Equol通过促进TRIM21介导的ANXA2泛素化,对绒毛膜癌细胞产生抗肿瘤作用。

IF 5.7 2区 生物学 Q1 BIOLOGY Biology Direct Pub Date : 2024-09-06 DOI:10.1186/s13062-024-00519-5
Xiao-Mei Liu, Zi-Hao Wang, Qian-Xue Wei, Yang Song, Xiao-Xin Ma
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引用次数: 0

摘要

绒毛膜癌是一种恶性肿瘤,属于妊娠滋养细胞肿瘤(GTN)。本文对29名GTN患者和30名健康人进行了血清代谢组学分析,以确定GTN进展过程中的代谢变化特征。最终确定了 24 种差异代谢物(DMs),其中 Equol 在 GTN 患者中下调,其 VIP 评分在 24 种 DMs 中排名第三。Equol是代泽因的一种肠道代谢物,其抗癌潜力已在多种癌症中得到证实,但未在绒毛膜癌中得到证实。因此,研究人员使用了人类绒毛膜癌细胞系 JEG-3 和 Bewo,并建立了源自 JEG-3 的皮下异种移植模型,以评估 Equol 对绒毛膜癌的影响。结果表明,Equol 能有效抑制绒毛膜癌细胞增殖,诱导细胞凋亡,减少肿瘤发生。无标记定量蛋白质组学显示,136 个蛋白质受到 Equol 的显著影响,20 个蛋白质富集在与蛋白质降解相关的基因本体术语中。Equol 上调了含有三方基序 21 (TRIM21) 的 E3 泛素连接酶。抑制 TRIM21 可逆转 Equol 诱导的对绒毛膜癌细胞的影响。Annexin A2(ANXA2)与 TRIM21 相互作用,其泛素化受 TRIM21 的调节。我们发现,TRIM21 负责 Equol 诱导的蛋白酶体介导的 ANXA2 降解,而 Equol 对绒毛膜癌细胞恶性行为的抑制作用是通过 TRIM21 介导的 ANXA2 下调实现的。此外,Equol 还能抑制 β-catenin 的活化,这也取决于 TRIM21 介导的 ANXA2 下调。综上所述,Equol 可能是一种治疗绒毛膜癌的新型候选药物。
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Equol exerts anti-tumor effects on choriocarcinoma cells by promoting TRIM21-mediated ubiquitination of ANXA2.

Choriocarcinoma is a malignant cancer that belongs to gestational trophoblastic neoplasia (GTN). Herein, serum metabolomic analysis was performed on 29 GTN patients and 30 healthy individuals to characterize the metabolic variations during GTN progression. Ultimately 24 differential metabolites (DMs) were identified, of which, Equol was down-regulated in GTN patients, whose VIP score is the 3rd highest among the 24 DMs. As an intestinal metabolite of daidzein, the anticancer potential of Equol has been demonstrated in multiple cancers, but not choriocarcinoma. Hence, human choriocarcinoma cell lines JEG-3 and Bewo were used and JEG-3-derived subcutaneous xenograft models were developed to assess the effect of Equol on choriocarcinoma. The results suggested that Equol treatment effectively suppressed choriocarcinoma cell proliferation, induced cell apoptosis, and reduced tumorigenesis. Label-free quantitative proteomics showed that 136 proteins were significantly affected by Equol and 20 proteins were enriched in Gene Ontology terms linked to protein degradation. Tripartite motif containing 21 (TRIM21), a E3 ubiquitin ligase, was up-regulated by Equol. Equol-induced effects on choriocarcinoma cells could be reversed by TRIM21 inhibition. Annexin A2 (ANXA2) interacted with TRIM21 and its ubiquitination was modulated by TRIM21. We found that TRIM21 was responsible for proteasome-mediated degradation of ANXA2 induced by Equol, and the inhibitory effects of Equol on the malignant behaviors of choriocarcinoma cells were realized by TRIM21-mediated down-regulation of ANXA2. Moreover, β-catenin activation was inhibited by Equol, which also depended on TRIM21-mediated down-regulation of ANXA2. Taken together, Equol may be a novel candidate for the treatment for choriocarcinoma.

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来源期刊
Biology Direct
Biology Direct 生物-生物学
CiteScore
6.40
自引率
10.90%
发文量
32
审稿时长
7 months
期刊介绍: Biology Direct serves the life science research community as an open access, peer-reviewed online journal, providing authors and readers with an alternative to the traditional model of peer review. Biology Direct considers original research articles, hypotheses, comments, discovery notes and reviews in subject areas currently identified as those most conducive to the open review approach, primarily those with a significant non-experimental component.
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