WITHDRAWN: Novel lncRNA-HZ04 Promotes BPDE-Induced Human Trophoblast Cell Apoptosis and Miscarriage by Up-Regulating IP3R1/CaMKII/SGCB Pathway by Competitively Binding with miR-hz04

Abstract BackgroundMiscarriage seriously hinders human reproduction. BaP (benzo(a)pyrene) and its metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) could cause trophoblast cell dysfunctions and might further induce human miscarriage. However, the underlying mechanisms remain largely unknown. ResultsHerein, we identified a novel lnc-HZ04 up-regulated and a novel miR-hz04 down-regulated in the unexplained recurrent miscarriage (RM) villous tissues relative to the healthy control tissues and also in the BPDE-exposed trophoblast cells. Lnc-HZ04 served as competing endogenous RNA (ceRNA), directly and specifically bound with miR-hz04 on its target site, and diminished the inhibition effects of miR-hz04 on IP 3 R 1 mRNA expression level and its mRNA stability, thus activated Ca 2+ -mediated IP 3 R 1 /p-CaMKII/SGCB apoptosis pathway, which further promoted trophoblast cell apoptosis. The miR-hz04 target site, but not its mutant, on lnc-HZ04 played important roles in these regulations. In normal trophoblast, relatively less lnc-HZ04 and more miR-hz04 inhibited this apoptosis pathway and gave normal pregnancy. After exposure to BPDE or in the RM tissues, relatively more lnc-HZ04 and less miR-hz04 activated this apoptosis pathway and induced miscarriage. BaP could also induce mice miscarriage by up-regulating this corresponding murine apoptosis pathway. ConclusionsThis work discovered that lnc-HZ04 served as a ceRNA for miR-hz04 and up-regulated IP 3 R 1 /CaMKII/SGCB pathway, which promoted the BPDE-induced human trophoblast cell apoptosis and the occurrence of miscarriage, providing novel scientific and clinical understanding in the occurrence of unexplained miscarriage.