Recent studies have reported that miR plays an

Recent studies have reported that miR-454 plays an important role in various cellular processes and diseases, such as inflammation, infection, osteogenic differentiation, and cancers [25,27,29,30]. Multiple evidence has documented that miR-454 promotes the proliferation, migration and invasion, and represses the apoptosis of melanoma, lung cancer, and breast cancer SYBR Safe DNA Gel Stain through targeting PTEN and promoting Akt signaling [[31], [32], [33]]. Interestingly, PTEN has also been reported to regulate placental development and the proliferation and invasion of trophoblast cells [34,35]. However, whether miR-454 regulates trophoblast cell proliferation and invasion through regulating PTEN remains unclear. Moreover, miR-454 is also reported to promote the proliferation and invasion of cancer cells through targeting CHD5, NDRG2, and CYLD [26,36,37]. In the present study, we found that miR-454 overexpression significantly promoted the proliferation and invasion and repressed the apoptosis of trophoblasts cells. By contrast, the negative effect of miR-454 on cell proliferation and invasion is also reported. miR-454 has been reported to inhibit the proliferation and invasion and promote apoptosis of cancer cells through targeting PDK1, c-Met, and B cell translocation gene 1 [30,38,39]. It is well known that miRNA can target a variety of target genes. Therefore, the precise role of miR-454 in regulating cell function may be disparate due to different targeted genes. In this study, we identified EPHB4 as a potential target gene of miR-454, which is involved in regulating the biological behaviors of trophoblast cells. EPHB4 is found expressed in the placenta, and the downregulation of EPHB4 during placental development is associated with trophoblast commitment to uterine invasion [[20], [21], [22]]. EPHB4 expression is highly expressed in the placenta of PE pregnancies compared to that of uncomplicated pregnancies [23]. in vitro experiments showed that overexpression of EPHB4 in HTR-8/SVneo cells inhibited proliferation, promoted apoptosis, and repressed migration and invasion [23]. Interestingly, downregulation of EPHB4 in human umbilical vein endothelial cells promotes the invasion and displacement of trophoblast cells in the endothelial–trophoblast co-culture model [40]. Importantly, HOXA9 is reported to transcriptionally regulate EPHB4 expression to regulate trophoblast cell migration and invasion [24]. However, the epigenetic regulation of EPHB4 expression during PE development remains unclear. In this study, we found that EPHB4 expression was epigenetically regulated by miR-454 in PE and trophoblast cells. We found that miR-454 directly targeted the 3’-UTR of EPHB4 and regulated EPHB4 expression. Our results demonstrated that miR-454 expression was significantly downregulated in the placenta of PE pregnancies and inversely correlated with EPHB expression. Therefore, the increased expression of EPHB4 may be caused by the decreased expression of miR-454, thus leading to impaired trophoblast cell proliferation and invasion. Notably, a previous study has reported that EPHB4 is targeted and regulated by miR-20b in trophoblast cells [41]. However, whether miR-20b/EPHB4 regulates the biological behaviors of trophoblast cells is unknown. In this study, we demonstrated that miR-454 promoted the proliferation and invasion of trophoblast cells by downregulation of EPHB4. Our results indicate that miR-454/EPHB4 axis may play an important role in the development of PE by regulating the biological behaviors of trophoblast cells.
Conflict of interest
Eph receptors constitute the largest family of tyrosine kinase receptors, and together with their membrane-bound ephrin ligands, play a critical role in embryonic patterning, neuronal targeting, vascular development and adult neovascularisation. There is growing evidence that Eph receptor signalling may contribute to tumourigenesis in a wide variety of human cancers, either directly in tumour cells or indirectly via tumour vascularisation: for instance, Eph receptors and their ephrin ligands are frequently overexpressed in various tumour types, including breast, prostate, non-small cell lung and colon cancers.