HMGB1 knockdown increases MM cell vulnerability by regulating autophagy and DNA damage repair.
HMGB1 knockdown increases MM cell vulnerability by regulating autophagy and DNA damage repair.
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HMGB1 敲低通过调节自噬和 DNA 损伤修复来增加 MM 细胞的脆弱性
DOI：
10.1186/s13046-018-0883-3
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发表时间：
2018-08-29
期刊：
影响因子：
--
通讯作者：
Cai Z
中科院分区：
文献类型：
--
作者：
Guo X;He D;Zhang E;Chen J;Chen Q;Li Y;Yang L;Yang Y;Zhao Y;Wang G;He J;Cai Z
背景随着新型治疗药物的开发，多发性骨髓瘤（MM）患者的生存率有了很大的提高。然而，由于耐药性，这种疾病是无法治愈的。既往研究发现高迁移率组框1 （HMGB1）参与炎症、血管生成、DNA损伤修复、肿瘤侵袭、进展、转移和耐药等过程，高表达与MM预后不良相关，但HMGB1在MM中的作用和机制尚不清楚。方法通过基因表达和Oncomine数据库分析，发现HMGB1与MM患者预后不良相关。采用RNA干扰、基因阵列分析、细胞增殖和凋亡检测、自噬检测、western blotting和体内异种移植模型等方法评价HMGB1的作用及其参与MM耐药的机制。结果MM细胞系和原代MM样品中HMGB1表达水平较高，与MM患者的3年生存率呈负相关。HMGB1在MM细胞中的下调通过诱导凋亡增强了地塞米松化疗的抑制作用。HMGB1的下调激活了mTOR通路，通过调节相关基因的表达抑制了自噬，加重了Dex诱导的DNA损伤。在体内，异种移植模型显示，经Dex治疗后，hmgb1敲低小鼠的肿瘤负荷较对照小鼠减轻。结论研究表明HMGB1参与自噬和DNA损伤修复，下调HMGB1可增强MM细胞对Dex的敏感性，提示HMGB1可能是MM治疗的靶点。
BackgroundWith the development of novel therapeutic agents, the survival of multiple myeloma (MM) patients has much improved. However, the disease is incurable due to drug resistance. Previous studies have found that high-mobility group box 1 (HMGB1) is involved in inflammation, angiogenesis, DNA damage repair, and cancer invasion, progression, metastasis and drug resistance and that high HMGB1 expression is associated with poor MM prognosis, yet the role and mechanism of HMGB1 in MM remains unclear.MethodsThrough gene expression and Oncomine database analyses, we found that HMGB1 is associated with a poor prognosis in MM patients. RNA interference together with gene array analysis, cell proliferation and apoptosis assays, autophagy detection assays, western blotting, and in vivo xenograft models were employed to evaluate the effect of HMGB1 and the mechanism involved in MM drug resistance.ResultsMM cell lines and primary MM samples were found to express high levels of HMGB1, which was negatively associated with the 3-year survival of MM patients. HMGB1 knockdown in MM cells enhanced the inhibitory effect of chemotherapy with dexamethasone (Dex) via apoptosis induction. Furthermore, downregulation of HMGB1 activated the mTOR pathway, inhibited autophagy and increased DNA damage induced by Dex by modulating expression of related genes. In vivo, xenograft models showed that after Dex treatment, the tumor burden of HMGB1-knockdown mice was decreased compared with that of control mice.ConclusionsOur research shows that HMGB1 participates in autophagy and DNA damage repair and that downregulation of HMGB1 enhances the sensitivity of MM cells to Dex, suggesting that HMGB1 may serve as a target for MM treatment.
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Lycorine 下调 HMGB1 以抑制自噬并增强多发性骨髓瘤中硼替佐米的活性
影响因子：
12.4
作者：
Roy M;Liang L;Xiao X;Peng Y;Luo Y;Zhou W;Zhang J;Qiu L;Zhang S;Liu F;Ye M;Zhou W;Liu J
通讯作者：
Liu J
影响因子：
10.6
作者：
Kang, Rui;Chen, Ruochan;Zhang, Qiuhong;Hou, Wen;Wu, Sha;Cao, Lizhi;Huang, Jin;Yu, Yan;Fan, Xue-gong;Yan, Zhengwen;Sun, Xiaofang;Wang, Haichao;Wang, Qingde;Tsung, Allan;Billiar, Timothy R.;Zeh, Herbert J., III;Lotze, Michael T.;Tang, Daolin
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Tang, Daolin
影响因子：
168.9
作者：
Roellig, Christoph;Knop, Stefan;Bornhaeuser, Martin
通讯作者：
Bornhaeuser, Martin
影响因子：
20.3
作者：
Chen, Q;Van der Sluis, PC;Dalton, WS
通讯作者：
Dalton, WS
影响因子：
--
作者：
Mao, Xing-Jiang;Wang, Geng-Fu;Wang, Hui-Ling
通讯作者：
Wang, Hui-Ling