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Deep Infiltrating Endometriosis and Endometrial Adenocarcinoma Express High Levels of Myostatin and Its Receptors Messenger RNAs

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Abstract

Myostatin is a growth factor member of the transforming growth factor β superfamily, which is known to play major roles in cell proliferation and differentiation. The present study investigated the messenger RNA (mRNA) expression of myostatin and myostatin receptors (activin receptor-like kinase 4 [ALK4], transforming growth factor (TGF)-β type I receptor kinase [ALK5] and activin receptor type IIB [ActRIIB]) in endometrium of healthy women during menstrual cycle as well as in benign (endometriosis, polyps) and malignant (endometrial adenocarcinoma) conditions. Endometrial specimens were collected by hysteroscopy, whereas endometriotic lesions were collected by laparoscopy, and adenocarcinomas were sampled after hysterectomy. Total RNA was extracted from tissue homogenates, and gene expression was assessed by quantitative real-time polymerase chain reaction. Myostatin and myostatin receptors mRNAs were expressed by healthy endometrium throughout the menstrual cycle, with no differences between the proliferative and secretory phase. The highest myostatin mRNA expression was found in patients with deep infiltrating endometriosis (DIE) and in endometrial carcinoma; expression was also found in ovarian endometrioma (OMA ) and endometrial polyps. Myostatin receptors mRNA expression was higher in DIE and adenocarcinomas compared to control endometrium. The expression of ALK5 and ActRIIB in OMA was higher than in controls, whereas polyps had an increased expression of ALK5 mRNA. In conclusion, the present data showed for the first time the expression of myostatin in healthy endometrium and a higher expression in endometriosis and endometrial cancer, suggesting myostatin involvement in human endometrial physiology and related pathologies.

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References

  1. Jones RL, Stoikos C, Findlay JK, Salamonsen LA. TGF-beta superfamily expression and actions in the endometrium and placenta. Reproduction. 2006;132(2):217–232.

    Article  CAS  PubMed  Google Scholar 

  2. Ciarmela P, Bloise E, Gray PC, et al. Activin-A and myostatin response and steroid regulation in human myometrium: disruption of their signalling in uterine fibroid. J Clin Endocrinol Metab. 2011;96(3):755–765.

    Article  CAS  PubMed  Google Scholar 

  3. Dela Cruz C, Reis FM. The role of TGFβ superfamily members in the pathophysiology of endometriosis. Gynecol Endocrinol. 2015; 31(7):511–515.

    Article  CAS  PubMed  Google Scholar 

  4. Wijayarathna R, de Kretser DM. Activins in reproductive biology and beyond. Hum Reprod Update. 2016;22(3):342–357.

    Article  CAS  PubMed  Google Scholar 

  5. Schuelke M, Wagner KR, Stolz LE, et al. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med. 2004;350(26):2682–2688.

    Article  CAS  PubMed  Google Scholar 

  6. McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature. 1997;387(6628):83–90.

    Article  CAS  PubMed  Google Scholar 

  7. Rodriguez J, Vernus B, Chelh I, et al. Myostatin and the skeletal muscle atrophy and hypertrophy signaling pathways. Cell Mol Life Sci. 2014;71(22):4361–4371.

    Article  CAS  PubMed  Google Scholar 

  8. Morissette MR, Cook SA, Foo S, et al. Myostatin regulates cardiomyocyte growth through modulation of Akt signaling. Circ Res. 2006;99(1):15–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Li N, Yang Q, Walker RG, Thompson TB, Du M, Rodgers BD. Myostatin attenuation in vivo reduces adiposity, but activates adipogenesis. Endocrinology. 2016;157(1):282–291.

    Article  CAS  PubMed  Google Scholar 

  10. Ciarmela P, Wiater E, Smith SM, Vale W. Presence, actions, and regulation of myostatin in rat uterus and myometrial cells. Endocrinology. 2009;150(2):906–914.

    Article  CAS  PubMed  Google Scholar 

  11. Islam MS, Catherino WH, Protic O, et al. Role of activin-A and myostatin and their signaling pathway in human myometrial and leiomyoma cell function. J Clin Endocrinol Metab. 2014;99(5): E775–E785.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mitchell MD, Osepchook CC, Leung KC, McMahon CD, Bass JJ. Myostatin is a human placental product that regulates glucose uptake. J Clin Endocrinol Metab. 2006;91(4):1434–1437.

    Article  CAS  PubMed  Google Scholar 

  13. Peiris HN, Mitchell MD. The expression and potential functions of placental myostatin. Placenta. 2012;33(11):902–927.

    Article  CAS  PubMed  Google Scholar 

  14. Kubota K, Sato F, Aramaki S, Soh T, Yamauchi N, Hattori MA. Ubiquitous expression of myostatin in chicken embryonic tissues: its high expression in testis and ovary. Comp Biochem Physiol A Mol Integr Physiol. 2007;148(3):550–555.

    Article  PubMed  CAS  Google Scholar 

  15. Florio P, Rossi M, Viganò P, et al. Interleukin 1beta and progesterone stimulate activin a expression and secretion from cultured human endometrial stromal cells. Reprod Sci. 2007;14(1):29–36.

    Article  CAS  PubMed  Google Scholar 

  16. Ferreira MC, Witz CA, Hammes LS, et al. Activin A increases invasiveness of endometrial cells in an in vitro model of human peritoneum. Mol Hum Reprod. 2008;14(5):301–307.

    Article  CAS  PubMed  Google Scholar 

  17. Torres PB, Florio P, Galleri L, Reis FM, Borges LE, Petraglia F. Activin A, activin receptor type II, nodal, and cripto mRNA are expressed by eutopic and ectopic endometrium in women with ovarian endometriosis. Reprod Sci. 2009;16(8):727–733.

    Article  CAS  PubMed  Google Scholar 

  18. Rocha AL, Carrarelli P, Novembri R, et al. Altered expression of activin, cripto, and follistatin in the endometrium of women with endometrioma. Fertil Steril. 2011;95(7):2241–2246.

    Article  CAS  PubMed  Google Scholar 

  19. Wakefield LM, Hill CS. Beyond TGFb: roles of other TGFb superfamily members in cancer. Nat Rev Cancer. 2013;13(5): 328–341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rebbapragada A, Benchabane H, Wrana JL, Celeste AJ, Attisano L. Myostatin signals through a transforming growth factor betalike signaling pathway to block adipogenesis. Mol Cell Biol. 2003;23(20):7230–7242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Derynck R, Zhang Y, Feng XH. Smads: transcriptional activators of TGF-beta responses. Cell. 1998; 11;95(6):737–740.

    Article  CAS  PubMed  Google Scholar 

  22. Ciarmela P, Islam MS, Reis FM, et al. Growth factors and myometrium: biological effects in uterine fibroid and possible clinical implications. Hum Reprod Update. 2011;17(6):772–790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tsigkou A, Reis FM, Ciarmela P, et al. Expression levels of myostatin and matrix metalloproteinase 14 mRNAs in uterine leiomyoma are correlated with dysmenorrhea. Reprod Sci. 2015;22(12):1597–1602.

    Article  CAS  PubMed  Google Scholar 

  24. Carrarelli P, Yen CF, Arcuri F, et al. Myostatin, follistatin and activin type II receptors are highly expressed in adenomyosis. Fertil Steril. 2015;104(3):744–752.e1.

    Article  CAS  PubMed  Google Scholar 

  25. Zhao Y, Park S, Bagchi MK, Taylor RN, Katzenellenbogen BS. The coregulator, repressor of estrogen receptor activity (REA), is a crucial regulator of the timing and magnitude of uterine decidualization. Endocrinology. 2013;154(3):1349–1360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Stoikos CJ, Harrison CA, Salamonsen LA, Dimitriadis E. A distinct cohort of the TGFbeta superfamily members expressed in human endometrium regulate decidualization. Hum Reprod. 2008;23(6):1447–1456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Florio P, Severi FM, Luisi S, et al. Endometrial expression and secretion of activin A but not follistatin, increase in the secretory phase of the menstrual cycle. J Soc Gynecol Investig. 2003;10(4):237–243.

    Article  CAS  PubMed  Google Scholar 

  28. Ferreira MC, Cavallo IK, Florio P, Petraglia F, Reis FM. Activin betaA subunit, follistatin and follistatin-like 3 are expressed in the endometrium of ovariectomized rats and regulated by estrogen replacement. J Mol Histol. 2008;39(5):535–541.

    Article  CAS  PubMed  Google Scholar 

  29. Ciarmela P, Wiater E, Vale W. Activin-A in myometrium: characterization of the actions on myometrial cells. Endocrinology. 2008;149(5):2506–2516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mabuchi Y, Yamoto M, Minami S, Umesaki N. Immunohistochemical localization of inhibin and activin subunits, activin receptors and Smads in ovarian endometriosis. Int J Mol Med. 2010;25(1):17–23.

    PubMed  Google Scholar 

  31. Tamura M, Fukaya T, Enomoto A, Murakami T, Uehara S, Yajima A. Transforming growth factor-beta isoforms and receptors in endometriotic cysts of the human ovary. Am J Reprod Immunol. 1999;42(3):160–167.

    Article  CAS  PubMed  Google Scholar 

  32. Florio P, Luisi S, Viganò P, et al. Healthy women and patients with endometriosis show high concentrations of inhibin A inhibin B and activin A in peritoneal fluid throughout the menstrual cycle. Hum Reprod. 1998;13(9):2606–2611.

    Article  CAS  PubMed  Google Scholar 

  33. Reis FM, Di Blasio AM, Florio P, Ambrosini G, Di Loreto C, Petraglia F. Evidence for local production of inhibin A and activin A in patients with ovarian endometriosis. Fertil Steril. 2001; 75(2):367–373.

    Article  CAS  PubMed  Google Scholar 

  34. Rombauts L, Donoghue J, Cann L, Jones RL, Healy DL. Activin-A secretion is increased in the eutopic endometriumfromwomen with endometriosis. Aust N Z J Obstet Gynaecol. 2006;46(2):148–153.

    Article  PubMed  Google Scholar 

  35. Rocha AL, Carrarelli P, Novembri R, et al. Activin A stimulates interleukin 8 and vascular endothelial growth factor release from cultured human endometrial stromal cells: possible implications for the pathogenesis of endometriosis. Reprod Sci. 2012;19(8): 832–838.

    Article  PubMed  CAS  Google Scholar 

  36. Torres PB, Florio P, Ferreira MC, Torricelli M, Reis FM, Petraglia F. Deranged expression of follistatin and follistatin-like protein in women with ovarian endometriosis. Fertil Steril. 2007; 88(1):200–205.

    Article  CAS  PubMed  Google Scholar 

  37. Mylonas I, Makovitzky J, Fernow A, et al. Expression of the inhibin/activin subunits alpha (alpha), beta-A (betaA) and beta- B (betaB) in benign human endometrial polyps and tamoxifenassociated polyps. Arch Gynecol Obstet. 2005;272(1):59–66.

    Article  CAS  PubMed  Google Scholar 

  38. Xuebing P, TinChiu L, Enlan X, Jing L, Xiaowu H. Is endometrial polyp formation associated with increased expression of vascular endothelial growth factor and transforming growth factor-beta1? Eur J Obstet Gynecol Reprod Biol. 2011;159(1):198–203.

    Article  PubMed  CAS  Google Scholar 

  39. Florio P, Ciarmela P, Reis FM, et al. Inhibin alpha-subunit and the inhibin coreceptor betaglycan are downregulated in endometrial carcinoma. Eur J Endocrinol. 2005;152(2):277–284.

    Article  CAS  PubMed  Google Scholar 

  40. Mylonas I, Makovitzky J, Hoeing A, et al. Inhibin/activin subunits beta-A (-betaA) and beta-B (-betaB) are differentially localised in normal, hyperplastic and malignant human endometrial tissue. Acta Histochem. 2006;108(1):1–11.

    Article  CAS  PubMed  Google Scholar 

  41. Worbs S, Shabani N, Mayr D, et al. Expression of the inhibin/ activin subunits (-alpha, -betaA and -betaB) in normal and carcinogenic endometrial tissue: possible immunohistochemical differentiation markers. Oncol Rep. 2007;17(1):97–104.

    CAS  PubMed  Google Scholar 

  42. Ciarmela P, Florio P, Sigurdardottir M, et al. Follistatin-related gene expression, but not follistatin expression, is decreased in human endometrial adenocarcinoma. Eur J Endocrinol. 2004; 151(2):251–257.

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Molecular and Developmental Medicine, Obstetrics and Gynecology, University of Siena, “S Maria alle Scotte”, Viale Bracci, 53100, Siena, Italy

    Patrizia Carrarelli PhD, Lucia Funghi PhD, Gabriele Centini MD, Silvia Vannuccini MD & Felice Petraglia MD

  2. Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy

    Pasquapina Ciarmela PhD

  3. Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy

    Pasquapina Ciarmela PhD

  4. Division of Human Reproduction, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

    Fernando M. Reis MD & Cynthia Dela Cruz PhD

  5. Division of Obstetrics and Gynecology, Careggi University Hospital, Florence, Italy

    Alberto Mattei MD

Authors
  1. Patrizia Carrarelli PhD
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  2. Lucia Funghi PhD
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  3. Pasquapina Ciarmela PhD
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  4. Gabriele Centini MD
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  5. Fernando M. Reis MD
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  6. Cynthia Dela Cruz PhD
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  7. Alberto Mattei MD
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  9. Felice Petraglia MD
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Corresponding author

Correspondence to Felice Petraglia MD.

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Carrarelli, P., Funghi, L., Ciarmela, P. et al. Deep Infiltrating Endometriosis and Endometrial Adenocarcinoma Express High Levels of Myostatin and Its Receptors Messenger RNAs. Reprod. Sci. 24, 1577–1582 (2017). https://doi.org/10.1177/1933719117698579

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