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Approximately 15-25% pregnant women end with miscarriage in the world. Environmental BaP (benzo(a)pyrene) and its terminal metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) may result in the dysfunctions of trophoblast cells, which might further lead to RM (recurrent miscarriage). However, potential mechanisms remain unelucidated. In this work, we identified a novel lnc-HZ05 highly expressed and a novel miR-hz05 lowly expressed in both trophoblast cells exposed to BPDE and human RM tissues. MiR-hz05 reduces FOXO3a mRNA level by weakening its mRNA stability. Lnc-HZ05 increases the expression of FOXO3a by acting as a ceRNA for miR-hz05, and then increases P21 level and reduces CDK2 level. Thus, cell cycle is arrested at G0/G1 phase and trophoblast proliferation is inhibited. Lnc-HZ05 harboring wild-type binding site for miR-hz05, but not its mutant site, could upregulate FOXO3a expression. In normal trophoblast cells, relatively less lnc-HZ05 and more miR-hz05 activate FOXO3a/P21/CDK2 pathway and promote trophoblast proliferation, giving normal pregnancy. In RM tissues and BPDE-treated human trophoblast cells, lnc-HZ05 is increased and miR-hz05 is reduced, both of which suppress this pathway and inhibit cell proliferation, and finally lead to miscarriage. Thus, lnc-HZ05 and miR-hz05 simultaneously regulate cell cycle and proliferation of BPDE-exposed trophoblast cells and miscarriage, providing new perspectives and clinical understandings in the occurrence of unexplained miscarriage., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Extracellular vesicles (EVs) derived from parental cells could communicate with neighboring or distant recipient cells. The components in EVs, especially non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, could regulate the functions of the recipient cells. Meanwhile, EVs could also be used as valuable biomarkers and drug delivery carriers. Moreover, environmental toxicants may alter EVs components and regulate EVs-mediated pathogenesis of various diseases. In this review, we mainly summarized the roles of EV-derived non-coding RNAs in the regulation of cell dysfunctions in various adverse pregnancy outcomes, such as preeclampsia (PE), gestational diabetes mellitus (GDM), and miscarriage. Moreover, the effects of environmental toxicants on the components and functions of EVs, as well as on their regulatory roles in these diseases, were also discussed.

Normal pregnancy is essential for human reproduction. However, environmental BaP (benzo(a)pyrene) and its metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) induce dysfunctions of human trophoblastic cells, which could further result in miscarriage. Yet, the molecular mechanisms remain poorly understood. In this work, a novel lnc-HZ03 and a novel miR-hz03 were identified. Both lnc-HZ03 and miR-hz03 were highly expressed in human recurrent miscarriage villous tissues and in BPDE-exposed trophoblastic cells. Lnc-HZ03 and miR-hz03 upregulated each other, forming a positive feedback loop. MiR-hz03 could also upregulate p53 level by enhancing its mRNA stability. Both lnc-HZ03 and p53 mRNA contained the target site for miR-hz03 and could directly interact with miR-hz03. It was this target site instead of its mutant on lnc-HZ03 that regulated p53 expression. Subsequently, the upregulated p53 facilitated SAT1 transcription and enhanced SAT1-catalyzed spermine metabolism, which further resulted in trophoblastic cell apoptosis and induced miscarriage. All together, the p53/SAT1 pathway upregulated by lnc-HZ03 and miR-hz03 could promote BPDE-induced human trophoblastic cell apoptosis and the occurrence of miscarriage, shedding novel light on the causes of miscarriage. Graphical abstract Lnc-HZ03 and miR-hz03 regulate the occurrence of recurrent miscarriage (RM). In human trophoblastic cells, lnc-HZ03 upregulates miR-hz03 level. MiR-hz03 increases the RNA stability of lnc-HZ03 and p53 mRNA. P53 promotes SAT1 transcription and reduces its cellular spermine content, resulting in cell apoptosis. Under normal conditions, lnc-HZ03/miR-hz03 and p53/SAT1 pathways are downregulated, maintaining normal pregnancy. After exposure to BPDE, lnc-HZ03/miR-hz03 and p53/SAT1 pathways are upregulated and finally induce miscarriage., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V. part of Springer Nature.)

Normal pregnancy is essential for human reproduction. However, BaP (benzo(a)pyrene) and its metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) could cause dysfunctions of human trophoblast cells and might further induce miscarriage. Yet, the underlying mechanisms remain largely unknown. Herein, we identified a novel upregulated lnc-HZ04 and a novel downregulated miR-hz04 in villous tissues of unexplained recurrent miscarriage (RM) relative to those in healthy control tissues and also in BPDE-treated human trophoblast cells. Lnc-HZ04 directly and specifically bound with miR-hz04, diminished the reduction effects of miR-hz04 on IP 3 R 1 mRNA expression level and on IP 3 R 1 mRNA stability, and then activated the Ca 2+ -mediated IP 3 R 1 /p-CaMKII/SGCB pathway, which further promoted trophoblast cell apoptosis. The miR-hz04 target site on lnc-HZ04 played crucial roles in these regulations. In normal trophoblast, relatively less lnc-HZ04 and more miR-hz04 suppressed this apoptosis pathway and gave normal pregnancy. After exposure to BPDE or in RM tissues, p53 was upregulated, which might promote p53-mediated lnc-HZ04 transcription. Relatively more lnc-HZ04 and less miR-hz04 activated this apoptosis pathway and might further induce miscarriage. BaP could also induce mice miscarriage by upregulating its corresponding murine apoptosis pathway. Therefore, BPDE-induced apoptosis of human trophoblast cells was associated with the occurrence of miscarriage. This work discovered the regulation roles of lnc-HZ04 and miR-hz04 and provided scientific and clinical understanding of the occurrence of unexplained miscarriage., (© 2021 Federation of American Societies for Experimental Biology.)

Long non-coding RNA (lncRNA) is one of the important regulators of many malignancies. However, the biological function and clinical significance of a large number of lncRNAs in gastric cancer remain unclear. Therefore, we analysed the TCGA data to find that LINC01303 is significantly up-regulated in gastric cancer tissues. However, the biological function of LINC01303 in GC remains unknown. In our study, we found that the expression of LINC01303 was significantly higher in GC tissues than in adjacent tissues by real-time quantitative PCR. We can significantly inhibit the malignant proliferation, migration and invasion of GC cells by silencing LINC01303 expression. In addition, LINC01303 knockdown can also inhibit GC growth in vivo. After the bioinformatics analysis, we found that LINC01303 can be used as a miR-101-3p sponge to competitively adsorb miR-101-3p with EZH2. Therefore, our results indicate that LINC01303 promotes the expression of EZH2 by inhibiting miR-101-3p activity and promotes GC progression. In summary, in this study, we demonstrated for the first time that the LINC01303/miR-101-3p/EZH2 axis promotes GC progression., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Proper migration and invasion of trophoblast cells into endometrium is vital for successful embryo implantation during early pregnancy. Benzo[a]pyrene-7, 8-diol-9, 10-epoxide (BPDE) is an ultimate carcinogenic product of benzo[a]pyrene (BaP), which causes multiple trophoblast-related diseases. However, the mechanism of BPDE-inhibited migration/invasion of trophoblast cells is still unclear. In this work, we found that BPDE significantly inhibited the filopodia formation and migration/invasion of human trophoblast Swan 71 cells. BPDE up-regulated the level of miR-194-3p, which further inhibited the phosphoinositide 3-kinase (PI3K)/AKT/ cell division cycle 42/ p21 (RAC1) activated kinase 1 signaling pathway and depressed the filophdia formation of Swan71 cells. Addition of 740 Y-P, the activator of phosphoinositide 3-kinase, could stimulate cell migration/invasion, confirming the involvement of this pathway. Knock-down of miR-194-3p up-regulated this pathway and promoted filopodia formation and migration/invasion. Conversely, overexpression of miR-194-3p down-regulated this pathway and inhibited cell migration/invasion. Therefore, miR-194-3p takes important roles in the BPDE-inhibited filopodia formation and cell migration/invasion, providing valuable information in the BPDE-induced dysfunctions of human extravillous trophoblast cells.