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c-Jun and Fra-2 pair up to Myc-anistically drive HCC. c-Jun 和 Fra-2 配对,以 Myc-anistically 驱动 HCC。
IF 3.4 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-11-24 DOI: 10.1080/15384101.2024.2429968
Latifa Bakiri, Erwin F Wagner

Hepatocellular carcinoma (HCC), a leading cause of cancer-related death with limited therapies, is a complex disease developing in a background of Hepatitis Virus infection or systemic conditions, such as the metabolic syndrome. Investigating HCC pathogenesis in model organisms is therefore crucial for developing novel diagnostic and therapeutic tools. Genetically engineered mouse models (GEMMs) have been instrumental in recapitulating the local and systemic features of HCC. Early studies using GEMMs and patient material implicated members of the dimeric Activator Protein-1 (AP-1) transcription factor family, such as c-Jun and c-Fos, in HCC formation. In a recent report, we described how switchable, hepatocyte-restricted expression of a single-chain c-Jun~Fra-2 protein, functionally mimicking the c-Jun/Fra-2 AP-1 dimer, results in spontaneous and largely reversible liver tumors in GEMMs. Dysregulated cell cycle, inflammation, and dyslipidemia are observed at early stages and tumors display molecular HCC signatures. We demonstrate that increased c-Myc expression is an essential molecular determinant of tumor formation that can be therapeutically targeted using the BET inhibitor JQ1. Here, we discuss these findings with additional results illustrating how AP-1 GEMMs can foster preclinical research on liver diseases with novel perspectives offered by the constantly increasing wealth of HCC-related datasets.

肝细胞癌(HCC)是一种在肝炎病毒感染或代谢综合征等全身性疾病背景下发展起来的复杂疾病,是癌症相关死亡的主要原因之一,但治疗手段有限。因此,在模型生物中研究 HCC 的发病机制对于开发新型诊断和治疗工具至关重要。基因工程小鼠模型(GEMMs)有助于重现 HCC 的局部和全身特征。利用基因工程小鼠和患者材料进行的早期研究表明,二聚体激活蛋白-1(AP-1)转录因子家族成员(如 c-Jun 和 c-Fos)与 HCC 的形成有关。在最近的一份报告中,我们描述了单链 c-Jun~Fra-2 蛋白(在功能上模拟 c-Jun/Fra-2 AP-1 二聚体)的可切换、肝细胞限制性表达是如何导致 GEMMs 中自发且基本可逆的肝脏肿瘤的。在早期阶段可观察到细胞周期失调、炎症和血脂异常,肿瘤显示出 HCC 分子特征。我们证明,c-Myc 表达的增加是肿瘤形成的一个重要分子决定因素,可以使用 BET 抑制剂 JQ1 靶向治疗。在这里,我们讨论了这些发现,并通过其他结果说明了 AP-1 GEMMs 如何通过不断增加的 HCC 相关数据集提供的新视角促进肝脏疾病的临床前研究。
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引用次数: 0
Expression of Concern: DDB2 association with PCNA is required for its degradation after UV-induced DNA damage. 关注表达:紫外线诱导 DNA 损伤后,PCNA 的降解需要 DDB2 与 PCNA 结合。
IF 3.4 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-09-27 DOI: 10.1080/15384101.2024.2396717
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引用次数: 0
Autophagy unrelated transcriptional mechanisms of hydroxychloroquine resistance revealed by integrated multi-omics of evolved cancer cells. 通过对进化癌细胞进行综合多组学研究揭示羟氯喹耐药性与自噬无关的转录机制
IF 3.4 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-09-19 DOI: 10.1080/15384101.2024.2402191
Silvia G Vaena, Martin J Romeo, Mirna Mina-Abouda, Emma C Funk, George Fullbright, David T Long, Joe R Delaney

Hydroxychloroquine (HCQ) and chloroquine are repurposed drugs known to disrupt autophagy, a molecular recycling pathway essential for tumor cell survival, chemotherapeutic resistance, and stemness. We pursued a multi-omic strategy in OVCAR3 ovarian cancer and CCL218 colorectal cancer cells. Two genome-scale screens were performed. In the forward genetic screen, cell populations were passaged for 15 drug pulse-chases with HCQ or vehicle control. Evolved cells were collected and processed for bulk RNA-seq, exome-seq, and single-cell RNA-seq (scRNA-seq). In the reverse genetic screen, a pooled CRISPR-Cas9 library was used in cells over three pulse-chases of HCQ or vehicle control treatments. HCQ evolved cells displayed remarkably few mutational differences, but substantial transcriptional differences. Transcriptomes revealed multiple pathways associated with resistance to HCQ, including upregulation of glycolysis, exocytosis, and chromosome condensation/segregation, or downregulation of translation and apoptosis. The Cas9 screen identified only one autophagy gene. Chromosome condensation and segregation were confirmed to be disrupted by HCQ in live cells and organelle-free in vitro extracts. Transcriptional plasticity was the primary mechanism by which cells evolved resistance to HCQ. Neither autophagy nor the lysosome were substantive hits. Our analysis may serve as a model for how to better position repurposed drugs in oncology.

羟基氯喹(HCQ)和氯喹是已知会破坏自噬的再利用药物,而自噬是肿瘤细胞存活、化疗抗性和干性所必需的分子循环途径。我们在 OVCAR3 卵巢癌和 CCL218 大肠癌细胞中采用了多基因组策略。我们进行了两个基因组规模的筛选。在正向基因筛选中,细胞群经过 15 次使用 HCQ 或药物对照的药物脉冲循环。收集并处理进化细胞,进行大量 RNA-seq、外显子组-seq 和单细胞 RNA-seq (scRNA-seq)。在反向遗传筛选中,在细胞中使用了一个汇集的 CRISPR-Cas9 文库,经过三个脉冲周期的 HCQ 或载体对照处理。HCQ进化细胞的突变差异极小,但转录差异很大。转录组揭示了与 HCQ 抗性相关的多种途径,包括糖酵解、细胞外分泌和染色体凝集/分离的上调,或翻译和细胞凋亡的下调。Cas9 筛选只发现了一个自噬基因。在活细胞和不含细胞器的体外提取物中,染色体的凝集和分离被证实受到 HCQ 的破坏。转录可塑性是细胞对 HCQ 产生抗性的主要机制。自噬和溶酶体均未受到实质性影响。我们的分析可作为如何更好地在肿瘤学中定位再利用药物的模型。
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引用次数: 0
Melatonin protects against defects induced by methoxychlor in porcine oocyte maturation. 褪黑素可防止甲氧氯诱导的猪卵母细胞成熟缺陷。
IF 3.4 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-09-16 DOI: 10.1080/15384101.2024.2402190
Zhaojun Geng, Mingjun Zhang, Shuming Shi, Bing Hu, Liying Liu, Zhichao Chi, Linyi Qu, Yongxun Jin, Xianfeng Yu

Methoxychlor (MXC) is a widely used organochlorine pesticide primarily targeting pests. However, MXC has been found to negatively impact the reproductive system of both humans and animals, triggering oxidative stress and apoptosis. Melatonin (MLT), an endogenous hormone, possesses various benefits, including circadian rhythm regulation and anti-inflammatory and antioxidative stress effects. Moreover, MLT plays a crucial role in the development of animal germ cells and embryos. This study aimed to investigate the impact of MLT on porcine oocytes exposed to MXC. The experimental findings revealed that 200 μM MXC had detrimental effects on the maturation of porcine oocytes. However, the addition of 10-8 M MLT mitigated the toxic effects of MXC. MXC induced oxidative stress in porcine oocytes, leading to an increase in reactive oxygen species and impairing mitochondrial function. Consequently, oocyte quality was affected, resulting in elevated levels of early apoptosis and DNA damage, ultimately negatively impacting subsequent embryonic development. However, the addition of MLT showed the potential to ameliorate the damage caused by MXC. In conclusion, our results suggest that MLT exhibits a protective effect against MXC-induced damage to porcine oocyte maturation.

甲氧氯(MXC)是一种广泛使用的有机氯杀虫剂,主要针对害虫。然而,研究发现甲氧氯会对人类和动物的生殖系统产生负面影响,引发氧化应激和细胞凋亡。褪黑素(MLT)是一种内源性激素,具有多种益处,包括昼夜节律调节、抗炎和抗氧化应激作用。此外,褪黑激素在动物生殖细胞和胚胎的发育过程中起着至关重要的作用。本研究旨在探讨 MLT 对暴露于 MXC 的猪卵母细胞的影响。实验结果表明,200 μM MXC 对猪卵母细胞的成熟有不利影响。然而,添加 10-8 MLT 可减轻 MXC 的毒性作用。MXC 在猪卵母细胞中诱导氧化应激,导致活性氧增加并损害线粒体功能。因此,卵母细胞质量受到影响,导致早期细胞凋亡和 DNA 损伤水平升高,最终对随后的胚胎发育产生负面影响。然而,添加 MLT 有可能改善 MXC 造成的损伤。总之,我们的研究结果表明,MLT 对 MXC 引起的猪卵母细胞成熟损伤具有保护作用。
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引用次数: 0
Cell cycle regulated expression of the WHI7 Start repressor gene. 细胞周期调控 WHI7 启动抑制基因的表达。
IF 3.4 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-09-16 DOI: 10.1080/15384101.2024.2402192
Cristina Ros-Carrero, Mercè Gomar-Alba, J Carlos Igual

Periodic transcriptional waves along the cell cycle ensure the accurate progression of the different cell cycle phases through the timely regulated expression of cell cycle proteins. The G1/S transition (Start) consists in the activation of a transcriptional program by G1 CDKs through the inactivation of Start transcriptional repressors, Whi5 and Whi7 in yeast or Rb in mammals. Here, we provide a comprehensive characterization of the transcriptional regulation of the Start repressor Whi7 in budding yeast. We found that WHI7 is a cell cycle regulated gene that shows periodic expression peaking in G1. Our results demonstrate that the three cell cycle transcriptional programs related to G1 and their corresponding transcription factors are involved in the transcriptional control of WHI7. Specifically, we identified that the transcriptional regulators Swi5 and Mcm1-Yox1, which are involved in late M and early G1 expression, and the transcription factors MBF and SBF, which are responsible for G1/S expression, are able to associate and regulate the WHI7 gene. In summary, in this work, we provide new mechanisms for the regulation of the Start repressor Whi7, which highlights the precise and complex control of the cell cycle machinery governing the G1/S transition.

细胞周期中的周期性转录波通过及时调控细胞周期蛋白的表达,确保不同细胞周期阶段的准确进展。G1/S转变(Start)是由G1 CDK通过Start转录抑制因子(酵母中的Whi5和Whi7或哺乳动物中的Rb)的失活激活转录程序。在这里,我们对芽殖酵母中Start转录抑制因子Whi7的转录调控进行了全面描述。我们发现,WHI7 是一个细胞周期调控基因,在 G1 期表现出周期性的表达高峰。我们的研究结果表明,与G1相关的三个细胞周期转录程序及其相应的转录因子参与了WHI7的转录调控。具体来说,我们发现参与M后期和G1早期表达的转录调节因子Swi5和Mcm1-Yox1,以及负责G1/S表达的转录因子MBF和SBF能够联合调控WHI7基因。总之,在这项工作中,我们提供了起始抑制因子Whi7的新调控机制,凸显了细胞周期机制对G1/S转换的精确而复杂的调控。
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引用次数: 0
Enhancing precision in colorectal cancer surgery: development of an LGR5-targeting RSPO1 peptide mimetic as a contrast agent for intraoperative fluorescence molecular imaging. 提高结直肠癌手术的精确性:开发一种 LGR5 靶向 RSPO1 肽模拟物,作为术中荧光分子成像的造影剂。
IF 3.4 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-07-10 DOI: 10.1080/15384101.2024.2364578
Erika Parasido, Patricia Ribeiro, Ramesh M Chingle, Thomas Rohwetter, Nikita Gupta, George Avetian, Elisa Bladelli, Mariaelena Pierobon, Yu Chen, Qinggong Tang, Martin Schnermann, Olga Rodriguez, David Robbins, Terrence R Burke, Chris Albanese, Chukwuemeka Ihemelandu

Colorectal cancer (CRC) is the third most common cancer worldwide. In the United States alone, CRC was responsible for approximately 52,550 deaths in 2023, with an estimated 153,020 new cases. CRC presents with synchronous peritoneal spread in 5-10% of patients, and up to 20-50% of patients with recurrent disease will develop metachronous colorectal cancer peritoneal metastatic (CRC-PM) disease. Eradication of the tumor, tumor margins and microscopic residual disease is paramount, as microscopic residual disease is associated with local recurrences, with 5-year survival rates of less than 35%. The success of resection and reduction of residual disease depends on the accuracy with which cancer cells and normal tissue can be intra-operatively distinguished. Fluorescence Molecular Imaging (IFMI) and tumor-targeted contrast agents represent a promising approach for intraoperative detection and surgical intervention. Proper target selection, the development of scalable imaging agents and enhanced real-time tumor and tumor microenvironment imaging are critical to enabling enhanced surgical resection. LGR5 (leucine-rich repeat-containing G-protein-coupled receptor 5), a colonic crypt stem cell marker and the receptor for the R-spondins (RSPO) in the Wnt signaling pathway, is also expressed on colorectal cancer stem cells (CSC) and on CRC tumors and metastases, suggesting it could be a useful target for imaging of CRC. However, there are numerous diverging reports on the role of LGR5 in CRC therapy and outcomes. Herein, we report on the synthesis and validation of a 37 amino acid RSPO1-mimetic peptide, termed RC18, that was specifically designed to access the R-spondin binding site of LGR5 to potentially be used for interoperative imaging of CRC-PM. The receptor-binding capabilities of the RC18 indicate that direct interactions with LGR5 neither significantly increased LGR5 signaling nor blocked RSPO1 binding and signal transduction, suggesting that the RSPO1-mimetic is functionally inert, making it an attractive contrast agent for intraoperative CRC-PM imaging.

结肠直肠癌(CRC)是全球第三大常见癌症。2023 年,仅在美国就有约 52,550 人死于 CRC,新增病例约 153,020 例。5%-10%的 CRC 患者会出现同步腹膜扩散,高达 20%-50%的复发患者会发展为转移性结直肠癌腹膜转移(CRC-PM)疾病。根除肿瘤、肿瘤边缘和显微镜下残留疾病至关重要,因为显微镜下残留疾病与局部复发有关,5 年生存率低于 35%。切除和减少残留疾病的成功与否取决于术中区分癌细胞和正常组织的准确性。荧光分子成像(IFMI)和肿瘤靶向造影剂是一种很有前景的术中检测和手术干预方法。正确的靶点选择、可扩展成像剂的开发以及增强的肿瘤和肿瘤微环境实时成像对于提高手术切除效果至关重要。LGR5(富亮氨酸重复含G蛋白偶联受体5)是结肠隐窝干细胞标志物,也是Wnt信号通路中的R-spondins(RSPO)受体,在结直肠癌干细胞(CSC)、CRC肿瘤和转移灶上也有表达,这表明它可能是CRC成像的一个有用靶点。然而,关于 LGR5 在 CRC 治疗和预后中的作用的报道众说纷纭。在此,我们报告了一种 37 个氨基酸的 RSPO1 拟态肽(称为 RC18)的合成和验证过程,该肽专门设计用于进入 LGR5 的 R-spondin 结合位点,可能用于 CRC-PM 的术间成像。RC18 的受体结合能力表明,它与 LGR5 的直接相互作用既不会显著增加 LGR5 的信号转导,也不会阻断 RSPO1 的结合和信号转导,这表明 RSPO1 拟态肽在功能上是惰性的,使其成为一种有吸引力的用于术中 CRC-PM 成像的造影剂。
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引用次数: 0
Statement of Retraction: Cdc25C/cdc2/cyclin B, raf/MEK/ERK and PERK/eIF2α/CHOP pathways are involved in forskolin-induced growth inhibition of MM.1S cells by G2/M arrest and mitochondrion-dependent apoptosis. 撤回声明:Cdc25C/cdc2/cyclin B、raf/MEK/ERK和PERK/eIF2α/CHOP通路参与了福斯可林诱导的MM.1S细胞通过G2/M停滞和线粒体依赖性凋亡抑制生长的过程。
IF 3.4 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-07-04 DOI: 10.1080/15384101.2024.2370720
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引用次数: 0
Statement of Retraction: miR-96-5p regulated TGF-β/SMAD signaling pathway and suppressed endometrial cell viability and migration via targeting TGFBR1. 撤稿声明:miR-96-5p 通过靶向 TGFBR1 调节 TGF-β/SMAD 信号通路,抑制子宫内膜细胞的活力和迁移。
IF 3.4 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-07-04 DOI: 10.1080/15384101.2024.2370717
{"title":"Statement of Retraction: miR-96-5p regulated TGF-β/SMAD signaling pathway and suppressed endometrial cell viability and migration via targeting TGFBR1.","authors":"","doi":"10.1080/15384101.2024.2370717","DOIUrl":"https://doi.org/10.1080/15384101.2024.2370717","url":null,"abstract":"","PeriodicalId":9686,"journal":{"name":"Cell Cycle","volume":" ","pages":"1"},"PeriodicalIF":3.4,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Statement of Retraction: Overexpression of HIF-1α protects PC12 cells against OGD/R-evoked injury by reducing miR-134 expression. 撤回声明:HIF-1α的过表达可通过减少miR-134的表达保护PC12细胞免受OGD/R诱发的损伤。
IF 3.4 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-07-04 DOI: 10.1080/15384101.2024.2370712
{"title":"Statement of Retraction: Overexpression of HIF-1α protects PC12 cells against OGD/R-evoked injury by reducing miR-134 expression.","authors":"","doi":"10.1080/15384101.2024.2370712","DOIUrl":"https://doi.org/10.1080/15384101.2024.2370712","url":null,"abstract":"","PeriodicalId":9686,"journal":{"name":"Cell Cycle","volume":" ","pages":"1"},"PeriodicalIF":3.4,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Statement of Retraction: Hsa-miR-425-5p promotes tumor growth and metastasis by activating the CTNND1-mediated β-catenin pathway and EMT in colorectal cancer. 撤回声明:Hsa-miR-425-5p通过激活CTNND1介导的β-catenin通路和EMT促进结直肠癌的肿瘤生长和转移。
IF 3.4 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-07-04 DOI: 10.1080/15384101.2024.2370718
{"title":"Statement of Retraction: Hsa-miR-425-5p promotes tumor growth and metastasis by activating the CTNND1-mediated β-catenin pathway and EMT in colorectal cancer.","authors":"","doi":"10.1080/15384101.2024.2370718","DOIUrl":"https://doi.org/10.1080/15384101.2024.2370718","url":null,"abstract":"","PeriodicalId":9686,"journal":{"name":"Cell Cycle","volume":" ","pages":"1"},"PeriodicalIF":3.4,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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