Decreased miR-486-5p is involved in LPS-induced HTR-8/SVneo cell dysfunction by promoting Smad2 expression

in Reproduction
Authors:
Yan Gu Y Gu, Reproductive Medicine Center, The Second Hospital of Tianjin Medical University, Tianjin, China

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Ning Song N Song, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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Long Yang L Yang, Reproductive Health institute, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China

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Yan Shi Y Shi, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China

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Hao-Ran Xu H Xu, Medical School, Fudan University, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China

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Ya-Wei Xin Y Xin, Reproductive Medicine Center, The Second Hospital of Tianjin Medical University, Tianjin, China

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Ling-Han Chen L Chen, Hangzhou Yuhang Center for Disease Control and Prevention, Hangzhou Yuhang Center for Disease Control and Prevention, Hangzhou, China

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Wen-Wen Gu W Gu, Medical School, Fudan University, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, 200032, China

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Jian Wang J Wang, School of Pharmacy, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China

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Correspondence: Wen-Wen Gu, Email: guwenwen@sibpt.com
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Placenta-associated pathologies, including early pregnancy loss (EPL) and preeclampsia (PE), share a common phenomenon of insufficient extravillous trophoblasts (EVTs) invasion. It was previously observed that down-regulated miR-486-5p expression inhibited the invasion of EVTs, and a decreased peripheral miR-486-5p was associated with EPL. However, the exact roles of miR-486-5p played in pathogenesis of EPL, as well as the molecular pathway underlying roles of miR-486-5p in EVTs invasion, remains poorly understood. In this study, a decreased miR-486-5p expression in uterine embryo implantation site at gestation day (GD) 8.5, and an increased expression of Smad2, a target of miR-486-5p, were observed in the lipopolysaccharide (LPS)-induced EPL mouse model. The invasion and viability of immortalized human EVTs line, HTR-8/SVneo, were inhibited by LPS, accompanied with a reduced miR-486-5p expression. LPS showed a promoting effect on the Smad2 expression, of which could be attenuated by miR-486-5p mimics. And the down-regulated Smad2 could effectively restore the impaired invasion and viability of HTR-8/SVneo cells caused by LPS or miR-486-5p inhibitor. Furthermore, LPS could promote the TNFα production in HTR-8/SVneo cells, whereas both of siSmad and miR-486-5p mimics could reverse such an effect. By analyzing the human decidua single-cell RNA sequencing and transcriptome datasets derived from the Gene Expression Omnibus, it was found that, compared to control early pregnant women, the Smad2 expression was significantly increased in recurrent miscarriages (RM) patients. Collectively, these data suggested that, decreased miR-486-5p expression might lead to EPL at least partially by inhibiting invasion and/or promoting TNFα production of EVTs via targeting Smad2.