关键词： FATP2   Lipofermata   PI3K/Akt/mTOR   ATF3   BLCA  

摘要： Bladder cancer (BLCA) is ranked among the main causes of mortality in male cancer patients, and research into targeted therapies guided by its genomics and molecular biology has been a prominent focus in BLCA studies. Fatty acid transporter protein 2 (FATP2), a member of the FATPs family,is a key contributor to the progression of cancers such as hepatocellular carcinomas and ***,its role in BLCA remains poorly understand. This study delved into the function of FATP2 in BLCA through a succession of experiments in vivo and in vitro, employing techniques as quantitative real-time polymerase chain reaction (qRT-PCR), RNA sequencing, transwell assays, immunofluorescence, western blot,and others to dissect its mechanistic actions. The findings revealed that an oncogenic function is executed by FATP2 in bladder cancer, significantly impacting the proliferation and migration capabilities, thereby affecting the prognosis of BLCA patients. Furthermore, A suppression that relies on both time and concentration of BLCA proliferation and migration, trigger of apoptosis, and blockage of the cell cycle at the G2/M phase were observed when the inhibitor of FATP2, Lipofermata, was applied. It was unveiled through subsequent investigations that ATF3 expression is indirectly promoted by Lipofermata through the inhibition of FATP2, ultimately inhibiting the signal transduction of the PI3K/Akt/ mTOR pathway. This effect was also responsible for the inhibitory impact on BLCA proliferation. Therefore, FATP2 emerges as an auspicious and emerging molecular target with potential applications in precision therapy in BLCA.

关键词： angiopoietin-like 4   ATF3   high fat diet   lipoprotein   osteoblast   triglyceride  

摘要： High fat diets overwhelm the physiological mechanisms for absorption, storage, and utilization of triglycerides (TG);consequently TG, TG-rich lipoproteins (TGRL), and TGRL remnants accumulate, circulate systemically, producing dyslipidemia. This associates with, or is causative for increased atherosclerotic cardiovascular risk, ischemic stroke, fatty liver disease, and pancreatitis. TGRL hydrolysis by endothelial surface-bound lipoprotein lipase (LPL) generates metabolites like free fatty acids which have proinflammatory properties. While osteoblasts utilize fatty acids as an energy source, dyslipidemia is associated with negative effects on the skeleton. In this study we investigated the effects of TGRL lipolysis products (TGRL-LP) on expression of a stress responsive transcription factor, termed activating transcription factor 3 (ATF3), reactive oxygen species (ROS), ATF3 target genes, and angiopoietin-like 4 (Angptl4) in osteoblasts. As ATF3 negatively associates with osteoblast differentiation, we also investigated the skeletal effects of global ATF3 deletion in mice. TGRL-LP increased expression of Atf3, proinflammatory proteins Ptgs2 and IL-6, and induced ROS in MC3T3-E1 osteoblastic cells. Angptl4 is an endogenous inhibitor of LPL which was transcriptionally induced by TGRL-LP, while recombinant Angptl4 prevented TG-driven Atf3 induction. Atf3 global knockout male mice demonstrated increased trabecular and cortical microarchitectural parameters. In summary, we find that TGRL-LP induce osteoblastic cell stress as evidenced by expression of ATF3, which may contribute to the negative impact of dyslipidemia in the skeleton. Further, concomitant induction of Angptl4 in osteoblasts might play a protective role by reducing local lipolysis.

关键词： Ferroptosis   Colorectal cancer (CRC)   ATF3-CBS signaling axis   Mitochondrial tricarboxylic acid (TCA) cycle  

摘要： The induction of ferroptosis is promising for cancer therapy. However, the mechanisms enabling cancer cells to evade ferroptosis, particularly in low-cystine environments, remain elusive. Our study delves into the intricate regulatory mechanisms of Activating transcription factor 3 (ATF3) on Cystathionine 8-synthase (CBS) under cystine deprivation stress, conferring resistance to ferroptosis in colorectal cancer (CRC) cells. Additionally, our findings establish a positively correlation between this signaling axis and CRC progression, suggesting its potential as a therapeutic target. Mechanistically, ATF3 positively regulates CBS to resist ferroptosis under cystine deprivation stress. In contrast, the suppression of CBS sensitizes CRC cells to ferroptosis through targeting the mitochondrial tricarboxylic acid (TCA) cycle. Notably, our study highlights that the ATF3-CBS signaling axis enhances ferroptosis-based CRC cancer therapy. Collectively, the findings reveal that the ATF3-CBS signaling axis is the primary feedback pathway in ferroptosis, and blocking this axis could be a potential therapeutic approach for colorectal cancer.

关键词： Glioblastoma   HOTAIR   MGMT   Temozolomide   Homologous recombination  

摘要： The efficacy of temozolomide (TMZ) treatment in glioblastoma (GBM) is influenced by various mechanisms, mainly including the level of O 6 -methylguanine-DNA methyltransferase (MGMT) and the activity of DNA damage repair (DDR) pathways. In our previous study, we had proved that long non -coding RNA HOTAIR regulated the GBM progression and mediated DDR by interacting with EZH2, the catalytic subunit of PRC2. In this study, we developed a small -molecule inhibitor called EPIC -0628 that selectively disrupted the HOTAIREZH2 interaction and promoted ATF3 expression. The upregulation of ATF3 inhibited the recruitment of p300, p -p65, p-Stat3 and SP1 to the MGMT promoter. Hence, EPIC -0628 silenced MGMT expression. Besides, EPIC -0628 induced cell cycle arrest by increasing the expression of CDKN1A and impaired DNA double -strand break repair via suppressing the ATF3-p38-E2F1 pathway. Lastly, EPIC -0628 enhanced TMZ efficacy in GBM in vitro and vivo . Hence, this study provided evidence for the combination of epigenetic drugs EPIC -0628 with TMZ for GBM treatment through the above mechanisms.

关键词： Peripheral nerve injury   Axonal regeneration   Bone marrow mesenchymal stromal cell   Activating transcription factor 3   DNA double strand break  

摘要： Background The repair of peripheral nerve injury poses a clinical challenge, necessitating further investigation into novel therapeutic approaches. In recent years, bone marrow mesenchymal stromal cell (MSC)-derived mitochondrial transfer has emerged as a promising therapy for cellular injury, with reported applications in central nerve injury. However, its potential therapeutic effect on peripheral nerve injury remains unclear. Methods We established a mouse sciatic nerve crush injury model. Mitochondria extracted from MSCs were intraneurally injected into the injured sciatic nerves. Axonal regeneration was observed through whole-mount nerve imaging. The dorsal root ganglions (DRGs) corresponding to the injured nerve were harvested to test the gene expression, reactive oxygen species (ROS) levels, as well as the degree and location of DNA double strand breaks (DSBs). Results The in vivo experiments showed that the mitochondrial injection therapy effectively promoted axon regeneration in injured sciatic nerves. Four days after injection of fluorescently labeled mitochondria into the injured nerves, fluorescently labeled mitochondria were detected in the corresponding DRGs. RNA-seq and qPCR results showed that the mitochondrial injection therapy enhanced the expression of Atf3 and other regeneration-associated genes in DRG neurons. Knocking down of Atf3 in DRGs by siRNA could diminish the therapeutic effect of mitochondrial injection. Subsequent experiments showed that mitochondrial injection therapy could increase the levels of ROS and DSBs in injury-associated DRG neurons, with this increase being correlated with Atf3 expression. ChIP and Co-IP experiments revealed an elevation of DSB levels within the transcription initiation region of the Atf3 gene following mitochondrial injection therapy, while also demonstrating a spatial proximity between mitochondria-induced DSBs and CTCF binding sites. Conclusion These findings suggest that MSC-derived mitochondria injected

摘要： High-grade serous ovarian cancer (HGSOC) represents the most common and lethal subtype of ovarian cancer. Despite initial response to platinum-based standard therapy, patients commonly suffer from relapse that likely originates from drug-tolerant persister (DTP) cells. We generated isogenic clones of treatment-na & iuml;ve and cisplatin-tolerant persister HGSOC cells. In addition, single-cell RNA sequencing of barcoded cells was performed in a xenograft model with HGSOC cell lines after platinum-based therapy. Published single-cell RNA-sequencing data from neo-adjuvant and non-treated HGSOC patients and patient data from TCGA were analyzed. DTP-derived cells exhibited morphological alterations and upregulation of epithelial-mesenchymal transition (EMT) markers. An aggressive subpopulation of DTP-derived cells showed high expression of the stress marker ATF3. Knockdown of ATF3 enhanced the sensitivity of aggressive DTP-derived cells to cisplatin-induced cell death, implying a role for ATF3 stress response in promoting a drug tolerant persister cell state. Furthermore, single cell lineage tracing to detect transcriptional changes in a HGSOC cell line-derived xenograft relapse model showed that cells derived from relapsed solid tumors express increased levels of EMT and multiple endoplasmic reticulum (ER) stress markers, including ATF3. Single cell RNA sequencing of epithelial cells from four HGSOC patients also identified a small cell population resembling DTP cells in all samples. Moreover, analysis of TCGA data from 259 HGSOC patients revealed a significant progression-free survival advantage for patients with low expression of the ATF3-associated partial EMT genes. These findings suggest that increased ATF3 expression together with partial EMT promote the development of aggressive DTP, and thereby relapse in HGSOC patients.

摘要： Anti-PD-L1 immunotherapy, a new lung cancer treatment, is limited to a few patients due to low PD-L1 expression and tumor immunosuppression. To address these challenges, the upregulation of PD-L1 has the potential to elevate the response rate and efficiency of anti-PD-L1 and alleviate the immunosuppression of the tumor microenvironment. Herein, we developed a novel usnic acid-derived Iridium(III) complex, Ir-UA, that boosts PD-L1 expression and converts "cold tumors" to "hot". Subsequently, we administered Ir-UA combined with anti-PD-L1 in mice, which effectively inhibited tumor growth and promoted CD4(+) and CD8(+) T cell infiltration. To our knowledge, Ir-UA is the first iridium-based complex to stimulate the expression of PD-L1 by explicitly regulating its transcription factors, which not only provides a promising platform for immune checkpoint blockade but, more importantly, provides an effective treatment strategy for patients with low PD-L1 expression.

关键词： 前列腺癌   ATF3   免疫组化   前列腺特异性抗原  

摘要： 目的:探究转录因子ATF3与前列腺癌的临床相关性,了解ATF3在前列腺癌组织中的表达以及其表达强度对前列腺癌患者预后的影响。方法:采用公共数据库挖掘的方法分析ATF3在前列腺癌组织中的突变情况以及ATF3在正常前列腺组织以及前列腺癌组织中的表达情况,kaplan-meier方法分析ATF3的表达强度与前列腺癌患者临床预后的相关性;免疫组化染色验证ATF3在正常前列腺组织和前列腺癌组织中的蛋白表达;患者临床信息分析ATF3的表达高低与前列腺癌临床特征的关联。结果:ATF3在前列腺癌组织中表现为高扩增突变,且ATF3在前列腺癌组织中的表达明显高于正常前列腺组织;ATF3与前列腺癌疾病的发生、进展(病灶转移)相关;高表达ATF3的前列腺癌患者预后较差。结论:ATF3的表达强度与前列腺癌的发生发展相关,可作为前列腺癌诊断及预后判断的重要指标。