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  • Another interesting finding from the present study is that s

    2020-06-29

    Another interesting finding from the present study is that silencing of ERRγ suppressed the expression of HSD17B1 in extravillous trophoblasts. HSD17B1 is a key enzyme in regulating estrogen activity and has been shown to promote the proliferation and migration of estrogen-dependent breast cancer WS 3 and non-small lung cancer cells [31,32]. Production of 17β-estradiol is catalyzed by HSD17B1 and it plays an important role during pregnancy, especially during the first trimester. The ability of placenta to synthesis estrogen significantly increases after the ninth week of gestation concomitant with vascularization of the placenta. Continued production of estrogen subsequently contributes to enlargement of uterine spiral arteries, increased blood flow, and reduced systematic vascular resistance [[33], [34], [35]]. Gene chip experiments have also demonstrated that expression of HSD17B1 is impaired when ERRγ is knocked down [17]. In the present study, silencing of ERRγ led to reduce expression of HSD17B1, indicating that aberrant ERRγ expression may lead to an estrogen deficit due to disruptions in downstream regulation of HSD17B1. However, the exact molecular mechanism involved remains to be elucidated. Then we further studied the relationship between ERRγ and HSD17B1. ERRγ has been shown to have critical regulatory roles in various tissues as a result of its binding directly to ERREs in the promoter regions of VEGFA, BMP2, KCNE1, and KLK1 [17,36,37]. In the present study, we showed that ERRγ also enhanced expression of HSD17B1 by directly binding response elements in its promoter. The results of our study suggested that down-regulation of ERRγ influenced the transcription of HSD17B1, thereby inhibiting trophoblast invasion and proliferation and contributing to the development of FGR (Fig. 4). Nuclear receptors may be the most effective therapeutic targets for a multitude of disorders [38]. While natural ligand(s) of ERRγ remain to be discovered, many synthetic ligands have been developed which alter the functional activity of ERRγ [39,40]. In addition, HSD17B1 is a key enzyme for the synthesis of estrogen and has become an important drug target based on its clinical application value. Future studies will most likely evaluate inhibitors of HSD17B1 in estrogen-related diseases, and the present findings provide support for the application of these inhibitors to FGR therapy as well.
    Conflicts of interest
    Acknowledgment This work was supported by the National Natural Science Foundation of China (No. 81741015).
    Introduction MicroRNAs (miRNAs) are an abundant class of endogenous, small (~22-nucleotide), single strand, and noncoding RNA molecules (Bartel, 2004). These miRNAs mediate post-transcriptional regulation of target gene through binding to sites of complementarity in 3′-UTRs of target mRNAs (Carthew and Sontheimer, 2009). Some miRNAs participate in various biological processes, including development, cellular differentiation, proliferation and tumor genesis (Ambros and Chen, 2007, Hagen and Lai, 2008, Trang et al., 2008). Recently, it has been reported that various miRNAs are closely related to osteoblast differentiation. Specifically, miR-29b contributes to positive regulation of osteoblast differentiation via targeting anti-osteogenic factors and modulating bone extracellular matrix proteins (Li et al., 2009). The miR-133 directly targets runt-related transcription factor 2 (Runx2), and miR-135 targets Smad5, a key transducer of the BMP2 osteogenic signal (Li et al., 2008). Runx2 is a multifunctional factor that controls osteoblast differentiation and skeletal development by regulating alkaline phosphatase (ALP), osteocalcin and bone sialoprotein gene expression (Franceschi et al., 2007, Komori, 2005). In addition, Runx2 increases ALP activity and mineralization in mesenchymal stem cells and pre-osteoblast cells (Banerjee et al., 1997, Ducy et al., 1997). Estrogen receptor-related receptors (ERRs) are closely related to estrogen receptor (ER) in their structures, and for example DNA binding domain of ERRs shares high homology with that of ER (Giguere, 2002). However, ERRs do not bind to the classical ER ligand. Based on their sequence similarity to ERα, three types of ERRs (ERRα, ERRβ and ERRγ) have been identified. ERRγ is the most recently described member of the ERR subfamily. It differs from the other family members in that it is a constitutively active nuclear receptor with high basal transcriptional activity (Sanyal et al., 2002). ERRγ increased miR-433 and miR-127, and their expression levels were suppressed by a small heterodimer partner (SHP, NR0B2) in Hepa-1 cells (Song and Wang, 2008). We recently reported that ERRγ or SHP mediates osteoblastic differentiation in pre-osteoblast MC3T3E1 or primary calvarial cells. Our previous results show that ERRγ is a negative regulator of osteoblast differentiation and bone formation by inhibiting of Runx2 transactivity (Jeong et al., 2009), and that SHP increases osteoblast differentiation and bone formation by increasing Runx2 transactivity (Jang et al., 2011, Jeong et al., 2010). However, negative regulatory mechanisms of ERRγ are not fully understood.