GRIM19 is involved in WT1 expression and epithelial-to-mesenchymal transition in adenomyotic lesions

in Reproduction
Authors:
Chen Geng Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China

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Hao-ran Liu Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China

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Yue Zhao Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China

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Yang Yang Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China

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Lan Chao Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China

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Correspondence should be addressed to L Chao; Email: qlszcl@163.com
DOI:
https://doi.org/10.1530/REP-21-0181
Volume/Issue:
Volume 162: Issue 5
Page Range:
385–395
Article Type:
Research Article
Online Publication Date:
07 Oct 2021
Copyright:
© Society for Reproduction and Fertility 2021
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The epithelial-to-mesenchymal transition may play a role in adenomyosis. GRIM19 expression is downregulated in adenomyotic lesions, and the effects of this downregulation in adenomyosis remain relatively unclear. In this study, we aimed to explore whether aberrant GRIM19 expression is associated with the epithelial-to-mesenchymal transition in adenomyosis and found that the expression of both GRIM19 and WT1 was low, and epithelial-to-mesenchymal transition, which included significant changes in CDH1, CDH2 and KRT8 expression, occurred in adenomyotic lesions, as confirmed by Western blotting and quantitative real-time PCR. We provided novel insights into WT1 expression in adenomyosis, revealing that WT1 expression was increased in the endometrial glands of adenomyotic lesions by immunohistochemistry. In vitro, knockdown of GRIM19 expression by small interfering RNA (siRNA) promoted the proliferation, migration and invasion of Ishikawa cells, as measured by Cell Counting Kit-8, wound healing assay and Transwell assays. Western blotting and quantitative real-time PCR confirmed that WT1 expression increased and epithelial-to-mesenchymal transition was induced, including the upregulation of CDH2 and downregulation of CDH1 and KRT8after transfecting the GRIM19 siRNA to Ishikawa cells. Furthermore, Wt1 expression was upregulated and epithelial-to-mesenchymal transition was observed, including downregulation of Cdh1 and Krt8 in Grim19 gene-knockdown mice. Upregulation of Wt1 expression in the endometrial glands of Grim19 knockdown mice was also verified by immunohistochemistry. Taken together, these results reveal that low expression of GRIM19 in adenomyosis may upregulate WT1 expression and induce epithelial-to-mesenchymal transition in the endometria, providing new insights into the pathogenesis of adenomyosis.

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Print ISSN:
1470-1626
Online ISSN:
1741-7899

  • Acs G, Pasha T & Zhang PJ 2004 WT1 is differentially expressed in serous, endometrioid, clear cell, and mucinous carcinomas of the peritoneum, fallopian tube, ovary, and endometrium. International Journal of Gynecological Pathology 23 110–118. (https://doi.org/10.1097/00004347-200404000-00004)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Angell JE, Lindner DJ, Shapiro PS, Hofmann ER & Kalvakolanu DV 2000 Identification of GRIM-19, a novel cell death-regulatory gene induced by the interferon-beta and retinoic acid combination, using a genetic approach. Journal of Biological Chemistry 275 33416–33426. (https://doi.org/10.1074/jbc.M003929200)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Artibani M, Sims AH, Slight J, Aitken S, Thornburn A, Muir M, Brunton VG, Del-Pozo J, Morrison LR & Katz E et al.2017 WT1 expression in breast cancer disrupts the epithelial/mesenchymal balance of tumour cells and correlates with the metabolic response to docetaxel. Scientific Reports 7 45255. (https://doi.org/10.1038/srep45255)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Benagiano G & Brosens I 1991 The history of endometriosis: identifying the disease. Human Reproduction 6 963–968. (https://doi.org/10.1093/oxfordjournals.humrep.a137470)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bourdon M, Santulli P, Jeljeli M, Vannuccini S, Marcellin L, Doridot L, Petraglia F, Batteux F & Chapron C 2021 Immunological changes associated with adenomyosis: a systematic review. Human Reproduction Update 27 108–129. (https://doi.org/10.1093/humupd/dmaa038)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H & Lewis WH 1990 Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms’ tumor locus. Cell 60 509–520. (https://doi.org/10.1016/0092-8674(9090601-a)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F & Nieto MA 2000 The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nature Cell Biology 2 76–83. (https://doi.org/10.1038/35000025)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chen YJ, Li HY, Huang CH, Twu NF, Yen MS, Wang PH, Chou TY, Liu YN, Chao KC & Yang MH 2010 Oestrogen-induced epithelial-mesenchymal transition of endometrial epithelial cells contributes to the development of adenomyosis. Journal of Pathology 222 261–270. (https://doi.org/10.1002/path.2761)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chen DY, Qiao H, Wang YT, Ling Z, Yin N, Fang LQ & Wang ZB 2020 Adenomyosis-derived extracellular vesicles endow endometrial epithelial cells with an invasive phenotype through epithelial-mesenchymal transition. Genes and Diseases 7 636–648(https://doi.org/10.1016/j.gendis.2020.01.011)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Critchley HOD, Babayev E, Bulun SE, Clark S, Garcia-Grau I, Gregersen PK, Kilcoyne A, Kim JJ, Lavender M & Marsh EE et al.2020 Menstruation: science and society. American Journal of Obstetrics and Gynecology 223 624–664. (https://doi.org/10.1016/j.ajog.2020.06.004)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dongre A & Weinberg RA 2019 New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nature Reviews: Molecular Cell Biology 20 69–84. (https://doi.org/10.1038/s41580-018-0080-4)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Donnez J, Donnez O & Dolmans MM 2018 Introduction: uterine adenomyosis, another enigmatic disease of our time. Fertility and Sterility 109 369–370. (https://doi.org/10.1016/j.fertnstert.2018.01.035)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fang Y, He W, Hu X & Wang H 2021 A method for sample size calculation via E-value in the planning of observational studies. Pharmaceutical Statistics 20 163–174. (https://doi.org/10.1002/pst.2064)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fearnley IM, Carroll J, Shannon RJ, Runswick MJ, Walker JE & Hirst J 2001 GRIM-19, a cell death regulatory gene product, is a subunit of bovine mitochondrial NADH: ubiquinone oxidoreductase (complex I). Journal of Biological Chemistry 276 38345–38348. (https://doi.org/10.1074/jbc.C100444200)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ferenczy A 1998 Pathophysiology of adenomyosis. Human Reproduction Update 4 312–322. (https://doi.org/10.1093/humupd/4.4.312)

  • Gordts S, Grimbizis G & Campo R 2018 Symptoms and classification of uterine adenomyosis, including the place of hysteroscopy in diagnosis. Fertility and Sterility 109 380.e1–388. e1. (https://doi.org/10.1016/j.fertnstert.2018.01.006)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hammes A, Guo JK, Lutsch G, Leheste JR, Landrock D, Ziegler U, Gubler MC & Schedl A 2001 Two splice variants of the Wilms’ tumor 1 gene have distinct functions during sex determination and nephron formation. Cell 106 319–329. (https://doi.org/10.1016/s0092-8674(0100453-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Han Y, Song C, Zhang TT, Zhou QQ, Zhang XQ, Wang J, Xu BQ, Zhang XS, Liu XQ & Ying XY 2020 Wilms’ tumor 1 (WT1) promotes ovarian cancer progression by regulating E-cadherin and ERK1/2 signaling. Cell Cycle 19 2662–2675. (https://doi.org/10.1080/15384101.2020.1817666)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hao H, Liu J, Liu G, Guan D, Yang Y, Zhang X, Cao X & Liu Q 2012 Depletion of GRIM-19 accelerates hepatocellular carcinoma invasion via inducing EMT and loss of contact inhibition. Journal of Cellular Physiology 227 1212–1219. (https://doi.org/10.1002/jcp.24025)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hao M, Liu X & Guo SW 2020 Adenomyosis in mice resulting from mechanically or thermally induced endometrial-myometrial interface disruption and its possible prevention. Reproductive Biomedicine Online 41 925–942. (https://doi.org/10.1016/j.rbmo.2020.07.023)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hashimoto R 2003 Development of the human Müllerian duct in the sexually undifferentiated stage. Anatomical Record: Part A, Discoveries in Molecular, Cellular, and Evolutionary Biology 272 514–519. (https://doi.org/10.1002/ar.a.10061)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hosono S, Gross I, English MA, Hajra KM, Fearon ER & Licht JD 2000 E-cadherin is a WT1 target gene. Journal of Biological Chemistry 275 10943–10953. (https://doi.org/10.1074/jbc.275.15.10943)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jeon JY, Buelow DR, Garrison DA, Niu M, Eisenmann ED, Huang KM, Zavorka Thomas ME, Weber RH, Whatcott CJ & Warner SL et al.2020 TP-0903 is active in models of drug-resistant acute myeloid leukemia. JCI Insight 5 e140169. (https://doi.org/10.1172/jci.insight.140169)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D & Jaenisch R 1993 WT-1 is required for early kidney development. Cell 74 679–691. (https://doi.org/10.1016/0092-8674(9390515-r)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Li TS, Chen L, Wang SC, Yang YZ, Xu HJ, Gu HM, Zhao XJ, Dong P, Pan Y & Shang ZQ et al.2019 Magnesium isoglycyrrhizinate ameliorates fructose-induced podocyte apoptosis through downregulation of miR-193a to increase WT1. Biochemical Pharmacology 166 139–152. (https://doi.org/10.1016/j.bcp.2019.05.016)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Liu Y, Wang X, Wan L, Liu X, Yu H, Zhang D, Sun Y, Shi Y, Zhang L & Zhou H et al.2020 TIPE2 inhibits the migration and invasion of endometrial cells by targeting β-catenin to reverse epithelial-mesenchymal transition. Human Reproduction 35 1377–1390. (https://doi.org/10.1093/humrep/deaa062)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lu B, Chen Q, Zhang X & Cheng L 2016 Serous carcinoma arising from uterine adenomyosis/adenomyotic cyst of the cervical stump: a report of 3 cases. Diagnostic Pathology 11 46. (https://doi.org/10.1186/s13000-016-0496-0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Makrigiannakis A, Coukos G, Mantani A, Prokopakis P, Trew G, Margara R, Winston R & White J 2001 Expression of Wilms’ tumor suppressor gene (WT1) in human endometrium: regulation through decidual differentiation. Journal of Clinical Endocrinology and Metabolism 86 5964–5972. (https://doi.org/10.1210/jcem.86.12.8074)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Martínez-Estrada OM, Lettice LA, Essafi A, Guadix JA, Slight J, Velecela V, Hall E, Reichmann J, Devenney PS & Hohenstein P et al.2010 Wt1 is required for cardiovascular progenitor cell formation through transcriptional control of Snail and E-cadherin. Nature Genetics 42 89–93. (https://doi.org/10.1038/ng.494)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Matsuzaki S, Canis M, Darcha C, Déchelotte PJ, Pouly JL & Mage G 2006 Expression of WT1 is down-regulated in eutopic endometrium obtained during the midsecretory phase from patients with endometriosis. Fertility and Sterility 86 554–558. (https://doi.org/10.1016/j.fertnstert.2006.02.101)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Moore AW, Schedl A, McInnes L, Doyle M, Hecksher-Sorensen J & Hastie ND 1998 YAC transgenic analysis reveals Wilms’ tumour 1 gene activity in the proliferating coelomic epithelium, developing diaphragm and limb. Mechanisms of Development 79 169–184. (https://doi.org/10.1016/s0925-4773(9800188-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nallar SC & Kalvakolanu DV 2017 GRIM-19: a master regulator of cytokine induced tumor suppression, metastasis and energy metabolism. Cytokine and Growth Factor Reviews 33 1–18. (https://doi.org/10.1016/j.cytogfr.2016.09.001)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Niksic M, Slight J, Sanford JR, Caceres JF & Hastie ND 2004 The Wilms’ tumour protein (WT1) shuttles between nucleus and cytoplasm and is present in functional polysomes. Human Molecular Genetics 13 463–471. (https://doi.org/10.1093/hmg/ddh040)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Park J, Kim DH, Shah SR, Kim HN, Kshitiz, Kim P, Quiñones-Hinojosa A & Levchenko A 2019 Switch-like enhancement of epithelial-mesenchymal transition by YAP through feedback regulation of WT1 and Rho-family GTPases. Nature Communications 10 2797. (https://doi.org/10.1038/s41467-019-10729-5)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rauscher 3rd FJ, Morris JF, Tournay OE, Cook DM & Curran T 1990 Binding of the Wilms’ tumor locus zinc finger protein to the EGR-1 consensus sequence. Science 250 1259–1262. (https://doi.org/10.1126/science.2244209)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tamm-Rosenstein K, Simm J, Suhorutshenko M, Salumets A & Metsis M 2013 Changes in the transcriptome of the human endometrial Ishikawa cancer cell line induced by estrogen, progesterone, tamoxifen, and mifepristone (RU486) as detected by RNA-sequencing. PLoS ONE 8 e68907. (https://doi.org/10.1371/journal.pone.0068907)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tempest N, Maclean A & Hapangama DK 2018 Endometrial stem cell markers: current concepts and unresolved questions. International Journal of Molecular Sciences 19 1–26. (https://doi.org/10.3390/ijms19103240)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wang J, Deng X, Yang Y, Yang X, Kong B & Chao L 2016 Expression of GRIM-19 in adenomyosis and its possible role in pathogenesis. Fertility and Sterility 105 1093–1101. (https://doi.org/10.1016/j.fertnstert.2015.12.019)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wang BY, Yang Y, Deng XH, Ban YL & Chao L 2020 Interaction of M2 macrophages and endometrial cells induces downregulation of GRIM-19 in endometria of adenomyosis. Reproductive Biomedicine Online 41 790–800. (https://doi.org/10.1016/j.rbmo.2020.04.022)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yoo JY, Ku BJ, Kim TH, Il Ahn J, Ahn JY, Yang WS, Lim JM, Taketo MM, Shin JH & Jeong JW 2020 Beta-catenin activates TGF-beta-induced epithelial-mesenchymal transition in adenomyosis. Experimental and Molecular Medicine 52 1754–1765. (https://doi.org/10.1038/s12276-020-00514-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yu O, Schulze-Rath R, Grafton J, Hansen K, Scholes D & Reed SD 2020 Adenomyosis incidence, prevalence and treatment: United States population-based study 2006–2015. American Journal of Obstetrics and Gynecology 223 94.e1–94.e10. (https://doi.org/10.1016/j.ajog.2020.01.016)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang J, Chu D, Kawamura T, Tanaka K & He S 2019 GRIM-19 repressed hypoxia-induced invasion and EMT of colorectal cancer by repressing autophagy through inactivation of STAT3/HIF-1α signaling axis. Journal of Cellular Physiology 234 12800–12808. (https://doi.org/10.1002/jcp.27914)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang Y, Yan WT, Yang ZY, Li YL, Tan XN, Jiang J, Zhang Y & Qi XW 2020 The role of WT1 in breast cancer: clinical implications, biological effects and molecular mechanism. International Journal of Biological Sciences 16 1474–1480. (https://doi.org/10.7150/ijbs.39958)

    • PubMed
    • Search Google Scholar
    • Export Citation