Vol 59, No 2 (2021)
Original paper
Published online: 2021-04-09

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Immunohistochemical analysis of ghrelin expression in various types of adrenal tumors

Hanna Komarowska1, Agnieszka Malinska2, Zhanat Komekbai3, Barbara Brominska1, Katarzyna Bednarek-Rajewska4, Marek Ruchala1, Marcin Rucinski2
Pubmed: 33834452
Folia Histochem Cytobiol 2021;59(2):86-94.

Abstract

Introduction. Ghrelin, originally isolated from the endocrine cells of the gastric mucosa, is also expressed in many peripheral tissues, including normal adrenals and adrenocortical tumors. It was shown that ghrelin stimulates proliferation and inhibits apoptosis of adrenocortical cells. In the current study, we compared ghrelin expression at the protein level in various adrenal tumors. We analyzed whether immunoreactive ghrelin could be considered as a potential marker for different types of adrenal tumors.

Material and methods. Study was carried out on 200 adrenal specimens arranged on microscope slide in tissue microarray format. We performed standardized immunohistochemical reactions with semiquantitative reaction intensity measurements.

Results. At the protein level, the expression of ghrelin was significantly reduced in adrenocortical adenocarcinoma in relation to the control group and pheochromocytoma as well as cancer-adjacent normal adrenal tissue. In contrast, a relatively high ghrelin expression was found in pheochromocytoma compared to all analyzed groups, with the exception of cancer-adjacent normal adrenal tissue.

Conclusions. The ghrelin expression profile at the protein level may be associated with the type of adrenal tumor. In this context, our results suggest that adrenal immunoreactive ghrelin may be considered as a sensitive and specific marker for differentiating adrenocortical carcinoma from adrenocortical adenoma and pheochromocytoma.

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References

  1. Dietrich CF, Correas JM, Dong Yi, et al. WFUMB position paper on the management incidental findings: adrenal incidentaloma. Ultrasonography. 2020; 39(1): 11–21.
  2. Lenders JWM, Eisenhofer G. Update on Modern Management of Pheochromocytoma and Paraganglioma. Endocrinol Metab (Seoul). 2017; 32(2): 152–161.
  3. Fassnacht M, Dekkers O, Else T, et al. European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2018; 179(4): G1–G46.
  4. Aubert S, Wacrenier A, Leroy X, et al. Weiss system revisited: a clinicopathologic and immunohistochemical study of 49 adrenocortical tumors. Am J Surg Pathol. 2002; 26(12): 1612–1619.
  5. Duregon E, Volante M, Bollito E, et al. Pitfalls in the diagnosis of adrenocortical tumors: a lesson from 300 consultation cases. Hum Pathol. 2015; 46(12): 1799–1807.
  6. Komarowska H, Bednarek-Rajewska K, Kański M, et al. Epithelioid angiomyolipoma mimicking adrenal cortical carcinoma: A diagnostic pitfall. Oncol Lett. 2015; 10(4): 2130–2134.
  7. Komarowska H, Bromińska B, Janicka-Jedyńska M, et al. Adrenal Incidentaloma: Nothing Is Ever as It Seems. Am J Med. 2020; 133(9): 1048–1050.
  8. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999; 402(6762): 656–660.
  9. Ueberberg B, Unger N, Saeger W, et al. Expression of ghrelin and its receptor in human tissues. Horm Metab Res. 2009; 41(11): 814–821.
  10. Raghay K, García-Caballero T, Bravo S, et al. Ghrelin localization in the medulla of rat and human adrenal gland and in pheochromocytomas. Histol Histopathol. 2008; 23(1): 57–65.
  11. Ghelardoni S, Carnicelli V, Frascarelli S, et al. Ghrelin tissue distribution: comparison between gene and protein expression. J Endocrinol Invest. 2006; 29(2): 115–121.
  12. Komarowska H, Waśko R, Iwanik K, et al. Ghrelin ovarian cell expression in patients with polycystic ovary syndrome: an immunohistochemical evaluation. Horm Metab Res. 2006; 38(12): 783–788.
  13. Gnanapavan S, Kola B, Bustin SA, et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab. 2002; 87(6): 2988.
  14. Andrusiewicz M, Komarowska H, Skibińska I, et al. Expression of ghrelin and ghrelin functional receptor GHSR1a in human pituitary adenomas. Pol Arch Intern Med. 2017; 127(3): 163–169.
  15. Komarowska H, Jaskula M, Stangierski A, et al. Influence of ghrelin on energy balance and endocrine physiology. Neuro Endocrinol Lett. 2012; 33(8): 749–756.
  16. Akalu Y, Molla MD, Dessie G, et al. Physiological Effect of Ghrelin on Body Systems. Int J Endocrinol. 2020; 2020: 1385138.
  17. Tokudome T, Otani K, Miyazato M, et al. Ghrelin and the heart. Peptides. 2019; 111: 42–46.
  18. Angel CZ, Iguacel I, Mullee A, et al. Appetite-regulating hormones-leptin, adiponectin and ghrelin-and the development of prostate cancer: a systematic review and exploratory meta-analysis. Prostate Cancer Prostatic Dis. 2020; 23(1): 11–23.
  19. Carraro G, Albertin G, Abudukerimu A, et al. Growth hormone secretagogue receptor subtypes 1a and 1b are expressed in the human adrenal cortex. Int J Mol Med. 2004; 13(2): 295–298.
  20. Andreis P, Malendowicz L, Trejter M, et al. Ghrelin and growth hormone secretagogue receptor are expressed in the rat adrenal cortex: evidence that ghrelin stimulates the growth, but not the secretory activity of adrenal cells. FEBS Letters. 2003; 536(1-3): 173–179.
  21. Mazzocchi G, Neri G, Rucinski M, et al. Ghrelin enhances the growth of cultured human adrenal zona glomerulosa cells by exerting MAPK-mediated proliferogenic and antiapoptotic effects. Peptides. 2004; 25(8): 1269–1277.
  22. Delhanty PJD, van Koetsveld PM, Gauna C, et al. Ghrelin and its unacylated isoform stimulate the growth of adrenocortical tumor cells via an anti-apoptotic pathway. Am J Physiol Endocrinol Metab. 2007; 293(1): E302–E309.
  23. Ueberberg B, Unger N, Sheu SY, et al. Differential expression of ghrelin and its receptor (GHS-R1a) in various adrenal tumors and normal adrenal gland. Horm Metab Res. 2008; 40(3): 181–188.
  24. Hosoda H, Kojima M, Matsuo H, et al. Purification and characterization of rat des-Gln14-Ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor. J Biol Chem. 2000; 275(29): 21995–22000.
  25. Seim I, Jeffery PL, Thomas PB, et al. Multi-species sequence comparison reveals conservation of ghrelin gene-derived splice variants encoding a truncated ghrelin peptide. Endocrine. 2016; 52(3): 609–617.
  26. Robin X, Turck N, Hainard A, et al. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics. 2011; 12: 77.
  27. Barzon L, Pacenti M, Masi G, et al. Loss of growth hormone secretagogue receptor 1a and overexpression of type 1b receptor transcripts in human adrenocortical tumors. Oncology. 2005; 68(4-6): 414–421.
  28. Komarowska H, Rucinski M, Tyczewska M, et al. Ghrelin as a potential molecular marker of adrenal carcinogenesis: In vivo and in vitro evidence. Clin Endocrinol (Oxf). 2018; 89(1): 36–45.
  29. Dossus L, McKay JD, Canzian F, et al. Polymorphisms of genes coding for ghrelin and its receptor in relation to anthropometry, circulating levels of IGF-I and IGFBP-3, and breast cancer risk: a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). Carcinogenesis. 2008; 29(7): 1360–1366.
  30. Vogel C, Marcotte EM. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet. 2012; 13(4): 227–232.
  31. Ambros V. The functions of animal microRNAs. Nature. 2004; 431(7006): 350–355.
  32. Gahete MD, Córdoba-Chacón J, Hergueta-Redondo M, et al. A novel human ghrelin variant (In1-ghrelin) and ghrelin-O-acyltransferase are overexpressed in breast cancer: potential pathophysiological relevance. PLoS One. 2011; 6(8): e23302.
  33. Grönberg M, Nilsson C, Markholm I, et al. Ghrelin expression is associated with a favorable outcome in male breast cancer. Sci Rep. 2018; 8(1): 13586.
  34. Łukaszyk A, Rafińska L, Sawiński P, et al. Immunohistochemical and hybridocytochemical study on ghrelin signalling in the rat seminiferous epithelium. Folia Histochem Cytobiol. 2009; 47(3): 415–423.
  35. Buyse J, Janssen S, Geelissen S, et al. Ghrelin modulates fatty acid synthase and related transcription factor mRNA levels in a tissue-specific manner in neonatal broiler chicks. Peptides. 2009; 30(7): 1342–1347.
  36. Laviano A, Molfino A, Rianda S, et al. The growth hormone secretagogue receptor (Ghs-R). Curr Pharm Des. 2012; 18(31): 4749–4754.
  37. Cassoni P, Papotti M, Ghè C, et al. Identification, characterization, and biological activity of specific receptors for natural (ghrelin) and synthetic growth hormone secretagogues and analogs in human breast carcinomas and cell lines. J Clin Endocrinol Metab. 2001; 86(4): 1738–1745.
  38. Aydin S, Ozercan IH, Dagli F, et al. Ghrelin immunohistochemistry of gastric adenocarcinoma and mucoepidermoid carcinoma of salivary gland. Biotech Histochem. 2005; 80(3-4): 163–168.
  39. Dagli AF, Aydin S, Karaoglu A, et al. Ghrelin expression in normal kidney tissue and renal carcinomas. Pathol Res Pract. 2009; 205(3): 165–173.
  40. Alnema MM, Aydin S, Ozkan Y, et al. Ghrelin and obestatin expression in oral squamous cell carcinoma: an immunohistochemical and biochemical study. Mol Cell Biochem. 2010; 339(1-2): 173–179.
  41. Obara-Moszyńska M, Kedzia A, Chmielnicka-Kopaczyk M. Expression of ghrelin in human fetal adrenal glands and paraadrenal nerve ganglions. Folia Histochem Cytobiol. 2009; 47(1): 25–28.
  42. Nanmoku T, Takekoshi K, Ishi K, et al. Effect of Ghrelin on catecholamine secretion in rat pheochromocytoma PC12 cells. Endocr Res. 2003; 29(1): 17–21.