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Environmental Pollutant Benzo[a]pyrene Upregulated Long Non-coding RNA HZ07 Inhibits Trophoblast Cell Migration by Inactivating PI3K/AKT/MMP2 Signaling Pathway in Recurrent Pregnancy Loss

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A Correction to this article was published on 21 September 2022

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Abstract

Benzo(a)pyrene (BaP) is a ubiquitous environmental endocrine-disrupting chemical that is known to have toxic effects on reproduction. However, the underlying mechanisms describing how BaP and its metabolite benzo[a]pyrene-7, 8-diol-9, 10-epoxide (BPDE) induce recurrent pregnancy loss (RPL) are still largely unclear. In this study, we identified a novel long non-coding RNA (lnc-HZ07, NCBI MT936329) that was upregulated in trophoblast cells after exposure to BPDE, and lnc-HZ07 expression was significantly higher in RPL villous tissues than that in control villous tissues. Knockdown of lnc-HZ07 promoted trophoblast cell migration, whereas overexpression of lnc-HZ07 inhibited trophoblast cell migration. Further study showed that lnc-HZ07 inhibited trophoblast migration by downregulating matrix metalloproteinase 2 (MMP2) expression via dephosphorylation of AKT. These results demonstrated a novel regulatory pathway in which BaP downregulated AKT phosphorylation and inhibited MMP2 expression by upregulating lnc-HZ07, suggesting that lnc-HZ07 could be considered as a potential pathological marker of BaP-induced RPL and therapeutic target for this disease.

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Funding

This study was supported by the National Key Research and Development Program of China (2018YFC1002804), National Natural Science Foundation of China (81771545 and 82073589), the Guangdong Basic and Applied Basic Research Foundation (2020B1515020001), and the Special Fund for Clinical Research of Chinese Medical Association (18010180747).

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Author notes

  1. Yang Ye & Sushi Jiang

    Present address: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, YanjiangWest Road, Guangzhou, Guangdong, China

  2. Yang Ye and Sushi Jiang contributed equally to this work.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, YanjiangWest Road, Guangzhou, Guangdong, China

    Yang Ye, Sushi Jiang, Tao Du, Miao Ding, Minzhi Hou & Xiaomiao Zhao

  2. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, YanjiangWest Road, Guangzhou, Guangdong, China

    Tao Du, Miao Ding, Minzhi Hou & Xiaomiao Zhao

  3. Research Center for Environment and Female Reproductive Health, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China

    Chenyang Mi, Tingting Liang, Jiayu Xie & Huidong Zhang

  4. State Key Laboratory of Pollution Control and Resources Reuse, School of the Environment, Nanjing University, Nanjing, China

    Huan Zhong

  5. Environmental and Life Sciences Program (EnLS), Trent University, Peterborough, Ontario, Canada

    Huan Zhong

  6. Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Sichuan University, Chengdu, China

    Wenming Xu

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Contributions

X. Zhao and H. Zhang designed the framework of the study and wrote the manuscript. Y. Ye and S. Jiang conceived, conducted experiments, and wrote the manuscript. M. Ding, M. Hou, and T. Du organized sampling and collected human villous tissue and clinical statistics. C. Mi, T. Liang, and J. Xie analyzed statistical significance of RNAs. H. Zhong and W. Xu coordinated the study. All authors reviewed and approved the final manuscript.

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Correspondence to Huidong Zhang or Xiaomiao Zhao.

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Ye, Y., Jiang, S., Du, T. et al. Environmental Pollutant Benzo[a]pyrene Upregulated Long Non-coding RNA HZ07 Inhibits Trophoblast Cell Migration by Inactivating PI3K/AKT/MMP2 Signaling Pathway in Recurrent Pregnancy Loss. Reprod. Sci. 28, 3085–3093 (2021). https://doi.org/10.1007/s43032-021-00630-2

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