The (pro)renin receptor and soluble (pro)renin receptor in choriocarcinoma

in Reproduction
Authors:
Saije K Morosin School of Biomedical Sciences and Pharmacy, Priority Research Centre for Reproductive Science, Pregnancy and Reproduction Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia

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Sarah J Delforce School of Biomedical Sciences and Pharmacy, Priority Research Centre for Reproductive Science, Pregnancy and Reproduction Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia

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Richard G S Kahl School of Biomedical Sciences and Pharmacy, Priority Research Centre for Reproductive Science, Pregnancy and Reproduction Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia

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Celine Corbisier de Meaultsart School of Biomedical Sciences and Pharmacy, Priority Research Centre for Reproductive Science, Pregnancy and Reproduction Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia

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Eugenie R Lumbers School of Biomedical Sciences and Pharmacy, Priority Research Centre for Reproductive Science, Pregnancy and Reproduction Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia

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Kirsty G Pringle School of Biomedical Sciences and Pharmacy, Priority Research Centre for Reproductive Science, Pregnancy and Reproduction Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia

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Correspondence should be addressed to K G Pringle; Email: kirsty.pringle@newcastle.edu.au
DOI:
https://doi.org/10.1530/REP-20-0650
Volume/Issue:
Volume 162: Issue 5
Page Range:
375–384
Article Type:
Research Article
Online Publication Date:
05 Oct 2021
Copyright:
© Society for Reproduction and Fertility 2021
Restricted access
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This study aimed to determine if the (pro)renin receptor (ATP6AP2) changes the cellular profile of choriocarcinomas from cytotrophoblast cells to terminally syncytialised cells and ascertain whether this impacts the invasive potential of choriocarcinoma cells. Additionally, we aimed to confirm that FURIN and/or site 1 protease (MBTPS1) cleave soluble ATP6AP2 (sATP6AP2) in BeWo choriocarcinoma cells and determine whether sATP6AP2 levels reflect the cellular profile of choriocarcinomas. BeWo choriocarcinoma cells were treated with ATP6AP2 siRNA, FURIN siRNA, DEC-RVKR-CMK (to inhibit FURIN activity), or PF 429242 (to inhibit MBTPS1 activity). Cells were also treated with forskolin, to induce syncytialisation, or vehicle and incubated for 48 h before collection of cells and supernatants. Syncytialisation was assessed by measuring hCG secretion (by ELISA) and E-cadherin protein levels (by immunoblot and immunocytochemistry). Cellular invasion was measured using the xCELLigence real-time cell analysis system and secreted sATP6AP2 levels measured by ELISA. Forskolin successfully induced syncytialisation and significantly increased both BeWo choriocarcinoma cell invasion (P < 0.0001) and sATP6AP2 levels (P = 0.02). Treatment with ATP6AP2 siRNA significantly inhibited syncytialisation (decreased hCG secretion (P = 0.005), the percent of nuclei in syncytia (P = 0.05)), forskolin-induced invasion (P = 0.046), and sATP6AP2 levels (P < 0.0001). FURIN siRNA and DEC-RVKR-CMK significantly decreased sATP6AP2 levels (both P < 0.0001). In conclusion, ATP6AP2 is important for syncytialisation of choriocarcinoma cells and thereby limits choriocarcinoma cell invasion. We postulate that sATP6AP2 could be used as a biomarker measuring the invasive potential of choriocarcinomas. Additionally, we confirmed that FURIN, not MBTPS1, cleaves sATP6AP2 in BeWo cells, but other proteases (inhibited by DEC-RVKR-CMK) may also be involved.

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

  • Bishop BN & Edemekong PF 2019 Choriocarcinoma. StatPearls Publishing.

  • Capecci J & Forgac M 2013 The function of vacuolar atpase (V-ATPase) a subunit isoforms in invasiveness of MCF10A and mcf10ca1a human breast cancer cells. Journal of Biological Chemistry 288 32731–32741. (https://doi.org/10.1074/jbc.M113.503771)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Costa MA 2016 Scrutinising the regulators of syncytialization and their expression inpregnancy-related conditions. Molecular and Cellular Endocrinology 420 180–193. (https://doi.org/10.1016/j.mce.2015.11.010)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cousin C, Bracquart D, Contrepas A, Corvol P, Muller L & Nguyen G 2009 Soluble form of the (pro)renin receptor generated by intracellular cleavage by furin is secreted in plasma. Hypertension 53 1077–1082. (https://doi.org/10.1161/HYPERTENSIONAHA.108.127258)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Coutifaris C, Kao LC, Sehdev HM, Chin U, Babalola GO, Blaschuk OW & Strauss 3rd JF 1991 E-cadherin expression during the differentiation of human trophoblasts. Development 113 767–777. (https://doi.org/10.1242/dev.113.3.767)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Couture F, D’Anjou F & Day R 2011 On the cutting edge of proprotein convertase pharmacology: from molecular concepts to clinical applications. Biomolecular Concepts 2 421–438. (https://doi.org/10.1515/bmc.2011.034)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Delforce SJ, Lumbers ER, Corbisier De Meaultsart C, Wang Y, Proietto A, Otton G, Scurry J, Verrills NM, Scott RJ & Pringle KG 2017 Expression of renin-angiotensin system (RAS) components in endometrial cancer. Endocrine Connections 6 9–19. (https://doi.org/10.1530/EC-16-0082)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dhillon AS, Hagan S, Rath O & Kolch W 2007 Map kinase signalling pathways in cancer. Oncogene 26 3279–3290. (https://doi.org/10.1038/sj.onc.1210421)

  • Endo M, Ohba K, Sato S, Yokota Y & Takahashi K 2020 Increased soluble (pro)renin receptor protein by autophagy inhibition in cultured cancer cells. Genes to Cells 25 483–497. (https://doi.org/10.1111/gtc.12776)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • GElifesciences 2014 Amershamtm imager 600 including: 600, 600 uv, 600 qc, 600 rgb operating instructions. In Gelifesciences. Sweden: GEhealthcare.

  • Guo YJ, Pan WW, Liu SB, Shen ZF, Xu Y & Hu LL 2020 ERK/MAPK signalling pathway and tumorigenesis. Experimental and Therapeutic Medicine 19 1997–2007. (https://doi.org/10.3892/etm.2020.8454)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gupta SK, Malhotra SS, Malik A, Verma S & Chaudhary P 2016 Cell signaling pathways involved during invasion and syncytialization of trophoblast cells. American Journal of Reproductive Immunology 75 361–371. (https://doi.org/10.1111/aji.12436)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Herr D, Rodewald M, Fraser HM, Hack G, Konrad R, Kreienberg R & Wulff C 2008 Regulation of endothelial proliferation by the renin-angiotensin system in human umbilical vein endothelial cells. Reproduction 136 125–130. (https://doi.org/10.1530/REP-07-0374)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hughes AL, Todd BL & Espenshade PJ 2005 SREBP pathway responds to sterols and functions as an oxygen sensor in fission yeast. Cell 120 831–842. (https://doi.org/10.1016/j.cell.2005.01.012)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Huppertz B 2019 Traditional and new routes of trophoblast invasion and their implications for pregnancy diseases. International Journal of Molecular Sciences 21 289. (https://doi.org/10.3390/ijms21010289)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ichihara A & Yatabe MS 2019 The (pro)renin receptor in health and disease. Nature Reviews: Nephrology 15 693–712. (https://doi.org/10.1038/s41581-019-0160-5)

  • James JL, Stone PR & Chamley LW 2005 Cytotrophoblast differentiation in the first trimester of pregnancy: evidence for separate progenitors of extravillous trophoblasts and syncytiotrophoblast. Reproduction 130 95–103. (https://doi.org/10.1530/rep.1.00723)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kinouchi K, Ichihara A, Sano M, Sun-Wada GH, Wada Y, Kurauchi-Mito A, Bokuda K, Narita T, Oshima Y & Sakoda M et al.2010 The (pro)renin receptor/ATP6AP2 is essential for vacuolar H+-ATPase assembly in murine cardiomyocytes. Circulation Research 107 30–34. (https://doi.org/10.1161/CIRCRESAHA.110.224667)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kulshrestha A, Katara GK, Ibrahim S, Pamarthy S, Jaiswal MK, Gilman Sachs A & Beaman KD 2015 Vacuolar ATPase ‘a2’ isoform exhibits distinct cell surface accumulation and modulates matrix metalloproteinase activity in ovarian cancer. Oncotarget 6 3797–3810. (https://doi.org/10.18632/oncotarget.2902)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lu X, Wang F, Xu C, Soodvilai S, Peng K, Su J, Zhao L, Yang KT, Feng Y & Zhou SF et al.2016 Soluble (pro)renin receptor via beta-catenin enhances urine concentration capability as a target of liver X receptor. PNAS 113 E1898–E1906. (https://doi.org/10.1073/pnas.1602397113)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Markman M & Kavanagh JJ 2011. Chapter 31. Gestational Trophoblastic Tumors. Kantarjian HM, Wolff RA, Koller CA (eds.) The MD Anderson Manual of Medical Oncology, 2e. New York, NY: The McGraw-Hill Companies.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Matsuura K, Jigami T, Taniue K, Morishita Y, Adachi S, Senda T, Nonaka A, Aburatani H, Nakamura T & Akiyama T 2011 Identification of a link between wnt/β-catenin signalling and the cell fusion pathway. Nature Communications 2 548. (https://doi.org/10.1038/ncomms1551)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mbikay M, Sirois F, Yao J, Seidah NG & Chrétien M 1997 Comparative analysis of expression of the proprotein convertases furin, PACE4, PC1 and PC2 in human lung tumours. British Journal of Cancer 75 1509–1514. (https://doi.org/10.1038/bjc.1997.258)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • McMahon S, Grondin F, Mcdonald PP, Richard DE & Dubois CM 2005 Hypoxia-enhanced expression of the proprotein convertase furin is mediated by hypoxia-inducible factor-1: impact on the bioactivation of proproteins. Journal of Biological Chemistry 280 6561–6569. (https://doi.org/10.1074/jbc.M413248200)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Morosin SK, Delforce SJ, Lumbers ER & Pringle KG 2020a The (pro)renin receptor (ATP6AP2) does not play a role in syncytialisation of term human primary trophoblast cells. Placenta 97 89–94. (https://doi.org/10.1016/j.placenta.2020.05.009)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Morosin SK, Delforce SJ, Lumbers ER & Pringle KG 2020b Cleavage of the soluble (pro)renin receptor (sATP6AP2) in the placenta. Placenta 101 49–56. (https://doi.org/10.1016/j.placenta.2020.08.019)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Morosin SK, Delforce SJ, Corbisier De Meaultsart C, Lumbers ER & Pringle KG 2021 Furin and placental syncytialisation: a cautionary tale. Cell Death and Disease 12 635. (https://doi.org/10.1038/s41419-021-03898-z)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Müller DN, Binger KJ & Riediger F 2012 Prorenin receptor regulates more than the renin-angiotensin system. Annals of Medicine 44 (Supplement 1) S43–S48. (https://doi.org/10.3109/07853890.2012.660496)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Olsen JJ, Pohl SÖ-G, Deshmukh A, Visweswaran M, Ward NC, Arfuso F, Agostino M & Dharmarajan A 2017 The role of wnt signalling in angiogenesis. Clinical Biochemist Reviews 38 131–142.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pai SG, Carneiro BA, Mota JM, Costa R, Leite CA, Barroso-Sousa R, Kaplan JB, Chae YK & Giles FJ 2017 Wnt/beta-catenin pathway: modulating anticancer immune response. Journal of Hematology and Oncology 10 101. (https://doi.org/10.1186/s13045-017-0471-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pollheimer J, Loregger T, Sonderegger S, Saleh L, Bauer S, Bilban M, Czerwenka K, Husslein P & Knöfler M 2006 Activation of the canonical wingless/T-cell factor signaling pathway promotes invasive differentiation of human trophoblast. American Journal of Pathology 168 1134–1147. (https://doi.org/10.2353/ajpath.2006.050686)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pringle KG, Tadros MA, Callister RJ & Lumbers ER 2011 The expression and localization of the human placental prorenin/renin-angiotensin system throughout pregnancy: roles in trophoblast invasion and angiogenesis? Placenta 32 956–962. (https://doi.org/10.1016/j.placenta.2011.09.020)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sanchez-Lopez E, Lopez AF, Esteban V, Yague S, Egido J, Ruiz-Ortega M & Alvarez-Arroyo MV 2005 Angiotensin II regulates vascular endothelial growth factor via hypoxia-inducible factor-1alpha induction and redox mechanisms in the kidney. Antioxidants and Redox Signaling 7 1275–1284. (https://doi.org/10.1089/ars.2005.7.1275)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Shibayama Y, Fujimori T, Nguyen G, Hirose T, Totsune K, Ichihara A, Kitada K, Nakano D, Kobori H & Kohno M et al.2015 (Pro)renin receptor is crucial for wnt/beta-catenin-dependent genesis of pancreatic ductal adenocarcinoma. Scientific Reports 5 8854. (https://doi.org/10.1038/srep08854)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Suda C, Yatabe J, Yatabe M, Yarita M & Ichihara A 2020 Soluble (pro)renin receptor increased by hypoxia maintains oxidative metabolism in trophoblasts. Journal of Molecular Endocrinology 64 145–154. (https://doi.org/10.1530/JME-19-0050)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wang Y & Zhao S 2010 Cell types of the placenta. In Vascular Biology of the Placenta. Eds Granger DN, Granger J. San Rafael (CA): Morgan & Claypool Life Sciences.

  • Wang Y, Pringle KG & Lumbers ER 2013 The effects of cyclic AMP, sex steroids and global hypomethylation on the expression of genes controlling the activity of the renin–angiotensin system in placental cell lines. Placenta 34 275–280. (https://doi.org/10.1016/j.placenta.2012.12.018)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wang J, Shibayama Y, Zhang A, Ohsaki H, Asano E, Suzuki Y, Kushida Y, Kobara H, Masaki T & Wang Z et al.2019 (Pro)renin receptor promotes colorectal cancer through the wnt/beta-catenin signalling pathway despite constitutive pathway component mutations. British Journal of Cancer 120 229–237. (https://doi.org/10.1038/s41416-018-0350-0)

    • PubMed
    • Search Google Scholar
    • Export Citation