表达 esRAGE 的 oHSV 可通过抑制内皮细胞活化提高抗肿瘤疗效。

IF 5.3 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Molecular Therapy Oncolytics Pub Date : 2023-01-16 eCollection Date: 2023-03-16 DOI:10.1016/j.omto.2023.01.003
Jessica Swanner, Ji Seon Shim, Kimberly A Rivera-Caraballo, Karina Vázquez-Arreguín, Bangxing Hong, Alberto J Bueso-Perez, Tae Jin Lee, Yeshavanth Kumar Banasavadi-Siddegowda, Balveen Kaur, Ji Young Yoo
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引用次数: 0

摘要

高迁移率基团框 1(HMGB1)是一种损伤相关分子模式(DAMP)分子,在炎症和肿瘤发生中发挥着重要作用。高级糖化终产物受体(RAGE)是细胞外 HMGB1 与之结合以介导其活性的主要受体之一。RAGE 在内皮细胞(EC)上高度表达,并在炎症过程中调节内皮的通透性。在这里,我们将 RAGE 的内源性分泌形式(esRAGE)作为 RAGE 配体的诱饵受体引入溶瘤性单纯疱疹病毒 1(oHSV)(OVesRAGE)。OVesRAGE 在体外和体内都能显著降低胶质母细胞瘤(GBM)细胞中 MEK1/2 和 Erk 的磷酸化,并增加 PARP 的裂解。OVesRAGE能有效分泌esRAGE,挽救病毒诱导的EC迁移和活化。当肿瘤细胞与心血管细胞共培养时,心血管细胞活化程度的降低有利于病毒在肿瘤细胞中的复制。最后,OVesRAGE 能显著提高对患 GBM 小鼠的疗效。总之,我们的数据表明,HMGB1-RAGE 信号转导可能是一个很有前景的靶点,抑制它是提高 oHSV 治疗效果的可行方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

esRAGE-expressing oHSV enhances anti-tumor efficacy by inhibition of endothelial cell activation.

esRAGE-expressing oHSV enhances anti-tumor efficacy by inhibition of endothelial cell activation.

esRAGE-expressing oHSV enhances anti-tumor efficacy by inhibition of endothelial cell activation.

esRAGE-expressing oHSV enhances anti-tumor efficacy by inhibition of endothelial cell activation.

High-mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) molecule that plays an important role in inflammation and tumorigenesis. Receptor for advanced glycation end products (RAGE) is one of the major receptors to which extracellular HMGB1 binds to mediate its activity. RAGE is highly expressed on the endothelial cells (ECs) and regulates endothelial permeability during inflammation. Here, we introduced the endogenous secretory form of RAGE (esRAGE) as a decoy receptor for RAGE ligands into an oncolytic herpes simplex virus 1 (oHSV) (OVesRAGE), which, upon release, can function to block RAGE signaling. OVesRAGE significantly decreased phosphorylation of MEK1/2 and Erk and increased cleaved PARP in glioblastoma (GBM) cells in vitro and in vivo. oHSV-infected GBM cells co-cultured with ECs were used to test OVesRAGE effect on EC activation, vessel leakiness, virus replication, and tumor cell killing. OVesRAGE could effectively secrete esRAGE and rescue virus-induced EC migration and activation. Reduced EC activation facilitated virus replication in tumor cells when co-cultured with ECs. Finally, OVesRAGE significantly enhanced therapeutic efficacy in GBM-bearing mice. Collectively, our data demonstrate that HMGB1-RAGE signaling could be a promising target and that its inhibition is a feasible approach to improve the efficacy of oHSV therapy.

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来源期刊
Molecular Therapy Oncolytics
Molecular Therapy Oncolytics Medicine-Oncology
CiteScore
10.90
自引率
3.50%
发文量
152
审稿时长
6 weeks
期刊介绍: Molecular Therapy — Oncolytics is an international, online-only, open access journal focusing on the development and clinical testing of viral, cellular, and other biological therapies targeting cancer.
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