Novel lncRNA‐HZ04 promotes BPDE‐induced human trophoblast cell apoptosis and miscarriage by upregulating IP3R1/CaMKII/SGCB pathway by competitively binding with miR‐hz04.

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 IP3R1 mRNA expression level and on IP3R1 mRNA stability, and then activated the Ca2+‐mediated IP3R1/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. [ABSTRACT FROM AUTHOR]