvironment at the distant sites, making it more hospitable to cancer cells upon their arrival. We will then discuss the idea and evidence that these devastating pro-metastatic effects of chemotherapy can be explained in the context of adaptive-response. At the end, we will discuss the potential relevance of these mouse data to human breast cancer and their implication on chemotherapy in the clinic.

关键词： ATF3   Sirolimus   Cutanous squamous cell carcinoma  

摘要： Background: Due to their immunosuppressive therapy, organtransplant recipients (OTR5) exhibit a high incidence for the development of cutaneous squamous cell carcinoma (cSCC). Randomized studies of kidney-transplanted patients indicate a significant lower susceptibility for cSCC among patients receiving the mTOR-inhibitor Sirolimus, compared to patients without mTOR-regimen. The exact mechanism, how mTOR inhibition affects keratinocyte carcinogenesis remains unclear. Objective: Our aim was to investigate the impact of Sirolimus on the expression level of the oncogene ATF3, which is involved in the development and progression of cSCC. Methods: We incubated human keratinocytes, cSSC cell lines and 3D skin equivalents with Sirolimus, exposed the cells to calcineurin inhibitors (CNI) and UVA-radiation and measured the expression level of ATF3 by real-time PCR and western blot. Results: We show that Sirolimus downregulates the expression of ATF3 induced by cyclosporine or cyclosporine plus UV-radiation in keratinocytes. In line with this we demonstrate a decrease in ATF3 expression, by incubating 3D skin equivalents with Sirolimus prior to cyclosporine and UV-light. However, Sirolimus has no significant impact on the ATF3 expression levels of cyclosporine stimulated cSCC cell lines. Conclusion: Taken together, our study demonstrates that Sirolimus downregulates the CNI or UV-induced ATF3 expression in human keratinocytes, which could be a potential molecular mechanism how Sirolimus reduces cSCC in OTRs. The lack of ATF3 suppression by Sirolimus in cSCC cell lines fits to observations from clinical studies which demonstrated a clinical benefit from the switch to a mTOR-regimen in patients with low tumor burden in early stage of disease. (C) 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

关键词： ATF3   CYR61   Hepatocellular carcinoma  

摘要： Background: Hepatocellular carcinoma (HCC) is one of the most common malignant cancers with a high incidence and high mortality in East Asia. Identifying biomarkers and clarifying the regulatory mechanisms of HCC are of great importance. Herein, we report the role and mechanism of activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element-binding protein family of transcription factors in HCC. Methods: ATF3 overexpression vector and shRNAs were transfected into HCC cancer cells to upregulate or downregulate ATF3 expression. In vitro and in vivo assays were performed to investigate the functional role of ATF3 in hepatocellular carcinoma. RNA-Seq was performed to screen the differentially expressed genes downstream of ATF3. The dual-luciferase reporter assay, chromatin immunoprecipitation (Ch-IP) analysis and functional rescue experiments were used to confirm the target gene regulated by ATF3. Tissue microarrays (TMAs) comprising 236 human primary HCC tissues were obtained and immunohistochemical staining were carried out to analyze the clinical significance of ATF3. Results: The results indicate that ATF3 significantly inhibited the proliferation and mobility of HCC cells both in vitro and in vivo. Cysteine-rich angiogenic inducer 61 (CYR61) is a key target for transcriptional regulation by ATF3. Both ATF3 and CYR61 were consistently downregulated in human HCC tissues, and their expression levels were significantly and positively correlated with each other. Conclusions: Our findings indicate that ATF3 functions as a tumor suppressor in HCC through targeting and regulating CYR61.

关键词： Atf3   Obesity   Adipocyte   Metabolic diseases   Sulfuretin  

摘要： Activating transcription factor 3 (Atf3) has been previously demonstrated to impact obesity and metabolism. However, a metabolic role of Atf3 in mice remains debatable. We investigated the role of Atf3 in mice and further investigated Atf3 expression as a therapeutic target for obesity and metabolic diseases. Atf3 knockout (KO) mice fed with a high fat diet (HFD) aggravated weight gain and impaired glucose metabolism compared to littermate control wild type (WT) mice. Atf3 KO aged mice fed with a chow diet (CD) for longer than 10 months also displayed increased body weight and fat mass compared to WT aged mice. We also assessed requirements of Atf3 in a phytochemical mediated anti-obese effect. Effect of sulfuretin, a previously known phytochemical Atf3 inducer, in counteracting weight gain and improving glucose tolerance was almost completely abolished in the absence of Atf3, indicating that Atf3 induction can be a molecular target for preventing obesity and metabolic diseases. We further identified other Atf3 small molecule inducers that exhibit inhibitory effects on lipid accumulation in adipocytes. These data highlight the role of Atf3 in obesity and further suggest the use of chemical Atf3 inducers for prevention of obesity and metabolic diseases. (C) 2018 Elsevier Inc. All rights reserved.

关键词： ATF3   绿脓杆菌   急性肺损伤   负性调控   保护作用  

摘要： 目的探讨绿脓杆菌致急性肺损伤小鼠的ATF3表达规律及意义。方法以荧光标记的绿脓杆菌(PA)(滴度1.5×108CFU/ml) 50μl经鼻滴入C57BL/6野生型小鼠气管构建急性肺损伤模型,通过肺泡灌洗液(BALF)中的蛋白含量、肺组织干湿比测定肺微血管通透性和肺水肿程度变化;采用组织切片和HE染色观察肺组织病理变化; qRT-PCR检测ATF3在野生型急性肺损伤小鼠肺组织中的表达规律。结果经鼻滴入绿脓杆菌后导致肺微血管通透性增加和肺水肿加重,小鼠肺组织呈典型急性肺损伤病理改变,结果支持成功构建了经鼻滴入绿脓杆菌致ALI模型。ATF3表达于正常小鼠肺组织,经鼻滴入绿脓杆菌后小鼠肺组织中ATF3 mRNA的表达于0、3、6、12 h及24 h时相点分别为1.006±0.136,9.954±0.624,4.578±1.463,2.342±0.122,3.249±0.680,其中在3 h时相点达最高峰,随之逐渐下降,于24 h时相点基本能回到正常水平。结论 ATF3作为负性调控因子对绿脓杆菌致急性肺损伤小鼠有一定保护作用。

关键词： ATF3   chemokine   hematoma   RAG   traumatic brain injury  

摘要： Traumatic brain injury (TBI) induces a neuroinflammatory response resulting in astrocyte and microglia activation at the lesion site. This involves upregulation of neuroinflammatory genes, including chemokines and interleukins. However, so far, there is lack of knowledge on transcription factors (TFs) modulating this TBI-associated gene expression response. Herein, we analyzed activating transcription factor 3 (ATF3), a TF encoding a regeneration-associated gene (RAG) predominantly studied in peripheral nervous system (PNS) injury. ATF3 contributes to PNS axon regeneration and was shown before to regulate inflammatory processes in other injury models. In contrast to PNS injury, data on ATF3 in central nervous system (CNS) injury are sparse. We used Atf3 mouse mutants and a closed-head weight-drop-based TBI model in adult mice to target the rostrolateral cortex resulting in moderate injury severity. Post-TBI, ATF3 was upregulated already at early time points (i.e,. 1-4h) post-injury in the brain. Mortality and weight loss upon TBI were slightly elevated in Atf3 mutants. ATF3 deficiency enhanced TBI-induced paresis and hematoma formation, suggesting that ATF3 limits these injury outcomes in wild-type mice. Next, we analyzed TBI-associated RAG and inflammatory gene expression in the cortical impact area. In contrast to the PNS, only some RAGs (Atf3, Timp1, and Sprr1a) were induced by TBI, and, surprisingly, some RAG encoding neuropeptides were downregulated. Notably, we identified ATF3 as TF-regulating proneuroinflammatory gene expression, including CCL and CXCL chemokines (Ccl2, Ccl3, Ccl4, and Cxcl1) and lipocalin. In Atf3 mutant mice, mRNA abundance was further enhanced upon TBI compared to wild-type mice, suggesting immune gene repression by wild-type ATF3. In accord, more immune cells were present in the lesion area of ATF3-deficient mice. Overall, we identified ATF3 as a new TF-mediating TBI-associated CNS inflammatory responses.

关键词： qRT-PCR   quantitative real-time PCR   TRPV1   transient receptor potential vanilloid type 1  

摘要： Melanoma is the most lethal form of skin cancer with increasing incidence over the years. Because of its rapid proliferative and drastic metastatic capacity, the prognosis of melanoma remains dismal, although the targeted therapy and immunotherapy have gained revolutionary progress recently. Therefore, it is of necessity to further clarify the mechanism of melanoma pathogenesis for developing an alternative treatment strategy. Transient receptor potential vanilloid 1 (TRPV1) is a nonselective Ca2+ channel greatly involved in regulating cell apoptosis, proliferation, metabolism, and cancer development, but its role in melanoma remains unknown. Herein, we first found that TRPV1 expression was significantly decreased in melanoma tissues and cell lines, compared with nevus tissues and normal melanocytes, respectively. We then proved that TRPV1 overexpression or its agonist capsaicin treatment inhibited melanoma growth by activating p53 and inducing cell apoptosis. A subsequent mechanistic study revealed that TRPV1 induced Ca2+ influx to regulate p53 activation via calcineurin-ATF3 transcriptional cascade. Finally, the effect of TRPV1 on melanoma growth was proved in vivo. Altogether, our study demonstrates that TRPV1 is a potential tumor suppressor in melanoma.

关键词： ATF3   breast cancer   MCF7 cells   radioresistance  

摘要： This study was designed to research the influence of activating transcription factor 3 (ATF3) on the radioresistance of breast cancer. ATF3 expression was measured by qRT-PCR and immunohistochemistry. Cancerous cell lines were cultured in vitro, and the expression of ATF3 was gauged by both qRT-PCR and Western blot before and after the radiation therapy. Cellular cycle and apoptosis were analysed by flow cytometry. Changes in the expression of corresponding proteins in the downstream pathways were identified by Western blot. Tumour xenograft was used to evaluate the effect of ATF3 in vivo. ATF3 was observed stronger in breast cancer tissues and cells. After radiation therapy, the expression of ATF3 in breast cancer cells was up-regulated. Silencing ATF3 could promote G2/M phase block, facilitate cell apoptosis and decrease clonogenic survival rate. The overexpression of ATF3 could curb G2/M-phase block, cell apoptosis and increase clonogenic survival rate. Overexpression ATF3 could increase radioresistance by up-regulating the level of phosphorylation of Akt in the PI3K/Akt signalling pathway. Radioresistance of breast cancer cells could be alleviated by inhibiting the PI3K/Akt signalling pathway. ATF3 could also promote radioresistance in vivo. ATF3 gene was able to promote radioresistance of breast cancer cells.

关键词： ATF3   PRAP1   CDDP-specific   Microvascular endothelial   Biomarkers  

摘要： Background: The early intervention is a rational approach to reduce the cardiovascular disease mortality in cancer patients. Here, we tried to identify potential biomarkers for the endothelial damage caused by cisplatin, a typical chemotherapy compound, and explore its underlying mechanisms. Methods: Microarray dataset GSE62523 were utilized to assess the gene differential expression from human micro-vascular endothelial cells (HMEC-1) treated with cisplatin. Then, the potential key genes were further validated by qRT-PCR and the gamma H2AX level was evaluated to monitor the DNA damages caused by cisplatin. Result: For the 'acute-exposure' settings that HMEC-1 were treated with 12.9 mu M cisplatin for 6, 24 and 48 h, ATF3, LRRTM2, VCAM1 and PAPPA were identified as potential key genes in endothelial damage, while for the `chronic-exposure' settings that cells were exposed to 0.52 mu M cisplatin twice a week, SULF2, ACTA2 and PRAP1 were identified. In addition, further in vitro validation showed that knockdown of ATF3 attenuated the gamma H2AX level in cells exposed to cisplatin for 6 or 24 h and knockdown of PRAP1 increased the gamma H2AX level in cells exposed to cisplatin for 2 days. Notably, ATF3 has the ability to regulate the expression of HIST1H1D, FBX06, APP, MDM2, STAT1 and TRAF1, while PRAP1 regulates YWHAB, MDM2, ISG15, LYN and CUL1 during cisplatin-induced DNA damage repair process. Conclusion: ATF3 and PRAP1 play important roles in cisplatin-induced DNA damage repair process. They may serve as potential early surrogate biomarkers of microvascular endothelial damage for cancer patients receiving chemotherapies.