HMGA2-FOXL2 Axis Regulates Metastases and Epithelial-to-Mesenchymal Transition of Chemoresistant Gastric Cancer
HMGA2-FOXL2 Axis Regulates Metastases and Epithelial-to-Mesenchymal Transition of Chemoresistant Gastric Cancer
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HMGA2-FOXL2 轴调节化疗耐药性胃癌的转移和上皮间质转化
DOI：
10.1158/1078-0432.ccr-16-2180
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发表时间：
2017-07-01
影响因子：
11.5
通讯作者：
Fan, Daiming
中科院分区：
文献类型：
--
作者：
Dong, Jiaqiang;Wang, Rui;Fan, Daiming
目的：化疗耐药性是癌症治疗失败的主要原因，并与远处转移和上皮向间质转化（EMT）有关。本研究旨在探讨胃癌化疗耐药的转移和EMT的机制。实验设计：通过基因表达谱和生物信息学分析，在胃癌化疗耐药模型中确定一个关键的分子通路。FOXL 2、HMGA 2和ITGA 2的作用通过体外和原位胃癌动物模型中的功能丧失和功能获得实验来验证。通过免疫沉淀和荧光素酶报告基因测定探索HMGA 2对FOXL 2的调节。结果：HMGA 2和FOXL 2直接调控化疗耐药胃癌的转移和EMT。HMGA 2和pRb之间的相互作用促进了E2 F1对FOXL 2的反式激活，ITGA 2是HMGA 2-FOXL 2通路的下游效应子。HMGA 2、FOXL 2和ITGA 2与胃癌的TNM分期和分型有关，在转移淋巴结和远处转移灶中表达增高。HMGA 2、FOXL 2和ITGA 2水平升高与胃癌患者总生存期缩短相关。结论：本研究表明，HMGA 2和pRb之间相互作用驱动的FOXL 2反式激活可能对化疗耐药胃癌的转移和EMT发挥关键作用。阻断HMGA 2-FOXL 2-ITGA 2通路可能成为胃癌治疗的新策略。(C)2017年AACR。
Purpose: Chemoresistance is the main cause of treatment failure in cancer and is associated with distant metastases and epithelial-to-mesenchymal transition (EMT). This study was aimed to explore the mechanism of metastases and EMT in chemoresistant gastric cancer.Experimental Design: A key molecular pathway was identified via gene profiling and a bioinformatic analysis in a chemoresistant gastric cancer model. The roles of FOXL2, HMGA2, and ITGA2 were validated via loss-of-function and gain-of-function experiments in vitro and in an orthotopic gastric cancer animal model. The regulation of FOXL2 by HMGA2 was explored via immunoprecipitation and luciferase reporter assays. The expression of these proteins in gastric cancer tissues was examined by IHC.Results: HMGA2 and FOXL2 directly regulated the metastasis and EMT of chemoresistant gastric cancer. The interaction between HMGA2 and pRb facilitated the transactivation of FOXL2 by E2F1, and ITGA2 was the downstream effector of the HMGA2-FOXL2 pathway. HMGA2, FOXL2, and ITGA2 were associated with the TNM classification and staging of gastric cancer and were increased in metastatic lymph nodes and distant metastases. Increased HMGA2, FOXL2, and ITGA2 levels were associated with reduced overall survival periods of patients with gastric cancer.Conclusions: This study demonstrated that the transactivation of FOXL2 driven by interactions between HMGA2 and pRb might exert critical effects on the metastases and EMT of chemoresistant gastric cancer. Blocking the HMGA2-FOXL2-ITGA2 pathway could serve as a new strategy for gastric cancer treatment. (C) 2017 AACR.