Activin A stimulates migration of the fallopian tube epithelium, an origin of high-grade serous ovarian cancer, through non-canonical signaling.
Activin A stimulates migration of the fallopian tube epithelium, an origin of high-grade serous ovarian cancer, through non-canonical signaling.
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DOI：
10.1016/j.canlet.2017.01.011
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发表时间：
2017-04-10
期刊：
影响因子：
9.7
通讯作者：
Burdette JE
中科院分区：
文献类型：
--
作者：
Dean M;Davis DA;Burdette JE
刺激输卵管上皮（FTE）衍生的高级别浆液性卵巢癌（HGSOC）向卵巢迁移的因素尚不清楚。本研究探讨了卵巢激素激活素A对正常FTE和HGSOC的影响。激活素A和TGFβ1诱导小鼠输卵管上皮（MOE）细胞从上皮到间质转变，但只有激活素A增加了迁移。激活素A的迁移作用不依赖于Smad2/3，需要phospho-AKT、phospho-ERK和Rac1。外源性激活素A通过类似的机制刺激HGSOC细胞系OVCAR3的迁移。激活素A信号抑制剂SB431542和卵泡抑素可以减少OVCAR4细胞的迁移，OVCAR4细胞表达激活素A亚基（由INHBA编码）。小鼠超排卵增加了FTE的磷酸化- smad2 /3免疫染色。在Oncomine中，与正常卵巢相比，浆液性肿瘤中激活素A受体（ACVR1B和ACVR2A）的转录本较高，而激活素A信号传导抑制剂（INHA和TGFB3）的转录本较低。在浆液性癌症患者中，高表达INHBA和ACVR2A，但不表达TGFβ受体或共受体，与较短的无病生存期相关。这些结果表明激活素A刺激fte来源的肿瘤向卵巢的迁移。
Factors that stimulate the migration of fallopian tube epithelial (FTE)-derived high-grade serous ovarian cancer (HGSOC) to the ovary are poorly elucidated. This study characterized the effect of the ovarian hormone, activin A, on normal FTE and HGSOC. Activin A and TGFβ1 induced an epithelial-to-mesenchymal transition in murine oviductal epithelial (MOE) cells, but only activin A increased migration. The migratory effect of activin A was independent of Smad2/3 and required phospho-AKT, phospho-ERK, and Rac1. Exogenous activin A stimulated migration of the HGSOC cell line OVCAR3 through a similar mechanism. Activin A signaling inhibitors, SB431542 and follistatin, reduced migration in OVCAR4 cells, which expressed activin A subunits (encoded by INHBA). Murine superovulation increased phospho-Smad2/3 immunostaining in the FTE. In Oncomine, transcripts for the activin A receptors (ACVR1B and ACVR2A) were higher in serous tumors relative to the normal ovary, while inhibitors of activin A signaling (INHA and TGFB3) were lower. High expression of both INHBA and ACVR2A, but not TGFβ receptors or co-receptors, was associated with shorter disease-free survival in serous cancer patients. These results suggest activin A stimulates migration of FTE-derived tumors to the ovary.