辐射诱导的细胞外囊泡 (EV) 释放 miR-603 促进胶质母细胞瘤中 IGF1 介导的干细胞状态。

Radiation-induced extracellular vesicle (EV) release of miR-603 promotes IGF1-mediated stem cell state in glioblastomas.

机构信息

Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA.

VisiCELL Medical Inc., San Diego, CA 92121, USA.

出版信息

EBioMedicine. 2020 May;55:102736. doi: 10.1016/j.ebiom.2020.102736. Epub 2020 Apr 28.

DOI:10.1016/j.ebiom.2020.102736

PMID:32361246

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7195524/

Abstract

BACKGROUND

Recurrence after radiation therapy is nearly universal for glioblastomas, the most common form of adult brain cancer. The study aims to define clinically pertinent mechanisms underlying this recurrence.

METHODS

microRNA (miRNA) profiling was performed using matched pre- and post-radiation treatment glioblastoma specimens from the same patients. All specimens harbored unmethylated O-methylguanine-DNA methyltransferase promoters (umMGMT) and wild-type isocitrate dehydrogenase (wtIDH). The most altered miRNA, miR-603, was characterized.

FINDINGS

While nearly all miRNAs remained unchanged after treatment, decreased levels of few, select miRNAs in the post-treatment specimens were observed, the most notable of which involved miR-603. Unbiased profiling of miR-603 targets revealed insulin-like growth factor 1 (IGF1) and IGF1 receptor (IGF1R). Ionizing radiation (IR) induced cellular export of miR-603 through extracellular vesicle (EV) release, thereby de-repressing IGF1 and IGF1R. This de-repression, in turn, promoted cancer stem-cell (CSC) state and acquired radiation resistance in glioblastomas. Export of miR-603 additionally de-repressed MGMT, a DNA repair protein responsible for detoxifying DNA alkylating agents, to promote cross-resistance to these agents. Ectopic miR-603 expression overwhelmed cellular capacity for miR-603 export and synergized with the tumoricidal effects of IR and DNA alkylating agents.

INTERPRETATION

Profiling of matched pre- and post-treatment glioblastoma specimens revealed altered homeostasis of select miRNAs in response to radiation. Radiation-induced EV export of miR-603 simultaneously promoted the CSC state and up-regulated DNA repair to promote acquired resistance. These effects were abolished by exogenous miR-603 expression, suggesting potential for clinical translation.

FUNDING

NIH 1R01NS097649-01, 9R44GM128223-02, 1R01CA240953-01, the Doris Duke Charitable Foundation Clinical Scientist Development Award, The Sontag Foundation Distinguished Scientist Award, the Kimmel Scholar Award, and BWF 1006774.01 (C.C.C).

摘要

背景

对于胶质母细胞瘤，即成人中最常见的脑癌，放射治疗后复发几乎是普遍的。本研究旨在确定这种复发的潜在临床机制。

方法

对来自同一患者的放疗前后配对胶质母细胞瘤标本进行 microRNA（miRNA）谱分析。所有标本均携带未甲基化的 O-甲基鸟嘌呤-DNA 甲基转移酶启动子（umMGMT）和野生型异柠檬酸脱氢酶（wtIDH）。对最显著改变的 miRNA，miR-603 进行了特征分析。

发现

虽然治疗后几乎所有 miRNA 都保持不变，但在治疗后的标本中观察到少数 miRNA 的水平降低，其中最显著的涉及 miR-603。miR-603 靶标无偏分析显示胰岛素样生长因子 1（IGF1）和 IGF1 受体（IGF1R）。电离辐射（IR）通过细胞外囊泡（EV）释放诱导 miR-603 的细胞外排，从而解除 IGF1 和 IGF1R 的抑制。这种去抑制作用反过来又促进了胶质母细胞瘤中的癌症干细胞（CSC）状态和获得性辐射抵抗。miR-603 的外排还解除了 DNA 修复蛋白 MGMT 的抑制，MGMT 负责解毒 DNA 烷化剂，从而促进对这些药物的交叉耐药性。外源性 miR-603 表达克服了细胞对 miR-603 外排的能力，并与 IR 和 DNA 烷化剂的细胞毒性作用协同作用。