Department of Obstetrics and Gynecology, Chi‑Mei Medical Center, Tainan 710, Taiwan, R.O.C.
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, R.O.C.
Mol Med Rep. 2024 May;29(5). doi: 10.3892/mmr.2024.13209. Epub 2024 Mar 29.
Recurrent miscarriage is used to refer to more than three pregnancy failures before 20 weeks of gestation. Defective trophoblast cell growth and invasion are frequently observed in recurrent miscarriage. Several microRNAs (miRs), including miR‑155‑5p, are aberrantly upregulated in recurrent miscarriage; however, the underlying molecular mechanisms remain unclear. The centrosome orchestrates microtubule networks and coordinates cell cycle progression. In addition, it is a base for primary cilia, which are antenna‑like organelles that coordinate signaling during development and growth. Thus, deficiencies in centrosomal functions can lead to several disease, such as breast cancer and microcephaly. In the present study, the signaling cascades were analyzed by western blotting, and the centrosome and primary cilia were observed and analyzed by immunofluorescence staining. The results showed that overexpression of miR‑155‑5p induced centrosome amplification and blocked primary cilia formation in trophoblast cells. Notably, centrosome amplification inhibited trophoblast cell growth by upregulating apoptotic cleaved‑caspase 3 and cleaved‑poly (ADP‑ribose) polymerase in miR‑155‑5p‑overexpressing trophoblast cells. In addition, overexpression of miR‑155‑5p inhibited primary cilia formation, thereby inhibiting epithelial‑mesenchymal transition and trophoblast cell invasion. All phenotypes could be rescued when cells were co‑transfected with the miR‑155‑5p inhibitor, thus supporting the role of miR‑155‑5p in centrosomal functions. It was also found that miR‑155‑5p activated autophagy, whereas disruption of autophagy via the depletion of autophagy‑related 16‑like 1 alleviated miR‑155‑5p‑induced apoptosis and restored trophoblast cell invasion. In conclusion, the present study indicated a novel role of miR‑55‑5p in mediating centrosomal function in recurrent miscarriage.
复发性流产是指妊娠 20 周前发生的三次或三次以上的妊娠失败。在复发性流产中,常观察到滋养层细胞生长和侵袭缺陷。几种 microRNAs(miRs),包括 miR-155-5p,在复发性流产中异常上调;然而,其潜在的分子机制尚不清楚。中心体协调微管网络并协调细胞周期进程。此外,它是初级纤毛的基础,初级纤毛是类似天线的细胞器,在发育和生长过程中协调信号转导。因此,中心体功能缺陷可导致多种疾病,如乳腺癌和小头症。在本研究中,通过 Western blot 分析信号级联,通过免疫荧光染色观察和分析中心体和初级纤毛。结果表明,miR-155-5p 的过表达诱导滋养层细胞中心体扩增并阻断初级纤毛形成。值得注意的是,中心体扩增通过上调凋亡裂解 caspase 3 和裂解多聚(ADP-核糖)聚合酶,抑制 miR-155-5p 过表达滋养层细胞的生长。此外,miR-155-5p 的过表达抑制初级纤毛形成,从而抑制上皮-间充质转化和滋养层细胞侵袭。当细胞共转染 miR-155-5p 抑制剂时,所有表型均可恢复,从而支持 miR-155-5p 在中心体功能中的作用。还发现 miR-155-5p 激活自噬,而通过自噬相关 16-样 1(autophagy-related 16-like 1)耗竭破坏自噬则减轻 miR-155-5p 诱导的细胞凋亡并恢复滋养层细胞侵袭。总之,本研究表明 miR-155-5p 在介导复发性流产中的中心体功能中发挥了新的作用。