Glycogen synthase kinase (GSK) 3 in pregnancy and parturition: a systematic review of literature

Introduction: Multiple factors and pathways have been reported as critical machineries for cell differentiation and survival during pregnancy; a number of them involve glycogen synthase kinase (GSK) 3a/β. Several reports on GSK3's functional role exist; however, the specific role of GSK3 in reproductive tissues and its contribution to normal or abnormal parturition are still unclear. To fill this knowledge gap, a systematic review of literature was conducted to better understand the functional role of GSK3 in various intrauterine tissues during implantation, pregnancy, and parturition.
Methods: We conducted a systematic review of literature on GSK3's expression and function reported between 1980 and 2017 in reproductive tissues during pregnancy using three electronic databases (Web of Science, Medline, and ClinicalTrials.gov). Study selection, data extraction, quality assessment and analyses were performed in duplicate by two independent reviewers.
Results: A total of 738 citations were identified; 80 were selected for full text evaluation and 25 were included for final review. GSK3's regulation and function were mostly studied in tissues and cells from placentas (12), fetuses (8), uteruses (6), and ovaries (2). GSK3 is primarily reported as a downstream responder of protein kinase B (AKT)-, Wnt-, and reactive oxygen species (ROS)-related pathways where it plays a critical role in cell survival and growth in reproductive tissues.
Conclusions: Though GSK3 has been functionally linked to a number of biological processes in reproductive tissues, it has primarily been studied as a secondary signaler of various conserved cell signaling pathways. Lack of scientific rigor in studying GSK3's role in reproductive tissues makes this molecule's function still obscure. No studies have reported GSK3 in the cervix, and very few reports exist in myometrium and decidua. This systematic review suggests more functional and mechanistic studies focusing on GSK3 need to be conducted in reproductive biology.

引言：已有研究表明，多种因子与信号通路是妊娠期间细胞分化与存活的关键调控机制，其中糖原合酶激酶（glycogen synthase kinase, GSK）3α/β参与了其中多条通路。目前已有多项研究探讨了GSK3的功能作用，但GSK3在生殖组织中的具体功能，以及其对正常或异常分娩的调控贡献，目前仍不明确。为填补这一研究空白，本研究开展了一项系统文献综述，以期深入阐明GSK3在着床、妊娠及分娩阶段各类宫内组织中的功能作用。
方法：本研究基于1980年至2017年间发表的、关于妊娠期间生殖组织中GSK3表达与功能的相关文献，通过Web of Science、Medline及ClinicalTrials.gov三大电子数据库开展系统文献综述。研究筛选、数据提取、质量评估及数据分析均由两名独立评审人员重复完成。
结果：本研究共检索到738篇相关文献，其中80篇经全文评估后，最终纳入25篇进行综述分析。现有研究主要针对胎盘（12项）、胎儿（8项）、子宫（6项）及卵巢（2项）中的组织与细胞，探讨GSK3的调控机制与功能。现有研究表明，GSK3主要作为蛋白激酶B（protein kinase B, AKT）、Wnt及活性氧（reactive oxygen species, ROS）相关通路的下游应答分子，在生殖组织的细胞存活与增殖过程中发挥关键调控作用。
结论：尽管已有研究将GSK3与生殖组织中的多种生物学过程相关联，但现有研究多将其视为各类保守细胞信号通路的次级信号分子。由于目前针对生殖组织中GSK3功能的研究缺乏科学严谨性，该分子的具体功能仍不明确。目前尚无关于宫颈组织中GSK3的相关研究，针对子宫肌层与蜕膜的报道也极少。本系统综述表明，未来需在生殖生物学领域开展更多聚焦GSK3的功能与机制研究。