BMP4 通过 MEK1/ERK/ELK1 信号通路诱导上皮-间充质转化促进肝癌对奥沙利铂耐药。
BMP4 promotes oxaliplatin resistance by an induction of epithelial-mesenchymal transition via MEK1/ERK/ELK1 signaling in hepatocellular carcinoma.
机构信息
Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
出版信息
Cancer Lett. 2017 Dec 28;411:117-129. doi: 10.1016/j.canlet.2017.09.041. Epub 2017 Oct 4.
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.
背景
骨形态发生蛋白 4（BMP4）是上皮-间质转化（EMT）的关键调节因子，对于癌细胞获得化疗耐药性至关重要。需要阐明 BMP4 对 HCC 中 OXA 敏感性的影响。
方法
在人 HCC 标本、HCC 细胞系 HepG2 和 HCCLM3 以及接受 OXA 治疗的皮下肿瘤模型中，对 BMP4 在 EMT 调控的 OXA 敏感性中的功能进行了分析。对 HCC 中 BMP4 的下游信号靶标进行了分析和验证。
结果
BMP4 在 HCC 组织中的表达显著增加，与肿瘤去分化和不良预后相关。BMP4 促进 HCC 的 EMT，并与 OXA 耐药性相关。阻断 BMP4 可逆转 EMT 并增加体外和体内的 OXA 化疗敏感性。ELK1 是 EMT 中涉及的转录因子，是 BMP4 诱导 HCC 中 OXA 耐药的重要介质。阻断 MEK/ERK/ELK1 可减弱 BMP4 诱导的 EMT 并增强 OXA 敏感性。
结论
BMP4 通过 MEK/ERK/ELK1 信号通路诱导 HCC 中的 EMT 和 OXA 化疗耐药性。BMP4 可能是接受 OXA 为基础的化疗的 HCC 患者的有价值的治疗靶点。
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