Exosome-mediated transfer of MIF confers temozolomide resistance by regulating TIMP3/PI3K/AKT axis in gliomas.
Exosome-mediated transfer of MIF confers temozolomide resistance by regulating TIMP3/PI3K/AKT axis in gliomas.
复制标题
外泌体介导的 MIF 转移通过调节胶质瘤中的 TIMP3/PI3K/AKT 轴而赋予替莫唑胺耐药性。
DOI：
10.1016/j.omto.2021.08.004
复制
发表时间：
2021-09-24
期刊：
影响因子：
--
通讯作者：
Guo HB
中科院分区：
文献类型：
--
作者：
Wei QT;Liu BY;Ji HY;Lan YF;Tang WH;Zhou J;Zhong XY;Lian CL;Huang QZ;Wang CY;Xu YM;Guo HB
替莫唑胺耐药是胶质瘤临床治疗失败和预后不良的重要原因。越来越多的证据表明，癌症来源的外泌体有助于化学耐药；然而，胶质瘤源性外泌体的具体作用尚不清楚。本研究旨在探讨外泌体巨噬细胞迁移抑制因子（MIF）在胶质瘤TMZ耐药中的作用及其机制。我们首先证明了MIF在TMZ抗性细胞的外泌体中上调，导致TMZ抗性向敏感细胞转移。我们的研究结果表明，外泌体MIF通过增强TMZ暴露后的细胞增殖和抑制细胞凋亡，赋予TMZ对敏感细胞的抗性。MIF敲低通过上调金属蛋白酶抑制剂3 (TIMP3)，进而抑制PI3K/AKT信号通路，增强耐药胶质瘤细胞TMZ敏感性。此外，外泌体MIF在体内促进肿瘤生长和胶质瘤细胞对TMZ的抵抗，而IOS-1 （MIF抑制剂）在体内促进胶质瘤对TMZ敏感。综上所述，我们的研究表明，外泌体介导的MIF转移通过下调TIMP3并进一步激活PI3K/AKT信号通路，增强了胶质瘤中TMZ的耐药性，突出了TMZ治疗胶质瘤的预后生物标志物和有希望的治疗靶点。来自tmz耐药细胞的外泌体MIF可以通过下调TIMP3，激活PI3K/AKT信号通路，将化疗耐药特性传递给敏感的胶质瘤细胞。ISO-1 （MIF抑制剂）可以通过抑制MIF增强TMZ的敏感性，在动物模型中被证实是治疗TMZ耐药胶质瘤的一种很有前景的药物。
Temozolomide (TMZ) resistance is an important cause of clinical treatment failure and poor prognosis in gliomas. Increasing evidence indicates that cancer-derived exosomes contribute to chemoresistance; however, the specific contribution of glioma-derived exosomes remains unclear. The aim of this study was to explore the role and underlying mechanisms of exosomal macrophage migration inhibitory factor (MIF) on TMZ resistance in gliomas. We first demonstrated that MIF was upregulated in the exosomes of TMZ-resistant cells, engendering the transfer of TMZ resistance to sensitive cells. Our results indicated that exosomal MIF conferred TMZ resistance to sensitive cells through the enhancement of cell proliferation and the repression of cell apoptosis upon TMZ exposure. MIF knockdown enhanced TMZ sensitivity in resistant glioma cells by upregulating Metalloproteinase Inhibitor 3 (TIMP3) and subsequently suppressing the PI3K/AKT signaling pathway. Additionally, exosomal MIF promoted tumor growth and TMZ resistance of glioma cells in vivo, while IOS-1 (MIF inhibitor) promotes glioma TMZ sensitive in vivo. Taken together, our study demonstrated that exosome-mediated transfer of MIF enhanced TMZ resistance in glioma through downregulating TIMP3 and further activating the PI3K/AKT signaling pathway, highlighting a prognostic biomarker and promising therapeutic target for TMZ treatment in gliomas. Exosomal MIF derived from TMZ-resistant cells can transfer chemoresistance character to sensitive glioma cells by downregulating TIMP3, activating the PI3K/AKT signaling pathway. ISO-1 (MIF inhibitor) is verified to be a promising treatment for TMZ resistance gliomas in animal models because it could enhance the TMZ sensitivity by inhibiting MIF.
登录
查看更多内容
影响因子：
21.3
作者：
Costa-Silva B;Aiello NM;Ocean AJ;Singh S;Zhang H;Thakur BK;Becker A;Hoshino A;Mark MT;Molina H;Xiang J;Zhang T;Theilen TM;García-Santos G;Williams C;Ararso Y;Huang Y;Rodrigues G;Shen TL;Labori KJ;Lothe IM;Kure EH;Hernandez J;Doussot A;Ebbesen SH;Grandgenett PM;Hollingsworth MA;Jain M;Mallya K;Batra SK;Jarnagin WR;Schwartz RE;Matei I;Peinado H;Stanger BZ;Bromberg J;Lyden D
通讯作者：
Lyden D
影响因子：
8
作者：
Parekh, Aditya;Das, Subhayan;Mandal, Mahitosh
通讯作者：
Mandal, Mahitosh
组蛋白乙酰转移酶 KAT6A 通过 TRIM24 结合上调 PI3K/AKT 信号转导
影响因子：
11.2
作者：
Lv D;Jia F;Hou Y;Sang Y;Alvarez AA;Zhang W;Gao WQ;Hu B;Cheng SY;Ge J;Li Y;Feng H
通讯作者：
Feng H
影响因子：
50.3
作者：
Garofalo M;Di Leva G;Romano G;Nuovo G;Suh SS;Ngankeu A;Taccioli C;Pichiorri F;Alder H;Secchiero P;Gasparini P;Gonelli A;Costinean S;Acunzo M;Condorelli G;Croce CM
通讯作者：
Croce CM
影响因子：
6
作者：
Nawaz M;Shah N;Zanetti BR;Maugeri M;Silvestre RN;Fatima F;Neder L;Valadi H
通讯作者：
Valadi H