Lnc-HZ05 regulates BPDE-inhibited human trophoblast cell proliferation and affects the occurrence of miscarriage by directly binding with miR-hz05

Cell Biol Toxicol. 2022 Dec;38(6):1137-1157. doi: 10.1007/s10565-021-09687-w. Epub 2022 Jan 17.

Abstract

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.

Keywords: CDK2, Human trophoblast Swan 71 or HTR-8; Environmental BaP or BPDE, Recurrent miscarriage or spontaneous abortion, Lnc-HZ05; P21; SVneo cells, Cell cycle arrest and proliferation; miR-hz05 and FOXO3a.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide* / toxicity
  • Abortion, Spontaneous* / genetics
  • Abortion, Spontaneous* / metabolism
  • Benzo(a)pyrene / toxicity
  • Cell Line
  • Cell Movement
  • Cell Proliferation / genetics
  • Female
  • Humans
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Pregnancy
  • RNA, Long Noncoding* / genetics
  • Trophoblasts / metabolism

Substances

  • 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
  • Benzo(a)pyrene
  • MicroRNAs
  • RNA, Long Noncoding