Center for Reproductive Medicine, Shandong University, Jinan, Shandong, 250012, China; Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, 250012, China.
Center for Reproductive Medicine, Shandong University, Jinan, Shandong, 250012, China.
Placenta. 2022 Nov;129:62-69. doi: 10.1016/j.placenta.2022.10.004. Epub 2022 Oct 10.
Activin A has been widely regarded as an important promoter of trophoblast invasion during the first trimester of pregnancy. However, whether integrin β3 is involved in activin A-upregulated trophoblast invasion and the underlying molecular mechanisms remain largely unknown.
We utilized immortalized (HTR8/SVneo) and primary human extravillous trophoblast (EVT) cells, as well as first-trimester chorionic villous explants as study models to investigate the function and underlying molecular mechanisms of integrin β3 in activin A-promoted human trophoblast invasion.
We found that activin A increased integrin β3 mRNA and protein levels in both HTR8/SVneo and primary EVT cells, and knockdown of integrin β3 significantly decreased basal and activin A-upregulated trophoblast invasion. Moreover, SB431542 (a specific inhibitor of TGF-β type Ι receptor kinase) abolished activin A-upregulated integrin β3 expression and SMAD2/3 phosphorylation. In addition, siRNA-mediated knockdown of ALK4 or SMAD4 both abolished activin A-upregulated integrin β3 expression in HTR8/SVneo cells, while knockdown of ALK4 or SMAD4 attenuated activin A-upregulated integrin β3 expression in primary EVTs.
Our findings reveal the mediation role of integrin β3 in activin A-upregulated human trophoblast invasion and that activin An upregulates integrin β3 expression in an ALK4-SMAD4 signaling-dependent manner.
激活素 A 一直被广泛认为是妊娠早期滋养细胞侵袭的重要促进因子。然而，整合素β3 是否参与激活素 A 上调的滋养细胞侵袭及其潜在的分子机制仍知之甚少。
我们利用永生化（HTR8/SVneo）和原代人绒毛外滋养层（EVT）细胞以及第一孕期绒毛膜绒毛外植体作为研究模型，研究整合素β3 在激活素 A 促进人滋养细胞侵袭中的功能和潜在的分子机制。
我们发现激活素 A 增加了 HTR8/SVneo 和原代 EVT 细胞中整合素β3 的 mRNA 和蛋白水平，而整合素β3 的敲低显著降低了基础和激活素 A 上调的滋养细胞侵袭。此外，SB431542（TGF-β 型Ⅰ受体激酶的特异性抑制剂）消除了激活素 A 上调的整合素β3 表达和 SMAD2/3 磷酸化。此外，siRNA 介导的 ALK4 或 SMAD4 敲低均消除了 HTR8/SVneo 细胞中激活素 A 上调的整合素β3 表达，而 ALK4 或 SMAD4 的敲低则减弱了原代 EVT 中激活素 A 上调的整合素β3 表达。
我们的研究结果揭示了整合素β3 在激活素 A 上调的人滋养细胞侵袭中的中介作用，以及激活素 A 以 ALK4-SMAD4 信号依赖的方式上调整合素β3 的表达。
