通过 EZH2 沉默恢复 miR-26a-5p 可阻断 IL-6/STAT3 轴,从而抑制前列腺癌的生长。

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Expert Opinion on Therapeutic Targets Pub Date : 2023-07-01 Epub Date: 2023-12-30 DOI:10.1080/14728222.2023.2293750
Wenqiang Zhang, Qiwei Nie, Xuling Zhang, Long Huang, Guofu Pang, Jing Chu, Xiaoxu Yuan
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引用次数: 0

摘要

背景:白细胞介素-6(IL-6)参与了前列腺癌多种致癌途径的激活。然而,其上游跨信号通路在很大程度上仍不为人所知。本研究提出了IL-6在前列腺癌发生过程中的上游效应因子的机理解释:研究设计与方法:采集样本以验证 EZH2、miR-26a-5p 和 IL-6 的表达。此外,还评估了前列腺癌细胞中 STAT3(信号转导和转录激活因子 3)的蛋白及其磷酸化情况。我们利用功能试验探讨了这些效应因子对体外恶性表型和体内肿瘤生长的影响。我们使用生物信息学分析、双荧光素酶报告基因测定和染色质免疫沉淀(ChIP)测定来确定它们之间的结合关系:结果:在前列腺癌中观察到 EZH2 和 IL-6 过表达,miR-26a-5p 表达不足。抑制 IL-6 可抑制 STAT3,从而抑制前列腺癌细胞的恶性表型。从机制上讲,EZH2通过促进H3K27组蛋白甲基化来抑制miR-26a-5p的表达,而miR-26a-5p则通过靶向IL-6来限制前列腺癌的恶性表型。异位表达的EZH2通过抑制miR-26a-5p和激活IL-6/STAT3轴减少了异种移植的生长:结论:EZH2可能通过招募H3K27me3到miR-26a-5p启动子区域参与调节其表达,这可能会进一步影响IL6/STAT3通路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
miR-26a-5p restoration via EZH2 silencing blocks the IL-6/STAT3 axis to repress the growth of prostate cancer.

Background: Interleukin-6 (IL-6) is involved in the activation of several oncogenic pathways in prostate cancer. However, its upstream trans-signaling pathway remains largely unknown. This work proposes a mechanistic explanation of IL-6's upstream effectors in prostate carcinogenesis.

Research design & methods: Samples were harvested to validate the expression of EZH2, miR-26a-5p, and IL-6. Moreover, the protein and its phosphorylation of STAT3 (signal transducer and transcription activator 3) were assessed in prostate cancer cells. We explored the effects of these effectors on malignant phenotypes in vitro and tumor growth in vivo using functional assays. Bioinformatics analysis, dual-luciferase reporter gene assays, and chromatin immunoprecipitation (ChIP) assays were used to determine their binding relationships.

Results: Overexpression of EZH2 and IL-6, and under expression of miR-26a-5p was observed in prostate cancer. Silencing IL-6 repressed STAT3 to suppress the malignant phenotypes of prostate cancer cells. Mechanistically, EZH2 inhibited miR-26a-5p expression by promoting H3K27 histone methylation, and miR-26a-5p restricted the malignant phenotypes of prostate cancer by targeting IL-6. Ectopic EZH2 expression reduced xenograft growth by inhibiting miR-26a-5p and activating the IL-6/STAT3 axis.

Conclusion: EZH2 May potentially be involved in regulating its expression by recruiting H3K27me3 to the miR-26a-5p promoter region, which could further impact the IL6/STAT3 pathway.

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来源期刊
CiteScore
8.90
自引率
1.70%
发文量
58
审稿时长
3 months
期刊介绍: The journal evaluates molecules, signalling pathways, receptors and other therapeutic targets and their potential as candidates for drug development. Articles in this journal focus on the molecular level and early preclinical studies. Articles should not include clinical information including specific drugs and clinical trials. The Editors welcome: Reviews covering novel disease targets at the molecular level and information on early preclinical studies and their implications for future drug development. Articles should not include clinical information including specific drugs and clinical trials. Original research papers reporting results of target selection and validation studies and basic mechanism of action studies for investigative and marketed drugs. The audience consists of scientists, managers and decision makers in the pharmaceutical industry, academic researchers working in the field of molecular medicine and others closely involved in R&D.
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