发现一种新型 VDR 激动剂--牡荆素,它能缓解从慢性肠炎到结肠直肠癌的转变

IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yonger Chen, Jian Liang, Shuxian Chen, Nan Lin, Shuoxi Xu, Jindian Miao, Jing Zhang, Chen Chen, Xin Yuan, Zhuoya Xie, Enlin Zhu, Mingsheng Cai, Xiaoli Wei, Shaozhen Hou, Hailin Tang
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引用次数: 0

摘要

长期处于慢性炎症状态的炎症性肠病(IBD)患者经常会患上结肠炎相关性结直肠癌(CAC)。研究预防癌前病变和抑制其发展的药理制剂及其机制仍然是 CAC 研究的一个重点和挑战。以往的研究表明,荆芥苷能有效缓解 CAC,但其确切的作用机制还需要进一步探索。本研究发现,维生素 D 受体(VDR)的缺失会加速慢性结肠炎向结肠直肠癌的发展。我们的研究结果表明,荆芥苷能特异性地靶向 VDR 蛋白,促进其转位到细胞核内发挥转录活性。此外,通过巨噬细胞和癌细胞的共培养模型,我们观察到荆芥苷能促进巨噬细胞向 M1 表型极化,而这一过程依赖于 VDR。此外,ChIP-seq分析显示,牡荆素通过VDR调节酚嗪生物合成样结构域蛋白(PBLD)的转录激活。通过 ChIP 检测和双荧光素酶报告检测,确定了 PBLD 的功能调控区,证实了 VDR/PBLD 通路对于荆芥苷介导的巨噬细胞极化调控至关重要。最后,在骨髓 VDR 基因敲除的小鼠模型中,我们发现蔓荆子素对中期 CAC 的保护作用消失了。总之,我们的研究证实,牡荆素能靶向VDR,并通过VDR/PBLD途径调节巨噬细胞极化,从而缓解慢性结肠炎向结直肠癌的转变。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Discovery of vitexin as a novel VDR agonist that mitigates the transition from chronic intestinal inflammation to colorectal cancer
Colitis-associated colorectal cancer (CAC) frequently develops in patients with inflammatory bowel disease (IBD) who have been exposed to a prolonged state of chronic inflammation. The investigation of pharmacological agents and their mechanisms to prevent precancerous lesions and inhibit their progression remains a significant focus and challenge in CAC research. Previous studies have demonstrated that vitexin effectively mitigates CAC, however, its precise mechanism of action warrants further exploration. This study reveals that the absence of the Vitamin D receptor (VDR) accelerates the progression from chronic colitis to colorectal cancer. Our findings indicate that vitexin can specifically target the VDR protein, facilitating its translocation into the cell nucleus to exert transcriptional activity. Additionally, through a co-culture model of macrophages and cancer cells, we observed that vitexin promotes the polarization of macrophages towards the M1 phenotype, a process that is dependent on VDR. Furthermore, ChIP-seq analysis revealed that vitexin regulates the transcriptional activation of phenazine biosynthesis-like domain protein (PBLD) via VDR. ChIP assays and dual luciferase reporter assays were employed to identify the functional PBLD regulatory region, confirming that the VDR/PBLD pathway is critical for vitexin-mediated regulation of macrophage polarization. Finally, in a mouse model with myeloid VDR gene knockout, we found that the protective effects of vitexin were abolished in mid-stage CAC. In summary, our study establishes that vitexin targets VDR and modulates macrophage polarization through the VDR/PBLD pathway, thereby alleviating the transition from chronic colitis to colorectal cancer.
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来源期刊
Molecular Cancer
Molecular Cancer 医学-生化与分子生物学
CiteScore
54.90
自引率
2.70%
发文量
224
审稿时长
2 months
期刊介绍: Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.
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