暴露于苯并[a]芘及其代谢物 BPDE 的膀胱上皮细胞中,LOXL1 蛋白的表观遗传修饰下调介导了 EMT。

IF 4.8 2区 医学 Q2 IMMUNOLOGY
International immunopharmacology Pub Date : 2024-12-05 Epub Date: 2024-09-27 DOI:10.1016/j.intimp.2024.113232
Ronghao Zou, Juan Lu, Xiaoyue Bai, Yuyao Yang, Shouyue Zhang, Shuai Wu, Zhixin Tang, Kang Li, Xiaohui Hua
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引用次数: 0

摘要

苯并[a]芘(B[a]P)是一种众所周知的多环芳烃(PAH)污染物,具有高致癌性,广泛存在于环境中,对公众健康构成严重威胁。流行病学研究表明,暴露于 B[a]P 及其代谢物 7,8- 二羟基-9,10-环氧苯并[a]芘(BPDE)与包括膀胱癌在内的多种癌症的发生和发展有关。然而,其潜在机制仍不清楚。我们的研究发现,B[a]P 和 BPDE 可诱导上皮-间质转化(EMT),这是细胞恶性转化的一个关键早期事件,涉及 E-Cadherin 蛋白水平的降低和 N-Cadherin 蛋白水平的上调,从而导致膀胱上皮细胞的细胞运动性和迁移性增强。进一步的研究表明,LOXL1 DNA 在甲基转移酶 3a(DNMT3a)和 DNMT3b 的影响下发生甲基化和修饰,导致 LOXL1 蛋白水平下降。减少的 LOXL1 会促进锌指转录因子 SLUG,进而抑制 E-Cadherin 蛋白水平,启动 EMT 过程。此外,DNMT3a/3b的表达似乎受细胞内氧化应激水平的影响。这些发现表明,暴露于 B[a]P/BPDE 会通过关键因子 LOXL1 促进 EMT 过程,从而导致膀胱癌的发生。我们的研究为将 LOXL1 视为早期诊断的潜在生物标志物和精确诊断与治疗膀胱癌的新靶点提供了理论依据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The epigenetic-modified downregulation of LOXL1 protein mediates EMT in bladder epithelial cells exposed to benzo[a]pyrene and its metabolite BPDE.

Benzo[a]pyrene (B[a]P) is a well-known polycyclic aromatic hydrocarbon (PAH) pollutant with high carcinogenicity, widespread environmental presence, and significant threat to public health. Epidemiological studies have linked exposure to B[a]P and its metabolite 7,8-dihydroxy-9,10-epoxybenzo[a]pyrene (BPDE) to the development and progression of various cancers, including bladder cancer. However, its underlying mechanism remains unclear. Our study revealed that B[a]P and BPDE induced epithelial-mesenchymal transition (EMT), a critical early event in cell malignant transformation, involving a decrease in E-Cadherin and upregulation of N-Cadherin protein levels, leading to increased cell motility and migration in bladder epithelial cells. Further studies have indicated that LOXL1 DNA undergoes methylation and modification influenced by methyltransferase 3a (DNMT3a) and DNMT3b, resulting in decreased LOXL1 protein levels. The decreased LOXL1 promotes the zinc finger transcription factor SLUG, which then inhibits E-Cadherin protein levels and initiates the EMT process. Moreover, DNMT3a/3b expression appears to be influenced by intracellular oxidative stress levels. These findings suggest that exposure to B[a]P/BPDE promotes the EMT process through the pivotal factor LOXL1, thereby contributing to bladder carcinogenesis. Our study provides a theoretical basis for considering LOXL1 as a potential biomarker for early diagnosis and a novel target for the precise diagnosis and treatment of bladder cancer.

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来源期刊
CiteScore
8.40
自引率
3.60%
发文量
935
审稿时长
53 days
期刊介绍: International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.
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