HSP27-Mediated Extracellular and Intracellular Signaling Pathways Synergistically Confer Chemoresistance in Squamous Cell Carcinoma of Tongue
HSP27-Mediated Extracellular and Intracellular Signaling Pathways Synergistically Confer Chemoresistance in Squamous Cell Carcinoma of Tongue
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HSP27 介导的细胞外和细胞内信号通路协同赋予舌鳞状细胞癌化疗耐药性
DOI：
10.1158/1078-0432.ccr-17-2619
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发表时间：
2017-12
影响因子：
11.5
通讯作者：
He Zhimin
中科院分区：
文献类型：
--
作者：
Zheng Guopei;Zhang Zhijie;Liu Hao;Xiong Yan;Luo Liyun;Jia Xiaoting;Peng Cong;Zhang Qiong;Li Nan;Gu Yixue;Lu Minying;Song Ying;Pan Hao;Liu Jinbao;Liu Wanqing;He Zhimin
目的：舌鳞状细胞癌（Squamous Cell Carcinoma of Tongue，SCCT）是口腔癌中最常见的类型. SCCT的化疗耐药性很常见，其潜在机制在很大程度上仍不清楚。我们的目的是确定关键分子和信号通路介导的化疗耐药的SCCT。实验设计：使用蛋白质组学方法，我们发现HSP 27是SCCT细胞中化学抗性的潜在介导物。为了进一步验证HSP 27的这种作用，我们使用体外和体内模型以及来自SCCT患者的血清和组织样品进行了各种机制研究。结果：HSP 27蛋白在SCCT多药耐药细胞及细胞培养液中表达明显增加。HSP 27敲除和抗HSP 27抗体治疗都逆转了化学抗性。然而，HSP 27过表达和重组人HSP 27蛋白处理均增强了化疗耐药性。此外，化疗显著诱导HSP 27蛋白在SCCT细胞及其培养液，以及在SCCT患者的肿瘤组织和血清中的表达。HSP 27过表达预示接受化疗的SCCT患者预后不良在机械上，细胞外HSP 27与TLR 5结合，然后激活NF-κB信号传导以维持SCCT细胞存活。TLR 5敲低或IκBα蛋白水平恢复可破坏细胞外HSP 27诱导的NF-κB反式激活和化疗耐药性。此外，细胞内HSP 27与BAX和BIM结合，以抑制它们易位到线粒体，并随后在化疗时释放细胞色素C，从而抑制线粒体凋亡途径。结论：HSP 27通过细胞内外信号的协同作用在SCCT细胞的化疗耐药性中发挥重要作用。HSP 27可能代表精确SCCT治疗的潜在生物标志物和治疗靶点。临床癌症研究; 24（5）; 1163-75。©2017 AACR.
Purpose: Squamous cell carcinoma of tongue (SCCT) is the most common type of oral cavity carcinoma. Chemoresistance in SCCT is common, and the underlying mechanism remains largely unknown. We aimed to identify key molecules and signaling pathways mediating chemoresistance in SCCT. Experimental Design: Using a proteomic approach, we found that the HSP27 was a potential mediator for chemoresistance in SCCT cells. To further validate this role of HSP27, we performed various mechanistic studies using in vitro and in vivo models as well as serum and tissue samples from SCCT patients. Results: The HSP27 protein level was significantly increased in the multidrug-resistant SCCT cells and cell culture medium. Both HSP27 knockdown and anti-HSP27 antibody treatment reversed chemoresistance. Inversely, both HSP27 overexpression and recombinant human HSP27 protein treatment enhanced chemoresistance. Moreover, chemotherapy significantly induced HSP27 protein expression in both SCCT cells and their culture medium, as well as in tumor tissues and serum of SCCT patients. HSP27 overexpression predicts a poor outcome for SCCT patients receiving chemotherapy. Mechanically, extracellular HSP27 binds to TLR5 and then activates NF-κB signaling to maintain SCCT cell survival. TLR5 knockdown or restored IκBα protein level disrupts extracellular HSP27-induced NF-κB transactivation and chemoresistance. Moreover, intracellular HSP27 binds to BAX and BIM to repress their translocation to mitochondrion and subsequent cytochrome C release upon chemotherapy, resulting in inhibition of the mitochondrial apoptotic pathway. Conclusions: HSP27 plays a pivotal role in chemoresistance of SCCT cells via a synergistic extracellular and intracellular signaling. HSP27 may represent a potential biomarker and therapeutic target for precision SCCT treatment. Clin Cancer Res; 24(5); 1163–75. ©2017 AACR.
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影响因子：
5.3
作者：
Kristina S. Sinsimer;Frances M. Gratacós;A. Knapinska;Jiebo Lu;Christopher D. Krause;Alexandria V Wierzbowski;Lauren R. Maher;S. Scrudato;Y. Rivera;Swati Gupta;Danielle K. Turrin;Mary Pauline De La Cruz;S. Pestka;G. Brewer
通讯作者：
Kristina S. Sinsimer;Frances M. Gratacós;A. Knapinska;Jiebo Lu;Christopher D. Krause;Alexandria V Wierzbowski;Lauren R. Maher;S. Scrudato;Y. Rivera;Swati Gupta;Danielle K. Turrin;Mary Pauline De La Cruz;S. Pestka;G. Brewer
DOI：
10.1096/fj.12-226977
发表时间：
2013-10
期刊：
The FASEB Journal
影响因子：
--
作者：
D. Thuringer;G. Jego;G. Wettstein;O. Terrier;L. Cronier;Nadhir Yousfi;S. Hébrard;A. Bouchot;A. Hazoumé;Anne-Laure Joly;M. Gleave;M. Rosa-Calatrava;E. Solary;C. Garrido
通讯作者：
D. Thuringer;G. Jego;G. Wettstein;O. Terrier;L. Cronier;Nadhir Yousfi;S. Hébrard;A. Bouchot;A. Hazoumé;Anne-Laure Joly;M. Gleave;M. Rosa-Calatrava;E. Solary;C. Garrido
影响因子：
4.8
作者：
Havasi, Andrea;Li, Zhijian;Borkan, Steven C.
通讯作者：
Borkan, Steven C.
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影响因子：
8
作者：
Sun, L.;Yao, Y.;Li, J.
通讯作者：
Li, J.
影响因子：
11.2
作者：
Zhimin He;Baozhong Xin;Xinhai Yang;Ching-ping Chan;Liang Cao
通讯作者：
Zhimin He;Baozhong Xin;Xinhai Yang;Ching-ping Chan;Liang Cao