小鼠体内三肽链蛋白的低表达激活了表型可塑性,并为向致命性前列腺癌的过渡奠定了基础。

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Journal of Clinical Investigation Pub Date : 2024-11-19 DOI:10.1172/JCI175680
Katherine L Morel, Beatriz Germán, Anis A Hamid, Jagpreet S Nanda, Simon Linder, Andries M Bergman, Henk van der Poel, Ingrid Hofland, Elise M Bekers, Shana Y Trostel, Deborah L Burkhart, Scott Wilkinson, Anson T Ku, Minhyung Kim, Jina Kim, Duanduan Ma, Jasmine T Plummer, Sungyong You, Xiaofeng A Su, Wilbert Zwart, Adam G Sowalsky, Christopher J Sweeney, Leigh Ellis
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引用次数: 0

摘要

表型可塑性是癌症的一大特征,而且越来越多的人认识到它是雄激素受体(AR)靶向疗法的一种耐药机制。现在,许多前列腺癌(PCa)患者都要先接受AR靶向药物治疗,因此确定驱动表型可塑性的可行机制以防止耐药性的出现至关重要。我们的研究表明,tristetraprolin(TTP,基因ZFP36)的缺失会增加NF-κB的激活,并与原发性PCa的侵袭性疾病和早期复发率升高有关。我们还研究了 ZFP36 基因缺失与 PTEN 基因共同缺失对临床和生物学的影响,PTEN 基因是已知的 PCa 驱动因子。对多个独立原发性PCa队列的分析表明,PTEN和ZFP36的共同缺失与复发风险的增加有关。体内前列腺特异性 Zfp36 基因缺失会诱发前列腺上皮内瘤变,与 Pten 基因共同缺失会导致前列腺上皮内瘤变迅速发展为耐阉割腺癌。Zfp36缺失改变了由Pten缺失驱动的细胞状态,表现为EMT、炎症、TNFα/NF-κB、IL6-JAK/STAT3基因组的富集。此外,我们的研究还发现,ZFP36 的缺失还诱导了涉及单核细胞迁移、趋化和增殖的多个基因集的富集。使用NF-κB抑制剂二甲氨基苯乙酰胆碱(DMAPT)可对PTEN和ZFP36共同缺失的肿瘤产生明显的治疗反应,并逆转阉割抗性。
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Low tristetraprolin expression activates phenotypic plasticity and primes transition to lethal prostate cancer in mice.

Phenotypic plasticity is a hallmark of cancer and increasingly realized as a mechanism of resistance to androgen receptor (AR)-targeted therapy. Now that many prostate cancer (PCa) patients are treated upfront with AR-targeted agents, it's critical to identify actionable mechanisms that drive phenotypic plasticity, to prevent the emergence of resistance. We showed that loss of tristetraprolin (TTP, gene ZFP36) increased NF-κB activation, and was associated with higher rates of aggressive disease and early recurrence in primary PCa. We also examined the clinical and biological impact of ZFP36 loss with co-loss of PTEN, a known driver of PCa. Analysis of multiple independent primary PCa cohorts demonstrated that PTEN and ZFP36 co-loss was associated with increased recurrence risk. Engineering prostate-specific Zfp36 deletion in vivo, induced prostatic intraepithelial neoplasia, and, with Pten co-deletion, resulted in rapid progression to castration-resistant adenocarcinoma. Zfp36 loss altered the cell state driven by Pten loss, demonstrated by enrichment of EMT, inflammation, TNFα/NF-κB, IL6-JAK/STAT3 gene sets. Additionally, our work revealed that ZFP36 loss also induced enrichment of multiple gene sets involved in mononuclear cell migration, chemotaxis, and proliferation. Use of the NF-κB inhibitor, dimethylaminoparthenolide (DMAPT) induced marked therapeutic responses in tumors with PTEN and ZFP36 co-loss and reversed castration resistance.

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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
期刊最新文献
Mechanosensitive channels TMEM63A and TMEM63B mediate lung inflation-induced surfactant secretion. An inducible RIPK3-driven necroptotic system enhances cancer cell-based immunotherapy and ensures safety. G-CSF resistance of ELANE mutant neutropenia depends on SERF1 containing truncated neutrophil elastase aggregates. Low tristetraprolin expression activates phenotypic plasticity and primes transition to lethal prostate cancer in mice. Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.
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