Inhibition of TMEM16A impedes embryo implantation and decidualization in mice

in Reproduction

Correspondence should be addressed to Q Xie; Email: drqingzhenxie@126.com
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Recent studies revealed that TMEM16A is involved in several reproductive processes, including ovarian estrogen secretion and ovulation, sperm motility and acrosome reaction, fertilization and myometrium contraction. However, little is known about the expression and function of TMEM16A in embryo implantation and decidualization. In this study, we focused on the expression and regulation of TMEM16A in mouse uterus during early pregnancy. We found that TMEM16A is upregulated in uterine endometrium in response to embryo implantation and decidualization. Progesterone treatment could induce TMEM16A expression in endometrial stromal cells through progesterone receptor/c-Myc pathway, which is blocked by progesterone receptor antagonist or the inhibitor of c-Myc signaling pathway. Inhibition of TMEM16A by small molecule inhibitor (T16Ainh-A01) resulted in impaired embryo implantation and decidualization in mice. Treatment with either specific siRNA of Tmem16a or T16Ainh-A01 inhibited the decidualization and proliferation of mouse endometrial stromal cells. In conclusion, our results revealed that TMEM16A is involved in embryo implantation and decidualization in mice, compromised function of TMEM16A may lead to impaired embryo implantation and decidualization.

 

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  • ChaJYWeeJJungJJangYLeeBHongGSChangBCChoiYLShinYKMinHY et al. 2015 Anoctamin 1 (TMEM16A) is essential for testosterone-induced prostate hyperplasia. PNAS 112 97229727. (https://doi.org/10.1073/pnas.1423827112)

    • Search Google Scholar
    • Export Citation
  • Cordero-MartinezJReyes-MiguelTRodriguez-PaezLGarduno-SicilianoLMaldonado-GarciaDRoa-EspitiaALHernandez-GonzalezEO 2018 TMEM16A inhibition impedes capacitation and acquisition of hyperactivated motility in guinea pig sperm. Journal of Cellular Biochemistry 119 59445959. (https://doi.org/10.1002/jcb.26789)

    • Search Google Scholar
    • Export Citation
  • DanielssonJVinkJHyugaSFuXWFunayamaHWapnerRBlanksAMGallosG 2018 Anoctamin channels in human myometrium: a novel target for tocolysis. Reproductive Sciences 25 15891600. (https://doi.org/10.1177/1933719118757683).

    • Search Google Scholar
    • Export Citation
  • DengLYangJChenHMaBPanKSuCXuFZhangJ 2016 Knockdown of TMEM16A suppressed MAPK and inhibited cell proliferation and migration in hepatocellular carcinoma. OncoTargets and Therapy 9 325333. (https://doi.org/10.2147/OTT.S95985)

    • Search Google Scholar
    • Export Citation
  • DuvvuriUShiwarskiDJXiaoDBertrandCHuangXEdingerRSRockJRHarfeBDHensonBJKunzelmannK et al. 2012 TMEM16A induces MAPK and contributes directly to tumorigenesis and cancer progression. Cancer Research 72 32703281. (https://doi.org/10.1158/0008-5472.CAN-12-0475-T)

    • Search Google Scholar
    • Export Citation
  • EdlundAEsguerraJLWendtAFlodstrom-TullbergMEliassonL 2014 CFTR and Anoctamin 1 (ANO1) contribute to cAMP amplified exocytosis and insulin secretion in human and murine pancreatic beta-cells. BMC Medicine 12 87. (https://doi.org/10.1186/1741-7015-12-87)

    • Search Google Scholar
    • Export Citation
  • GodseNRKhanNYochumZAGomez-CasalRKempCShiwarskiDJSeethalaRSKulichSSeshadriMBurnsTF et al. 2017 TMEM16A/ANO1 inhibits apoptosis via downregulation of bim expression. Clinical Cancer Research 23 73247332. (https://doi.org/10.1158/1078-0432.CCR-17-1561)

    • Search Google Scholar
    • Export Citation
  • HuangWLiuMZhuLLiuSLuoHMaLWangHLuRSunXChenL et al. 2014 Functional expression of chloride channels and their roles in the cell cycle and cell proliferation in highly differentiated nasopharyngeal carcinoma cells. Physiological Reports 2 e12137. (https://doi.org/10.14814/phy2.12137)

    • Search Google Scholar
    • Export Citation
  • KamikawaAIchiiOSakazakiJIshikawaT 2016 Ca2+-activated Cl- channel currents in mammary secretory cells from lactating mouse. American Journal of Physiology: Cell Physiology 311 C808C819. (https://doi.org/10.1152/ajpcell.00050.2016)

    • Search Google Scholar
    • Export Citation
  • KusamaKYoshieMTamuraKImakawaKIsakaKTachikawaE 2015 Regulatory action of calcium ion on cyclic AMP-enhanced expression of implantation-related factors in human endometrial cells. PLoS ONE 10 e0132017. (https://doi.org/10.1371/journal.pone.0132017)

    • Search Google Scholar
    • Export Citation
  • NizyaevaNVSukhachevaTVSerovRAKulikovaGVNagovitsynaMNKanNETyutyunnikVLPavlovichSVPoltavtsevaRAYarotskayaEL et al. 2018 Ultrastructural and immunohistochemical features of telocytes in placental villi in preeclampsia. Scientific Reports 8 3453. (https://doi.org/10.1038/s41598-018-21492-w)

    • Search Google Scholar
    • Export Citation
  • OusingsawatJMartinsJRSchreiberRRockJRHarfeBDKunzelmannK 2009 Loss of TMEM16A causes a defect in epithelial Ca2+-dependent chloride transport. Journal of Biological Chemistry 284 2869828703. (https://doi.org/10.1074/jbc.M109.012120)

    • Search Google Scholar
    • Export Citation
  • PaulinoCKalienkovaVLamAKMNeldnerYDutzlerR 2017a Activation mechanism of the calcium-activated chloride channel TMEM16A revealed by cryo-EM. Nature 552 421425. (https://doi.org/10.1038/nature24652)

    • Search Google Scholar
    • Export Citation
  • PaulinoCNeldnerYLamAKKalienkovaVBrunnerJDSchenckSDutzlerR 2017b Structural basis for anion conduction in the calcium-activated chloride channel TMEM16A. Elife 6 e26232. (https://doi.org/10.7554/eLife.26232)

    • Search Google Scholar
    • Export Citation
  • QiQRZhaoXYZuoRJWangTSGuXWLiuJLYangZM 2015 Involvement of atypical transcription factor E2F8 in the polyploidization during mouse and human decidualization. Cell Cycle 14 18421858. (https://doi.org/10.1080/15384101.2015.1033593)

    • Search Google Scholar
    • Export Citation
  • RockJRFuttnerCRHarfeBD 2008 The transmembrane protein TMEM16A is required for normal development of the murine trachea. Developmental Biology 321 141149. (https://doi.org/10.1016/j.ydbio.2008.06.009)

    • Search Google Scholar
    • Export Citation
  • RuanYCGuoJHLiuXZhangRTsangLLDongJDChenHYuMKJiangXZhangXH et al. 2012 Activation of the epithelial Na+ channel triggers prostaglandin E(2) release and production required for embryo implantation. Nature Medicine 18 11121117. (https://doi.org/10.1038/nm.2771)

    • Search Google Scholar
    • Export Citation
  • SunMSuiYLiLSuWHaoFZhuQDiWGaoHMaT 2014 Anoctamin 1 calcium-activated chloride channel downregulates estrogen production in mouse ovarian granulosa cells. Endocrinology 155 27872796. (https://doi.org/10.1210/en.2013-2155)

    • Search Google Scholar
    • Export Citation
  • WangHZouLMaKYuJWuHWeiMXiaoQ 2017 Cell-specific mechanisms of TMEM16A Ca(2+)-activated chloride channel in cancer. Molecular Cancer 16 152. (https://doi.org/10.1186/s12943-017-0720-x)

    • Search Google Scholar
    • Export Citation
  • WuHWangHGuanSZhangJChenQWangXMaKZhaoPZhaoHYaoW et al. 2017 Cell-specific regulation of proliferation by Ano1/TMEM16A in breast cancer with different ER, PR, and HER2 status. Oncotarget 8 8499685013. (https://doi.org/10.18632/oncotarget.18662)

    • Search Google Scholar
    • Export Citation
  • ZhangRJZouLBZhangDTanYJWangTTLiuAXQuFMengYDingGLLuYC et al. 2012 Functional expression of large-conductance calcium-activated potassium channels in human endometrium: a novel mechanism involved in endometrial receptivity and embryo implantation. Journal of Clinical Endocrinology and Metabolism 97 543553. (https://doi.org/10.1210/jc.2011-2108)

    • Search Google Scholar
    • Export Citation
  • ZhangSLinHKongSWangSWangHArmantDR 2013 Physiological and molecular determinants of embryo implantation. Molecular Aspects of Medicine 34 939980. (https://doi.org/10.1016/j.mam.2012.12.011)

    • Search Google Scholar
    • Export Citation
  • ZuoRJGuXWQiQRWangTSZhaoXYLiuJLYangZM 2015 Warburg-like glycolysis and lactate shuttle in mouse decidua during early pregnancy. Journal of Biological Chemistry 290 2128021291. (https://doi.org/10.1074/jbc.M115.656629)

    • Search Google Scholar
    • Export Citation