Department of General Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No. 1 Minde Road, Nanchang, Jiangxi Province, 330006, China.
Department of General Surgery, The Affiliated Children's Hospital of Nanchang Medical College, Nangchang, 330000, China.
Cancer Chemother Pharmacol. 2024 Nov;94(5):669-683. doi: 10.1007/s00280-024-04704-1. Epub 2024 Aug 5.
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).
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.
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.
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.
选择性核输出抑制剂 selinexor （XPO1 的靶向抑制剂）在胆管癌治疗中的作用尚未完全阐明。本研究通过全面的体外和体内研究来阐明 selinexor 对胆管癌的影响，重点研究其与 Paternally Expressed Gene 3（PEG3）细胞内定位的机制关系。
使用免疫缺陷小鼠中胆管癌患者的样本建立了患者衍生的异种移植（PDX）模型，以评估 selinexor 的体内作用。此外，培养胆管癌细胞系 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中进行进一步研究。采用免疫荧光和 Western blot 观察 PEG3 蛋白的表达和定位。
结果表明，sinexor 显著抑制胆管癌 PDX 模型中的肿瘤生长，并促进肿瘤细胞中 PEG3 蛋白在核内的积累。体外实验表明，sinexor 有效抑制胆管癌细胞增殖、侵袭和迁移，同时阻碍细胞周期并诱导细胞凋亡。值得注意的是，sinexor 显著促进了胆管癌细胞中 PEG3 蛋白的核内积累。然而，当敲低 PEG3 表达时，sinexor 对胆管癌的作用明显逆转。
这些发现表明，sinexor 通过靶向 XPO1 抑制胆管癌的进展，并促进 PEG3 蛋白的核内积累，从而阻碍细胞周期并诱导细胞凋亡。
