Irradiation-induced exosomal HMGB1 to confer radioresistance via the PI3K/AKT/FOXO3A signaling pathway in ESCC.
Irradiation-induced exosomal HMGB1 to confer radioresistance via the PI3K/AKT/FOXO3A signaling pathway in ESCC.
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辐射诱导的外泌体 HMGB1 通过 PI3K/AKT/FOXO3A 信号通路在 ESCC 中赋予放射抗性
DOI：
10.1186/s12967-022-03720-0
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发表时间：
2022-11-05
影响因子：
7.4
通讯作者：
Zhu, Shuchai
中科院分区：
文献类型：
--
作者：
Du, Xingyu;Zhang, Xueyuan;Dong, Jing;Zou, Naiyi;Guo, Dong;Yao, Weinan;Wang, Xiaobin;Li, Shuguang;Song, Chunyang;Yan, Ke;Shen, Wenbin;Zhu, Shuchai
放射抵抗是食管鳞状细胞癌（ESCC）放射治疗失败的主要原因之一，放射抵抗的潜在机制尚不清楚。辐射（IR）刺激肿瘤源性外泌体内容物的变化，其可被受体细胞摄取，在受体细胞的增殖、细胞周期和凋亡中起重要作用。本研究探讨了外泌体高迁移率族蛋白1（HMGB 1）对食管鳞癌细胞辐射抗性的影响。从21名ESCC患者和24名健康志愿者中分离血浆外泌体，并检测HMGB 1的表达。根据ESCC患者血浆外泌体HMGB 1的不同表达水平分析放疗的疗效。通过免疫荧光染色验证受体细胞对外泌体的摄取，并评估IR前后细胞中外泌体和HMGB 1的定位。研究了HMGB 1基因敲低后，IR诱导的exosomes对细胞增殖、侵袭、凋亡、细胞周期分布和辐射抗性的影响。Western blotting检测HMGB 1敲低exosome组和阴性对照组细胞周期蛋白B1（cyclin B1）、细胞周期蛋白依赖激酶1（CDK 1）、Bax、Bcl 2、磷酸化组蛋白H2 AX和PI 3 K/AKT/FOXO 3A通路的表达变化。ESCC患者血浆exosomes中HMGB 1的表达较健康人明显增高，血浆exosomes中HMGB 1的高表达与ESCC患者的放射抵抗有关（P = 0.016）。IR诱导外泌体HMGB 1的释放，促进受体细胞的增殖和辐射抗性，增敏增强比（SER）分别为0.906和0.919。此外，IR诱导的外泌体HMGB 1通过调节cyclin B1和CDK 1蛋白，促进G2/M期阻滞，与Bax和Bcl 2蛋白协同作用，通过PI 3 K/AKT/FOXO 3A信号通路降低细胞凋亡率，并通过γ H2 AX参与IR诱导的DNA损伤修复。这些发现表明，血浆外泌体HMGB 1的高表达与不良放疗反应相关。外泌体HMGB 1增强食管鳞癌细胞的辐射抗性
Radioresistance is a major cause of treatment failure in esophageal squamous cell carcinoma (ESCC) radiotherapy, and the underlying mechanisms of radioresistance are still unclear. Irradiation (IR) stimulates changes in tumor-derived exosome contents, which can be taken up by recipient cells, playing an important role in the proliferation, cell cycle and apoptosis of recipient cells. This study investigated the effect of IR-induced exosomal high mobility group box 1 (HMGB1) on radioresistance in ESCC cells. Plasma exosomes were isolated from 21 ESCC patients and 24 healthy volunteers, and the expression of HMGB1 was examined. Then, the therapeutic effect of radiotherapy was analyzed according to the different expression levels of plasma exosomal HMGB1 in ESCC patients. The uptake of exosomes by recipient cells was verified by immunofluorescence staining, and the localization of exosomes and HMGB1 in cells before and after IR was evaluated. The effects of IR-induced exosomes on cell proliferation, invasion, apoptosis, cell cycle distribution and radioresistance after HMGB1 knockdown were verified. Moreover, western blotting was used to measure changes in the expression of cyclin B1, CDK1, Bax, Bcl2, phosphorylated histone H2AX and the PI3K/AKT/FOXO3A pathway in the HMGB1-knockdown exosome group and the negative control group. The expression of HMGB1 in ESCC plasma exosomes was significantly increased compared with that in healthy volunteers, and high expression of HMGB1 in plasma exosomes was associated with radioresistance (P = 0.016). IR-induced the release of exosomal HMGB1 and promoted proliferation and radioresistance in recipient cells, with a sensitization enhancement ratio (SER) of 0.906 and 0.919, respectively. In addition, IR-induced exosomal HMGB1 promotes G2/M phase arrest by regulating the proteins cyclin B1 and CDK1, cooperating with the proteins Bax and Bcl2 to reduce the apoptosis rate through the PI3K/AKT/FOXO3A signaling pathway, and participated in IR-induced DNA damage repair through γH2AX. These findings indicate that high expression of plasma exosomal HMGB1 is associated with an adverse radiotherapy response. IR-induced exosomal HMGB1 enhances the radioresistance of ESCC cells.
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放疗诱导的细胞死亡激活旁分泌 HMGB1-TLR2 信号并加速胰腺癌转移
DOI：
10.1186/s13046-018-0726-2
发表时间：
2018-04-03
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Chen X;Zhang L;Jiang Y;Song L;Liu Y;Cheng F;Fan X;Cao X;Gong A;Wang D;Zhu H
通讯作者：
Zhu H
影响因子：
5.6
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Tuncay Cagatay S;Mayah A;Mancuso M;Giardullo P;Pazzaglia S;Saran A;Daniel A;Traynor D;Meade AD;Lyng F;Tapio S;Kadhim M
通讯作者：
Kadhim M
影响因子：
6
作者：
Ginini, Lana;Billan, Salem;Fridman, Eran;Gil, Ziv
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Gil, Ziv
影响因子：
14.9
作者：
Amato, Jussara;Cerofolini, Linda;Pagano, Bruno
通讯作者：
Pagano, Bruno
影响因子：
1.7
作者：
Jelonek, Karol;Wojakowska, Anna;Pietrowska, Monika
通讯作者：
Pietrowska, Monika