miR-126-3p contributes to parathyroid tumor angiogenesis

in Endocrine-Related Cancer
View More View Less
  • 1 Laboratory of Experimental Endocrinology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
  • 2 Department of Pathophysiology and Organ Transplantation, University of Milan, Milan, Italy
  • 3 Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
  • 4 Endocrine Surgery, IRCCS Ospedale San Raffaele, Milan, Italy
  • 5 Endocrine Surgery, IRCCS Istituto Auxologico Italiano, Milan, Italy
  • 6 Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
  • 7 Endocrinology and Diabetology Service, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy

Correspondence should be addressed to S Corbetta: sabrina.corbetta@unimi.it

*(V Vaira and S Corbetta contributed equally to this work)

Restricted access

Tumors of the parathyroid glands are highly vascularized and display a microRNA (miRNA) profile divergent from normal parathyroid glands (PaNs). Angiogenic miRNAs, namely miR-126-3p, miR-126-5p, and miR-296-5p, have been found downregulated in parathyroid tumors. Here, we show that miR-126-3p expression levels are reduced in parathyroid adenomas (PAds; n = 12) compared with PaNs (n = 4). In situ hybridization (ISH) of miR-126-3p and miR-296-5p in 10 PAds show that miR-126-3p is expressed by endothelial cells lining the walls of great vessels and by cells within the thin stroma surrounding acinar structures. At variance, miR-296-5p was detectable in most PAd epithelial cells. Combining ISH for miR-126-3p with immunohistochemistry for the endothelial and mesenchymal markers CD34, CD31 and α-smooth muscle actin (αSMA), we could identify that miR-126-3p is localized in the αSMA-positive thin stroma. Further, miR-126-3p-expressing cells are enriched in the CD34-positive stromal cells surrounding epithelial cell acinar structures, a cellular pattern consistent with tumor-associated myofibroblasts (TAMs). In line with this, CD34-positive cells, sorted by FACS from PAds tissues, express miR-126-3p at higher levels than CD34-negative cells, suggesting that miR-126-3p downregulation promotes the endothelial-to-αSMA+ mesenchymal transition. In human mesenchymal stem cells derived from bone marrow (hBM-MSCs), a model of TAMs, the co-culture with PAds-derived cells for 5 days decreases miR-126-3p, while it increases VEGFA expression. At variance, adrenomedullin (ADM) expression is unaffected. Finally, overexpression of the miR-126-3p mimic in both hBM-MSCs and PAds-derived explants downregulates VEGFA expression levels. In conclusion, miR-126-3p is expressed by both endothelial cells and TAMs in PAds, and its downregulation promotes neoangiogenesis, possibly through VEGFA overexpression.

Supplementary Materials

    • Supplementary Figure 1
    • Supplementary Figure 2
    • Supplementary Figure 3
    • Supplementary Table 1. Clinical and biochemical data of the series of 13 parathyroid adenomas analyzed for the miR-126-3p expression.

 

Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 629 629 37
Full Text Views 72 72 2
PDF Downloads 31 31 3
  • Arneth B 2019 Tumor microenvironment. Medicina 56 15. (https://doi.org/10.3390/medicina56010015)

  • Baeriswyl V & Christofori G 2009 The angiogenic switch in carcinogenesis. Seminars in Cancer Biology 19 329337. (https://doi.org/10.1016/j.semcancer.2009.05.003)

    • Search Google Scholar
    • Export Citation
  • Benyahia Z, Dussault N, Cayol M, Sigaud R, Berenguer-Daizé C, Delfino C, Tounsi A, Garcia S, Martin PM & Mabrouk K et al. 2017 Stromal fibroblasts present in breast carcinomas promote tumor growth and angiogenesis through adrenomedullin secretion. Oncotarget 8 1574415762. (https://doi.org/10.18632/oncotarget.14999)

    • Search Google Scholar
    • Export Citation
  • Chen H, Li L, Wang S, Lei Y, Ge Q, Lv N, Zhou X & Chen C 2014 Reduced miR-126 expression facilitates angiogenesis of gastric cancer through its regulation on VEGF-A. Oncotarget 5 1187311885. (https://doi.org/10.18632/oncotarget.2662)

    • Search Google Scholar
    • Export Citation
  • Cinti S & Sbarbati A 1995 Ultrastructure of human parathyroid cells in health and disease. Microscopy Research and Technique 32 164179. (https://doi.org/10.1002/jemt.1070320210)

    • Search Google Scholar
    • Export Citation
  • Corbetta S, Belicchi M, Pisati F, Meregalli M, Eller-Vainicher C, Vicentini L, Beck-Peccoz P, Spada A & Torrente Y 2009 Expression of parathyroid specific genes in vascular endothelial progenitors of normal and tumoral parathyroid cells. American Journal of Pathology 175 12001207. (https://doi.org/10.2353/ajpath.2009.080979)

    • Search Google Scholar
    • Export Citation
  • Corbetta S, Vaira V, Guarnieri V, Scillitani A, Eller-Vainicher C, Ferrero S, Vicentini L, Chiodini I, Bisceglia M & Beck-Peccoz P et al. 2010 Differential expression of microRNAs in human parathyroid carcinomas compared with normal parathyroid tissue. Endocrine-Related Cancer 1 7 135146. (https://doi.org/10.1677/ERC-09-0134)

    • Search Google Scholar
    • Export Citation
  • Ebrahimi F, Gopalan V, Smith RA & Lam AK 2014 miR-126 in human cancers: clinical roles and current perspectives. Experimental and Molecular Pathology 96 98107. (https://doi.org/10.1016/j.yexmp.2013.12.004)

    • Search Google Scholar
    • Export Citation
  • Ferrara N 2009 Vascular endothelial growth factor. Arteriosclerosis, Thrombosis, and Vascular Biology 29 789791. (https://doi.org/10.1161/ATVBAHA.108.179663)

    • Search Google Scholar
    • Export Citation
  • Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Whythe JD, Ivey KN, Bruneau BG, Stainier DYR & Srivastava D 2008 miR-126 regulates angiogenic signaling and vascular integrity. Developmental Cell 15 272284. (https://doi.org/10.1016/j.devcel.2008.07.008)

    • Search Google Scholar
    • Export Citation
  • Garcia de la Torre N, Buley I, Wass JAH, Hackson DG & Turner HE 2004 Angiogenesis and lymphangiogenesis in parathyroid proliferative lesions. Journal of Clinical Endocrinology and Metabolism 89 28902896. (https://doi.org/10.1210/jc.2003-031651)

    • Search Google Scholar
    • Export Citation
  • Hanahan D & Weinberg RA 2011 Hallmarks of cancer: the next generation. Cell 144 646674. (https://doi.org/10.1016/j.cell.2011.02.013)

  • Hong Z, Hong C, Ma B, Wang Q, Zhang X, Li L, Wang C & Chen D 2019 MicroRNA-126-3p inhibits the proliferation, migration, invasion, and angiogenesis of triple-negative breast cancer cells by targeting RGS3. Oncology Reports 42 15691579. (https://doi.org/10.3892/or.2019.7251)

    • Search Google Scholar
    • Export Citation
  • Hu Y, Zhang X, Cui M, Su Z, Wang M, Liao Q & Zhao Y 2018 Verification of candidate microRNA markers for parathyroid carcinoma. Endocrine 60 246254. (https://doi.org/10.1007/s12020-018-1551-2)

    • Search Google Scholar
    • Export Citation
  • Huang TH & Chu TY 2014 Repression of miR-126 and up-regulation of adrenomedullin in the stromal endothelium by cancer-stromal crosstalks confers angiogenesis of cervical cancer. Oncogene 33 36363647. (https://doi.org/10.1038/onc.2013.335)

    • Search Google Scholar
    • Export Citation
  • Kong F, Li L, Du Y, Zhu H, Li Z & Kong X 2018 Exosomal adrenomedullin derived from cancer-associated fibroblasts promotes lipolysis in adipose tissue. Gut 67 22262227. (https://doi.org/10.1136/gutjnl-2017-315778)

    • Search Google Scholar
    • Export Citation
  • Lecarpentier Y, Schussler O, Sakic A, Rincon-Garriz JM, Soulie P, Bochaton-Piallat ML & Kindler V 2018 Human bone marrow contains mesenchymal stromal stem cells that differentiate in vitro into contractile myofibroblasts controlling T lymphocyte proliferation. Stem Cells International 2018 6134787. (https://doi.org/10.1155/2018/6134787)

    • Search Google Scholar
    • Export Citation
  • Mathiyalaga P, Liang Y, Kim D, Misener S, Thorne T, Kamide CE, Klyachko E, Losordo DW, Hajjar RJ & Sahoo S 2017 Angiogenic mechanisms of human CD34+ stem cell exosomes in the repair of ischemic hindlimb. Circulation Research 120 14661476. (https://doi.org/10.1161/CIRCRESAHA.116.310557)

    • Search Google Scholar
    • Export Citation
  • McGregor DH, Lotuaco LG, Rao MS & Chu LL 1978 Functioning oxyphil adenoma of parathyroid gland: an ultrastructural and biochemical study. American Journal of Pathology 92 691711.

    • Search Google Scholar
    • Export Citation
  • Mishra PJ, Mishra PJ, Humeniuk R, Medina DJ, Alexe G, Mesirov JP, Ganesan S, Glod JW & Benerjee D 2008 Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Research 68 43314339. (https://doi.org/10.1158/0008-5472.CAN-08-0943)

    • Search Google Scholar
    • Export Citation
  • Qu Q, Bing W, Meng X, Xi J, Bai X, Liu Q, Guo Y, Zhao X & Bi Y 2017 Upregulation of miR-126-3p promotes human saphenous vein endothelial cell proliferation in vitro and prevents vein graft neointimal formation ex vivo and in vivo. Oncotarget 8 106790106806. (https://doi.org/10.18632/oncotarget.22365)

    • Search Google Scholar
    • Export Citation
  • Rahbari R, Holloway AK, He M, Khanafshar E, Clark OH & Kebebew E 2011 Identification of differentially expressed microRNA in parathyroid tumors. Annals of Surgical Oncology 18 11581165. (https://doi.org/10.1245/s10434-010-1359-7)

    • Search Google Scholar
    • Export Citation
  • Ritter CS, Haughey BH, Miller B & Brown AJ 2012 Differential gene expression by oxyphil and chief cells of human parathyroid glands. Journal of Clinical Endocrinology and Metabolism 97 E1499E1505. (https://doi.org/10.1210/jc.2011-3366)

    • Search Google Scholar
    • Export Citation
  • Saponaro F, Cetani F, Repaci A, Pagotto U, Cipriani C, Pepe J, Minisola S, Cipri C, Vescini F & Scillitani A et al. 2018 Clinical presentation and management of patients with primary hyperparathyroidism in Italy. Journal of Endocrinological Investigation 41 13391348. (https://doi.org/10.1007/s40618-018-0879-z)

    • Search Google Scholar
    • Export Citation
  • Savi F, Forno I, Faversani A, Luciani A, Caldiera S, Gatti S, Foa P, Ricca D, Bulfamante G & Vaira V et al. 2014 miR-296/scribble axis is deregulated in human breast cancer and miR-296 restoration reduces tumour growth in vivo. Clinical Science 127 233242. (https://doi.org/10.1042/CS20130580)

    • Search Google Scholar
    • Export Citation
  • Spaeth EL, Dembiski JL, Sasser AK, Watson K, Klopp A, Hall B, Andreeff M & Marini F 2009 Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS ONE 4 e4992, 1–11. (https://doi.org/10.1371/journal.pone.0004992)

    • Search Google Scholar
    • Export Citation
  • Vaira V, Faversani A, Dohi T, Montorsi M, Augello C, Gatti S, Coggi G, Altieri DC & Bosari S 2012 miR-296 regulation of a cell polarity-cell plasticity module controls tumor progression. Oncogene 31 2738. (https://doi.org/10.1038/onc.2011.209)

    • Search Google Scholar
    • Export Citation
  • Verdelli C, Avagliano L, Creo P, Guarnieri V, Scillitani A, Vicentini L, Steffano GB, Beretta E, Soldati L & Costa E et al. 2015a Tumour-associated fibroblasts contribute to neoangiogenesis in human parathyroid neoplasia. Endocrine-Related Cancer 22 8798. (https://doi.org/10.1530/ERC-14-0161)

    • Search Google Scholar
    • Export Citation
  • Verdelli C, Forno I, Vaira V & Corbetta S 2015b MicroRNA deregulation in parathyroid tumours suggests an embryonic signature. Journal of Endocrinological Investigation 38 383388. (https://doi.org/10.1007/s40618-014-0234-y)

    • Search Google Scholar
    • Export Citation
  • Verdelli C, Forno I, Morotti A, Creo P, Guarnieri V, Scillitani A, Cetani F, Vicentini L, Balza G & Beretta E et al. 2018 The aberrantly expressed miR-372 partly impairs sensitivity to apoptosis in parathyroid tumor cells. Endocrine-Related Cancer 25 761771. (https://doi.org/10.1530/ERC-17-0204)

    • Search Google Scholar
    • Export Citation
  • Verdelli C, Vaira V & Corbetta S 2020 Parathyroid tumor microenvironment. Advances in Experimental Medicine and Biology 1226 3750. (https://doi.org/10.1007/978-3-030-36214-0_3)

    • Search Google Scholar
    • Export Citation
  • Viacava P, Bocci G, Fanelli G, Cetani F, Marcocci C, Bevilacqua G & Naccarato AG 2006 Microvessel density in human normal and neoplastic parathyroids. Endocrine Pathology 17 175181. (https://doi.org/10.1385/EP:17:2:175)

    • Search Google Scholar
    • Export Citation
  • Wen Q, Zhao J, Bai L, Wang T, Zhang H & Ma Q 2015 miR-126 inhibits papillary thyroid carcinoma growth by targeting LRP6. Oncology Reports 34 22022210. (https://doi.org/10.3892/or.2015.4165)

    • Search Google Scholar
    • Export Citation
  • Würdinger T, Tannous BA, Saydam O, Skog J, Grau S, Soutschek J, Weissleder R, Breakefield XO & Krichevsky AM 2008 miR-296 regulates growth factor receptor overexpression in angiogenic endothelial cells. Cancer Cell 14 382393. (https://doi.org/10.1016/j.ccr.2008.10.005)

    • Search Google Scholar
    • Export Citation
  • Xi T, Jin F, Zhu Y, Wang J, Tang L, Wang Y, Liebeskind DS & He Z 2017 MicroRNA-126-3p attenuates blood-brain barrier disruption, cerebral hemorrhage and neuronal injury following intracerebral hemorrhage by regulating PIK3R2 and Akt. Biochemical and Biophysical Research Communications 494 144151. (https://doi.org/10.1016/j.bbrc.2017.10.064)

    • Search Google Scholar
    • Export Citation
  • Yang N, Zhu S, Lv X, Qiao Y, Liu YJ & Chen J 2018 MicroRNAs: pleiotropic regulators in the tumor microenvironment. Frontiers in Immunology 9 2491. (https://doi.org/10.3389/fimmu.2018.02491)

    • Search Google Scholar
    • Export Citation
  • Zhang J, Zhang Z, Zhang DY, Zhu J, Zhang T & Wang C 2013 MicroRNA 126 inhibits the transition of endothelial progenitor cells to mesenchymal cells via the PIK3R2-PI3K/Akt signalling pathway. PLoS ONE 8 e83294. (https://doi.org/10.1371/journal.pone.0083294)

    • Search Google Scholar
    • Export Citation
  • Zhu N, Zhand D, Xie H, Zhou Z, Chen H, Hu T, Bai Y, Shen Y, Yuan W & Jing Q et al. 2011 Endothelial-specific intron-derived miR-126 is down-regulated in human breast cancer and targets both VEGFA and PIK3R2. Molecular and Cellular Biochemistry 351 157164. (https://doi.org/10.1007/s11010-011-0723-7)

    • Search Google Scholar
    • Export Citation