以 XPO1 为靶点的 Selinexor 可促进 PEG3 的核积累并抑制胆管癌的进展。

IF 2.7 4区 医学 Q3 ONCOLOGY Cancer Chemotherapy and Pharmacology Pub Date : 2024-11-01 Epub Date: 2024-08-05 DOI:10.1007/s00280-024-04704-1
Deng Xiang, Min Wang, Huajun Wu, Xi Chen, Tianxiang Chen, Dongshan Yu, Lei Xiong, Han Xu, Ming Luo, Shouhua Zhang, Linquan Wu, Jinlong Yan
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引用次数: 0

摘要

背景:selinexor是一种输出蛋白1(XPO1)靶向抑制剂,它在治疗胆管癌中的作用尚未完全明了。本研究进行了全面的体外和体内研究,以阐明 selinexor 对胆管癌的影响,重点研究其与父系表达基因 3 (PEG3) 细胞定位的机理关系:方法:利用免疫缺陷小鼠中的胆管癌患者样本建立了患者衍生异种移植(PDX)模型,以评估selinexor的体内效应。此外,还培养了胆管癌细胞系 HuCC-T1 和 BRE,以评估 selinexor 对细胞增殖、侵袭、迁移、细胞周期和凋亡的影响。还将 HuCC-T1 细胞植入免疫缺陷小鼠体内进行进一步研究。采用免疫荧光和 Western 印迹技术观察 PEG3 蛋白的表达和定位:结果表明,selinexor能显著抑制胆管癌PDX模型的肿瘤生长,并促进PEG3蛋白在肿瘤细胞核内的积累。体外实验表明,selinexor能有效抑制胆管癌细胞的增殖、侵袭和迁移,同时还能阻碍细胞周期并诱导细胞凋亡。值得注意的是,selinexor 能明显促进 PEG3 蛋白在胆管癌细胞核内的积累。然而,当 PEG3 的表达被敲除时,selinexor 对胆管癌的影响就会明显逆转:这些研究结果表明,selinexor 通过靶向 XPO1 和促进 PEG3 蛋白的核积累,从而阻碍细胞周期并诱导细胞凋亡,从而抑制胆管癌的进展。
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Selinexor targeting XPO1 promotes PEG3 nuclear accumulation and suppresses cholangiocarcinoma progression.

Background: The role of selinexor, a targeted inhibitor of exportin 1 (XPO1), in the treatment of cholangiocarcinoma is not yet fully understood. This study conducted comprehensive in vitro and in vivo investigations to elucidate the effects of selinexor on cholangiocarcinoma, with a focus on its mechanistic relationship with the cellular localization of Paternally Expressed Gene 3 (PEG3).

Methods: A patient-derived xenograft (PDX) model was established using samples from a cholangiocarcinoma patient in immunodeficient mice to assess the in vivo effects of selinexor. Additionally, cholangiocarcinoma cell lines HuCC-T1 and BRE were cultured to evaluate selinexor's impact on cell proliferation, invasion, migration, cell cycle, and apoptosis. HuCC-T1 cells were also implanted in immunodeficient mice for further investigation. Immunofluorescence and Western blotting were employed to observe the expression and localization of the PEG3 protein.

Results: The results demonstrated that selinexor significantly inhibited tumor growth in the cholangiocarcinoma PDX model and promoted the accumulation of PEG3 protein within the nuclei of tumor cells. In vitro experiments showed that selinexor effectively suppressed cholangiocarcinoma cell proliferation, invasion, and migration, while also impeding the cell cycle and inducing apoptosis. Notably, selinexor markedly facilitated the nuclear accumulation of PEG3 protein in cholangiocarcinoma cells. However, when PEG3 expression was knocked down, the effects of selinexor on cholangiocarcinoma were significantly reversed.

Conclusion: These findings suggest that selinexor inhibits the progression of cholangiocarcinoma by targeting XPO1 and promoting the nuclear accumulation of PEG3 protein, thereby hindering the cell cycle and inducing apoptosis.

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来源期刊
CiteScore
6.10
自引率
3.30%
发文量
116
审稿时长
2.5 months
期刊介绍: Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
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