Decreased Indian hedgehog signaling activates autophagy in endometriosis and adenomyosis

in Reproduction
View More View Less
  • 1 Department of Laboratory Medicine, Huangyan Hospital of Wenzhou Medical University, Taizhou First People’s Hospital, Taizhou, Zhejiang Province, China
  • 2 Department of Obstetrics and Gynecology, Huangyan Hospital of Wenzhou Medical University, Taizhou First People’s Hospital, Taizhou, Zhejiang Province, China

Correspondence should be addressed to X Zhao or J Li; Email: 40676951@qq.com or liyijie12580@126.com
Restricted access

Indian hedgehog (Ihh) signaling regulates endometrial receptivity and is an indispensable mediator of embryonic implantation. Hedgehog signaling is known to regulate autophagy, and aberrant regulation of autophagy is critically implicated in the pathogenesis of endometriosis and adenomyosis. However, potential dysregulation of Ihh signaling and its role in autophagy modulation in these diseases remain obscure. In this study, we found that components of Ihh signaling were significantly decreased, whereas the autophagy marker protein, LC3BII, was significantly increased in endometrial tissues of women with endometriosis or adenomyosis. Inhibition of Ihh signaling with the small-molecule inhibitor GANT61 or Gli1 silencing in primary endometrial stromal cells increased autophagic activity, as measured by LC3 turnover assay and tandem mCherry-eGFP-LC3B fluorescence microscopy. Furthermore, we observed that GANT61 treatment significantly attenuated hydrogen peroxide-induced cell death, whereas disruption of autophagy with chloroquine diminished this effect. Collectively, these findings reveal that Ihh signaling is suppressed in endometrial tissues of patients with endometriosis or adenomyosis. This abnormal decrease may contribute to endometrial autophagy activation, which may promote aberrant survival of endometrial cells in ectopic sites in these two gynecological diseases.

 

     An official journal of

    Society for Reproduction and Fertility

 

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 182 182 182
Full Text Views 3 3 3
PDF Downloads 1 1 1
  • Allavena G, Carrarelli P, Del Bello B, Luisi S, Petraglia F & Maellaro E 2015 Autophagy is upregulated in ovarian endometriosis: a possible interplay with p53 and heme oxygenase-1. Fertility and Sterility 103 1244 .e1125 1.e1. (https://doi.org/10.1016/j.fertnstert.2015.02.007)

    • Search Google Scholar
    • Export Citation
  • Che X, Wang J, He J, Yu Q, Sun W, Chen S, Zou G, Li T, Guo X & Zhang X 2020 A new trick for an old dog: the application of mifepristone in the treatment of adenomyosis. Journal of Cellular and Molecular Medicine 24 17241737. (https://doi.org/10.1111/jcmm.14866)

    • Search Google Scholar
    • Export Citation
  • Choi J, Jo M, Lee E, Lee DY & Choi D 2015 Dienogest enhances autophagy induction in endometriotic cells by impairing activation of AKT, ERK1/2, and mTOR. Fertility and Sterility 104 655664. (https://doi.org/10.1016/j.fertnstert.2015.05.020)

    • Search Google Scholar
    • Export Citation
  • Dai P, Akimaru H, Tanaka Y, Maekawa T, Nakafuku M & Ishii S 1999 Sonic hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. Journal of Biological Chemistry 274 81438152. (https://doi.org/10.1074/jbc.274.12.8143)

    • Search Google Scholar
    • Export Citation
  • Felip I, Moiola CP, Megino-Luque C, Lopez-Gil C, Cabrera S, Sole-Sanchez S, Munoz-Guardiola P, Megias-Roda E, Perez-Montoyo H & Alfon J 2019 Therapeutic potential of the new TRIB3-mediated cell autophagy anticancer drug ABTL0812 in endometrial cancer. Gynecologic Oncology 153 425435. (https://doi.org/10.1016/j.ygyno.2019.03.002)

    • Search Google Scholar
    • Export Citation
  • Franco HL, Lee KY, Broaddus RR, White LD, Lanske B, Lydon JP, Jeong JW & DeMayo FJ 2010 Ablation of Indian hedgehog in the murine uterus results in decreased cell cycle progression, aberrant epidermal growth factor signaling, and increased estrogen signaling. Biology of Reproduction 82 783790. (https://doi.org/10.1095/biolreprod.109.080259)

    • Search Google Scholar
    • Export Citation
  • Garcia-Solares J, Donnez J, Donnez O & Dolmans MM 2018 Pathogenesis of uterine adenomyosis: invagination or metaplasia? Fertility and Sterility 109 371379. (https://doi.org/10.1016/j.fertnstert.2017.12.030)

    • Search Google Scholar
    • Export Citation
  • Gorojankina T 2016 Hedgehog signaling pathway: a novel model and molecular mechanisms of signal transduction. Cellular and Molecular Life Sciences 73 13171332. (https://doi.org/10.1007/s00018-015-2127-4)

    • Search Google Scholar
    • Export Citation
  • He Y, Guo Q, Cheng Y, Qu Y, Sun L, Kong C, Lei L & Zhang G 2018 Abnormal activation of the sonic hedgehog signaling pathway in endometriosis and its diagnostic potency. Fertility and Sterility 110 128 .e2136.e2. (https://doi.org/10.1016/j.fertnstert.2018.02.138)

    • Search Google Scholar
    • Export Citation
  • Jimenez-Sanchez M, Menzies FM, Chang YY, Simecek N, Neufeld TP & Rubinsztein DC 2012 The Hedgehog signalling pathway regulates autophagy. Nature Communications 3 1200. (https://doi.org/10.1038/ncomms2212)

    • Search Google Scholar
    • Export Citation
  • Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, Adachi H, Adams CM, Adams PD & Adeli K 2016 Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12 1 222. (https://doi.org/10.1080/15548627.2015.1100356)

    • Search Google Scholar
    • Export Citation
  • Kobayashi H, Kishi Y & Matsubara S 2020 Mechanisms underlying adenomyosis-related fibrogenesis. Gynecologic and Obstetric Investigation 85 112. (https://doi.org/10.1159/000502822)

    • Search Google Scholar
    • Export Citation
  • Lauth M, Bergstrom A, Shimokawa T & Toftgard R 2007 Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. PNAS 104 84558460. (https://doi.org/10.1073/pnas.0609699104)

    • Search Google Scholar
    • Export Citation
  • Lee K, Jeong J, Kwak I, Yu CT, Lanske B, Soegiarto DW, Toftgard R, Tsai MJ, Tsai S & Lydon JP 2006 Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus. Nature Genetics 38 12041209. (https://doi.org/10.1038/ng1874)

    • Search Google Scholar
    • Export Citation
  • Leidal AM, Levine B & Debnath J 2018 Autophagy and the cell biology of age-related disease. Nature Cell Biology 20 13381348. (https://doi.org/10.1038/s41556-018-0235-8)

    • Search Google Scholar
    • Export Citation
  • Li H, Li J, Li Y, Singh P, Cao L, Xu LJ, Li D, Wang Y, Xie Z & Gui Y 2012 Sonic hedgehog promotes autophagy of vascular smooth muscle cells. American Journal of Physiology: Heart and Circulatory Physiology 303 H1319H 1331. (https://doi.org/10.1152/ajpheart.00160.2012)

    • Search Google Scholar
    • Export Citation
  • Liu H, Zhang Z, Xiong W, Zhang L, Xiong Y, Li N, He H, Du Y & Liu Y 2017 Hypoxia-inducible factor-1alpha promotes endometrial stromal cells migration and invasion by upregulating autophagy in endometriosis. Reproduction 153 809820. (https://doi.org/10.1530/REP-16-0643)

    • Search Google Scholar
    • Export Citation
  • Liu H, Zhang W, Wang L, Zhang Z, Xiong W, Zhang L, Fu T, Li X, Chen Y & Liu Y 2019a GLI1 is increased in ovarian endometriosis and regulates migration, invasion and proliferation of human endometrial stromal cells in endometriosis. Annals of Translational Medicine 7 663. (https://doi.org/10.21037/atm.2019.10.76)

    • Search Google Scholar
    • Export Citation
  • Liu H, Zhang Z, Xiong W, Zhang L, Du Y, Liu Y & Xiong X 2019b Long non-coding RNA MALAT1 mediates hypoxia-induced pro-survival autophagy of endometrial stromal cells in endometriosis. Journal of Cellular and Molecular Medicine 23 439452. (https://doi.org/10.1111/jcmm.13947)

    • Search Google Scholar
    • Export Citation
  • Livak KJ & Schmittgen TD 2001 Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25 402408. (https://doi.org/10.1006/meth.2001.1262)

    • Search Google Scholar
    • Export Citation
  • Matsuzaki S, Pouly JL & Canis M 2018 In vitro and in vivo effects of MK2206 and chloroquine combination therapy on endometriosis: autophagy may be required for regrowth of endometriosis. British Journal of Pharmacology 175 16371653. (https://doi.org/10.1111/bph.14170)

    • Search Google Scholar
    • Export Citation
  • Mei J, Zhu XY, Jin LP, Duan ZL, Li DJ & Li MQ 2015 Estrogen promotes the survival of human secretory phase endometrial stromal cells via CXCL12/CXCR4 up-regulation-mediated autophagy inhibition. Human Reproduction 30 16771689. (https://doi.org/10.1093/humrep/dev100)

    • Search Google Scholar
    • Export Citation
  • Mizushima N 2018 A brief history of autophagy from cell biology to physiology and disease. Nature Cell Biology 20 521527. (https://doi.org/10.1038/s41556-018-0092-5)

    • Search Google Scholar
    • Export Citation
  • Mizushima N, Yoshimori T & Levine B 2010 Methods in mammalian autophagy research. Cell 140 313326. (https://doi.org/10.1016/j.cell.2010.01.028)

    • Search Google Scholar
    • Export Citation
  • Mori M, Ito F, Shi L, Wang Y, Ishida C, Hattori Y, Niwa M, Hirayama T, Nagasawa H & Iwase A 2015 Ovarian endometriosis-associated stromal cells reveal persistently high affinity for iron. Redox Biology 6 578586. (https://doi.org/10.1016/j.redox.2015.10.001)

    • Search Google Scholar
    • Export Citation
  • Petralia RS, Schwartz CM, Wang YX, Kawamoto EM, Mattson MP & Yao PJ 2013 Sonic hedgehog promotes autophagy in hippocampal neurons. Biology Open 2 499504. (https://doi.org/10.1242/bio.20134275)

    • Search Google Scholar
    • Export Citation
  • Ren Y, Mu L, Ding X & Zheng W 2010 Decreased expression of Beclin 1 in eutopic endometrium of women with adenomyosis. Archives of Gynecology and Obstetrics 282 401406. (https://doi.org/10.1007/s00404-009-1280-0)

    • Search Google Scholar
    • Export Citation
  • Ruiz I Altaba A 1999 Gli proteins encode context-dependent positive and negative functions: implications for development and disease. Development 126 32053216.

    • Search Google Scholar
    • Export Citation
  • Sanchez AM, Vigano P, Somigliana E, Panina-Bordignon P, Vercellini P & Candiani M 2014 The distinguishing cellular and molecular features of the endometriotic ovarian cyst: from pathophysiology to the potential endometrioma-mediated damage to the ovary. Human Reproduction Update 20 217230. (https://doi.org/10.1093/humupd/dmt053)

    • Search Google Scholar
    • Export Citation
  • Shen M, Liu X, Zhang H & Guo SW 2016 Transforming growth factor beta1 signaling coincides with epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis in mice. Human Reproduction 31 355369. (https://doi.org/10.1093/humrep/dev314)

    • Search Google Scholar
    • Export Citation
  • Shi Y & Long F 2017 Hedgehog signaling via Gli2 prevents obesity induced by high-fat diet in adult mice. eLife 6 e31649. (https://doi.org/10.7554/eLife.31649)

    • Search Google Scholar
    • Export Citation
  • Smith K, Alnifaidy R, Wei Q & Nieman LK 2011 Endometrial Indian hedgehog expression is decreased in women with endometriosis. Fertility and Sterility 95 2738 .e1274 1.e1. (https://doi.org/10.1016/j.fertnstert.2011.05.018)

    • Search Google Scholar
    • Export Citation
  • Vannuccini S, Tosti C, Carmona F, Huang SJ, Chapron C, Guo SW & Petraglia F 2017 Pathogenesis of adenomyosis: an update on molecular mechanisms. Reproductive Biomedicine Online 35 592601. (https://doi.org/10.1016/j.rbmo.2017.06.016)

    • Search Google Scholar
    • Export Citation
  • Wang Y, Han C, Lu L, Magliato S & Wu T 2013 Hedgehog signaling pathway regulates autophagy in human hepatocellular carcinoma cells. Hepatology 58 9951010. (https://doi.org/10.1002/hep.26394)

    • Search Google Scholar
    • Export Citation
  • Xiong Y, Liu Y, Xiong W, Zhang L, Liu H, Du Y & Li N 2016 Hypoxia-inducible factor 1alpha-induced epithelial-mesenchymal transition of endometrial epithelial cells may contribute to the development of endometriosis. Human Reproduction 31 13271338. (https://doi.org/10.1093/humrep/dew081)

    • Search Google Scholar
    • Export Citation
  • Yamaguchi K, Mandai M, Toyokuni S, Hamanishi J, Higuchi T, Takakura K & Fujii S 2008 Contents of endometriotic cysts, especially the high concentration of free iron, are a possible cause of carcinogenesis in the cysts through the iron-induced persistent oxidative stress. Clinical Cancer Research 14 3240. (https://doi.org/10.1158/1078-0432.CCR-07-1614)

    • Search Google Scholar
    • Export Citation
  • Yim WW & Mizushima N 2020 Lysosome biology in autophagy. Cell Discovery 6 6. (https://doi.org/10.1038/s41421-020-0141-7)

  • Yoo JY, Kim TH, Fazleabas AT, Palomino WA, Ahn SH, Tayade C, Schammel DP, Young SL, Jeong JW & Lessey BA 2017 KRAS activation and over-expression of SIRT1/BCL6 contributes to the pathogenesis of endometriosis and progesterone resistance. Scientific Reports 7 6765. (https://doi.org/10.1038/s41598-017-04577-w)

    • Search Google Scholar
    • Export Citation
  • Zhan L, Yao S, Sun S, Su Q, Li J & Wei B 2018 NLRC5 and autophagy combined as possible predictors in patients with endometriosis. Fertility and Sterility 110 949956. (https://doi.org/10.1016/j.fertnstert.2018.06.028)

    • Search Google Scholar
    • Export Citation
  • Zhang L, Zhou Y, Xia Q, Chen Y & Li J 2020 All-trans-retinal induces autophagic cell death via oxidative stress and the endoplasmic reticulum stress pathway in human retinal pigment epithelial cells. Toxicology Letters 322 7786. (https://doi.org/10.1016/j.toxlet.2020.01.005)

    • Search Google Scholar
    • Export Citation
  • Zheng J, Luo X, Bao J, Huang X, Jin Y, Chen L & Zheng F 2018 Decreased expression of HOXA10 may activate the autophagic process in ovarian endometriosis. Reproductive Sciences 25 14461454. (https://doi.org/10.1177/1933719118768704)

    • Search Google Scholar
    • Export Citation
  • Zhu B, Chen Y, Shen X, Liu X & Guo SW 2016 Anti-platelet therapy holds promises in treating adenomyosis: experimental evidence. Reproductive Biology and Endocrinology 14 66. (https://doi.org/10.1186/s12958-016-0198-1)

    • Search Google Scholar
    • Export Citation
  • Zondervan KT, Becker CM & Missmer SA 2020 Endometriosis. New England Journal of Medicine 382 12441256. (https://doi.org/10.1056/NEJMra1810764)

    • Search Google Scholar
    • Export Citation