Roles Of LncRNA Urothelial Carcinoma Associated 1 In Regulation Of The Biological Behaviors Of Trophoblasts

Recurrent miscarriage is a pathological pregancy resulting from many undefined biological or non-biological reasons,which may exert heavily physical and psychological effects on pregnant women.However,the underlying mechanisms related to recurrent miscarriage still remains largely unknown.Several studies have indicated that long non-coding RNAs(LncRNAs)-urothelial carcinoma associated 1(UCA1)is highly up-regulated in endometrial cancer,as well as other several human cancers including bladder cancer,liver cancer and breast cancer.The high UCA1 level may contribute to the rapid cell proliferation,migration,invasion and drug resistance of these cancers.It also has been reported that trophoblasts have tumor-like biological behaviors and are tightly connected with the replasticity of endometrium and other disorders including recurrent miscarriages,and recurrent miscarriage may affect the pathologies and progression of many benign or malignant endometrial disorders.However,the role of UCA1 in trophoblasts at early pregnancy and recurrent miscarriages remains poorly understood.In this study,expression levels of UCA1 in recurrent miscarriage patients were determined by quantitative reverse transcription-PCR(qRT-PCR).UCA1 was then either over-expressed or down-regulated in trophoblasts for the evaluation of its functions in trophoblast invasion at the maternal interface by using and a villous explant culture experiment.The underlying molecular mechanisms were further determined by several related experiments including gelatin zymography,western blotting and chromatin immunoprecipitation(ChIP).Our studies reveal that depletion of UCA1 through siRNA strategy in human trophoblasts can markedly reduce their proliferation and invasion abilities.Conversely,over-expression of wild-type UCA1 promotes cell growth and invasion of trophoblasts.Knockdown of UCA1 also remarkably suppresses the invasion ability of trophoblasts in a villous explant ex vivo culture model.Mechanistically,qRT-PCR screening reveals that over-expression of UCA1 significantly promotes MMP9 mRNA level in trophoblasts.Furthermore,the up-regulation of UCA1 enhances the invasion capacities of trophoblasts from recurrent miscarriage patients through the up-regulation of protein level and enzyme activity of MMP9.We also demonstrate that the transcription factor of YY1 plays an important role in the transactivation of UCA1.In summary,our data reveal that UCA1 may play a key role in the trophoblast invasion.Down-regulation of YY1/UCA1/MMP9 signaling may lead to the reduction of trophoblast invasion,followed by the decrease in occurrence of recurrent miscarriage.These results also provide important implications to explore the functions of UCA1 in the early onset of other benign or malignant endometrial disorders.