BMP4 promotes oxaliplatin resistance by an induction of epithelial-mesenchymal transition via MEK1/ERK/ELK1 signaling in hepatocellular carcinoma
BMP4 promotes oxaliplatin resistance by an induction of epithelial-mesenchymal transition via MEK1/ERK/ELK1 signaling in hepatocellular carcinoma
复制标题
BMP4 通过 MEK1/ERK/ELK1 信号传导诱导肝细胞癌中的上皮间质转化，从而促进奥沙利铂耐药
DOI：
10.1016/j.canlet.2017.09.041
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发表时间：
2017-12-28
期刊：
影响因子：
9.7
通讯作者：
Shen, Hong
中科院分区：
文献类型：
--
作者：
Ma, Junli;Zeng, Shan;Shen, Hong
背景资料：骨形态发生蛋白-4（BMP 4）是上皮-间质转化（EMT）的关键调节因子，EMT是癌细胞获得化疗耐药性的关键。BMP 4对OXA敏感性在HCC中的影响需要阐明。方法：在人HCC标本中，在HCC细胞系HepG 2和HCCLM 3中，以及在接受OXA治疗的皮下肿瘤模型中，对BMP 4对EMT调节的OXA敏感性进行功能分析。结果：HCC组织中BMP 4表达明显增高，且与肿瘤去分化、预后不良有关。BMP 4促进HCC EMT，并与OXA耐药相关。在体外和体内阻断BMP 4逆转EMT并增加OXA化疗敏感性。ELK 1是一种参与EMT的转录因子，是BMP 4诱导HCC对OXA耐药的重要介质。结论：BMP 4通过MEK/ERK/ELK 1信号通路诱导肝癌细胞EMT和OXA化疗耐药。BMP 4可能是接受OXA化疗的HCC患者的有价值的治疗靶点。(c)2017爱思唯尔B. V.保留所有权利。
Background: Bone morphogenetic protein-4 (BMP4) is a key regulator of epithelial-mesenchymal transition (EMT), which is crucial for cancer cells to acquire chemoresistance. The effects of BMP4 on OXA sensitivity in HCC need to be elucidated.Methods: Functional analysis of BMP4 on EMT-regulated OXA sensitivity was performed in human HCC specimens, in the HCC cell lines HepG2 and HCCLM3, and in a subcutaneous tumor model receiving OXA treatment. The downstream signaling targets of BMP4 in HCC were profiled and confirmed.Results: BMP4 expression was significantly increased in HCC tissue, and was correlated with tumor de-differentiation and unfavorable prognosis. BMP4 promoted HCC EMT and was correlated with OXA resistance. Blocking of BMP4 reversed EMT and increased OXA chemosensitivity in vitro and in vivo. ELK1, a transcription factor involved in EMT, was an important mediator of BMP4-induced OXA resistance in HCC. Blocking of MEK/ERK/ELK1 attenuated BMP4-induced EMT and enhanced OXA sensitivity.Conclusions: BMP4 induces EMT and OXA chemoresistance via MEK/ERK/ELK1 signaling pathway in HCC. BMP4 may be a valuable therapeutic target for HCC patients receiving OXA-based chemotherapy. (c) 2017 Elsevier B.V. All rights reserved.