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Open Access 01-12-2021 | Pituitary Adenoma | Research article

Up-regulation of sex-determining region Y-box 9 (SOX9) in growth hormone-secreting pituitary adenomas

Authors: Farzad Izak Shirian, Mohammad Ghorbani, Mohammad E. Khamseh, Mehrnaz Imani, Mahshid Panahi, Alimohammad Alimohammadi, Mitra Nourbakhsh, Vahid Salimi, Masoumeh Tavakoli-Yaraki

Published in: BMC Endocrine Disorders | Issue 1/2021

Abstract

Background

Pituitary adenomas are benign brain tumors that cause considerable morbidity and neurological symptoms. SOX9 as a regulatory transcriptional mediator affects normal and tumor cell growth with an undefined role in pituitary adenomas pathogenesis. Thus, in the present study, the expression pattern of SOX9 in GH-secreting pituitary tumors and normal pituitary tissues is investigated.

Methods

The SOX9 gene expression level was evaluated in 60 pituitary tissues including different types of GH-secreting adenomas and normal pituitary tissues through Real-Time PCR. The protein level of SOX9 was assessed using immunohistochemistry. The correlations of SOX9 gene and protein expression level with the patient’s clinical and pathological features were considered.

Results

The SOX9 over-expression was detected in GH-secreting adenomas tumor tissues compared to normal pituitary tissues which were accompanied by overexpression of SOX9 protein in tumor tissues. The over-expression of SOX9 had a significant impact on GH-secreting adenomas tumor incidence with the odds ratio of 8.4 and the diagnostic value of SOX9 was considerable. The higher level of SOX9 expression was associated with invasive and macro tumors in GH-secreting pituitary adenoma patients. The positive correlation of SOX9 gene and protein level was observed and the tumor size and tumor invasive features were valuable in predicting SOX9 expression level in GH-producing pituitary tumors.

Conclusion

The study provided the first shreds of evidence regarding the expression pattern of SOX9 in the GH- secreting pituitary adenomas at both gene and protein levels which may emphasize the possible involvement of SOX9 as a mediator in pituitary adenoma tumor formation also open up new intrinsic molecular mechanism regarding pituitary adenoma pathogenesis.

Barbieri F, Thellung S, Wurth R, Gatto F, Corsaro A, Villa V, Nizzari M, Albertelli M, Ferone D, Florio T. Emerging targets in pituitary adenomas: role of the CXCL12/CXCR4-R7 system. Int J Endocrinol. 2014;2014:753524.CrossRef

Lavrentaki A, Paluzzi A, Wass JA, Karavitaki N. Epidemiology of acromegaly: review of population studies. Pituitary. 2017;20(1):4–9. https://doi.org/10.1007/s11102-016-0754-x.CrossRefPubMed

Mazziotti G, Lania A, Canalis E. Management of endocrine disease: bone disorders associated with acromegaly: mechanisms and treatment. Eur J Endocrinol. 2019;181(2):R45–56. https://doi.org/10.1530/EJE-19-0184.CrossRefPubMed

Abucham J, Bronstein MD, Dias ML. Management of endocrine disease: acromegaly and pregnancy: a contemporary review. Eur J Endocrinol. 2017;177(1):R1–r12. https://doi.org/10.1530/EJE-16-1059.CrossRefPubMed

Keskin FE, Yetkin DO, Ozkaya HM, Haliloglu O, Sadri S, Gazioglu N, Tanriover N, Ak H, Hatipoglu E, Kadioglu P. The problem of unrecognized acromegaly: surgeries patients undergo prior to diagnosis of acromegaly. J Endocrinol Investig. 2015;38(6):695–700. https://doi.org/10.1007/s40618-015-0245-3.CrossRef

Florea V, Majid SS, Kanashiro-Takeuchi RM, Cai RZ, Block NL, Schally AV, Hare JM, Rodrigues CO. Agonists of growth hormone-releasing hormone stimulate self-renewal of cardiac stem cells and promote their survival. Proc Natl Acad Sci U S A. 2014;111(48):17260–5. https://doi.org/10.1073/pnas.1420375111.CrossRefPubMedPubMedCentral

Caffarini M, Orciani M, Trementino L, Di Primio R, Arnaldi G. Pituitary adenomas, stem cells, and cancer stem cells: what's new? J Endocrinol Investig. 2018;41(7):745–53. https://doi.org/10.1007/s40618-017-0803-y.CrossRef

Haston S, Manshaei S, Martinez-Barbera JP. Stem/progenitor cells in pituitary organ homeostasis and tumourigenesis. J Endocrinol. 2018;236(1):R1–r13. https://doi.org/10.1530/JOE-17-0258.CrossRefPubMed

Orciani M, Davis S, Appolloni G, Lazzarini R, Mattioli-Belmonte M, Ricciuti RA, Boscaro M, Di Primio R, Arnaldi G. Isolation and characterization of progenitor mesenchymal cells in human pituitary tumors. Cancer Gene Ther. 2015;22(1):9–16. https://doi.org/10.1038/cgt.2014.63.CrossRefPubMed

10.

Mirzaei A, Tavoosidana G, Rad AA, Rezaei F, Tavakoli-Yaraki M, Kadijani AA, Khalili E, Madjd Z. A new insight into cancer stem cell markers: could local and circulating cancer stem cell markers correlate in colorectal cancer? Tumour Biol. 2016;37(2):2405–14. https://doi.org/10.1007/s13277-015-3989-7.CrossRefPubMed

11.

Orciani M, Caffarini M, Sorgentoni G, Ricciuti RA, Arnaldi G, Di Primio R. Effects of somatostatin and its analogues on progenitor mesenchymal cells isolated from human pituitary adenomas. Pituitary. 2017;20(2):251–60. https://doi.org/10.1007/s11102-016-0770-x.CrossRefPubMed

12.

Hong Y, Chen W, Du X, Ning H, Chen H, Shi R, Lin S, Xu R, Zhu J, Wu S, et al. Upregulation of sex-determining region Y-box 9 (SOX9) promotes cell proliferation and tumorigenicity in esophageal squamous cell carcinoma. Oncotarget. 2015;6(31):31241–54. https://doi.org/10.18632/oncotarget.5160.CrossRefPubMedPubMedCentral

13.

Antoniou A, Raynaud P, Cordi S, Zong Y, Tronche F, Stanger BZ, Jacquemin P, Pierreux CE, Clotman F, Lemaigre FP. Intrahepatic bile ducts develop according to a new mode of tubulogenesis regulated by the transcription factor SOX9. Gastroenterology. 2009;136(7):2325–33. https://doi.org/10.1053/j.gastro.2009.02.051.CrossRefPubMedPubMedCentral

14.

Kawaguchi Y. Sox9 and programming of liver and pancreatic progenitors. J Clin Invest. 2013;123(5):1881–6. https://doi.org/10.1172/JCI66022.CrossRefPubMedPubMedCentral

15.

Rao P, Fuller GN, Prieto VG. Expression of Sox-9 in metastatic melanoma--a potential diagnostic pitfall. Am J Dermatopathol. 2010;32(3):262–6. https://doi.org/10.1097/DAD.0b013e3181b7fc8d.CrossRefPubMed

16.

Chen W, Zhao W, Chen S, Zhang L, Guo Z, Wang L, Wang J, Wan Z, Hong Y, Yu L. Expression and correlation of MALAT1 and SOX9 in non-small cell lung cancer. Clin Respir J. 2018;12(7):2284–91. https://doi.org/10.1111/crj.12906.CrossRefPubMed

17.

Xi M, Wan S, Hua W, Zhou Y, Jiang W, Hu J. Correlation of SOX9 and NM23 genes with the incidence and prognosis of prostate cancer. Oncol Lett. 2019;17(2):2296–302. https://doi.org/10.3892/ol.2018.9828.CrossRefPubMed

18.

Maneix L, Servent A, Poree B, Ollitrault D, Branly T, Bigot N, Boujrad N, Flouriot G, Demoor M, Boumediene K, et al. Up-regulation of type II collagen gene by 17beta-estradiol in articular chondrocytes involves Sp1/3, Sox-9, and estrogen receptor alpha. J Mole Med. 2014;92(11):1179–200.CrossRef

19.

Lynn FC, Smith SB, Wilson ME, Yang KY, Nekrep N, German MS. Sox9 coordinates a transcriptional network in pancreatic progenitor cells. Proc Natl Acad Sci U S A. 2007;104(25):10500–5. https://doi.org/10.1073/pnas.0704054104.CrossRefPubMedPubMedCentral

20.

Vankelecom H, Roose H. The stem cell connection of pituitary tumors. Front Endocrinol. 2017;8:339. https://doi.org/10.3389/fendo.2017.00339.CrossRef

21.

Barooni AB, Ghorbani M, Salimi V, Alimohammadi A, Khamseh ME, Akbari H, Imani M, Nourbakhsh M, Sheikhi A, Shirian FI, Ameri M, Tavakoli-Yaraki M. Up-regulation of 15-lipoxygenase enzymes and products in functional and non-functional pituitary adenomas. Lipids Health Dis. 2019;18(1):152. https://doi.org/10.1186/s12944-019-1089-1.CrossRefPubMedPubMedCentral

22.

Akbari N, Ghorbani M, Salimi V, Alimohammadi A, Khamseh ME, Akbari H, Nourbakhsh M, Sheikhi A, Taghavi SF, Tavakoli-Yaraki M. Cyclooxygenase enzyme and PGE2 expression in patients with functional and non-functional pituitary adenomas. BMC Endocr Disord. 2020;20(1):39. https://doi.org/10.1186/s12902-020-0515-8.CrossRefPubMedPubMedCentral

23.

Han X, Geng X, Li Z, Chen Z, Liu Y, Liu P, Wang Q, Li C, Ai D, Li Z. The relationship between Phospho-p38, matrix metalloproteinase 9, and major histocompatibility complex class I chain-related molecule a expression in pituitary adenomas demonstrates a new mechanism of pituitary adenoma immune escape. World Neurosurg. 2019;123:e116–24. https://doi.org/10.1016/j.wneu.2018.11.077.CrossRefPubMed

24.

Vaitkiene P, Valiulyte I, Glebauskiene B, Liutkeviciene R. N-myc downstream-regulated gene 2 (NDRG2) promoter methylation and expression in pituitary adenoma. Diagn Pathol. 2017;12(1):33. https://doi.org/10.1186/s13000-017-0622-7.CrossRefPubMedPubMedCentral

25.

Yu C, Li J, Sun F, Cui J, Fang H, Sui G. Expression and clinical significance of miR-26a and pleomorphic adenoma gene 1 (PLAG1) in invasive pituitary adenoma. Med Sci Monit. 2016;22:5101–8. https://doi.org/10.12659/MSM.898908.CrossRefPubMedPubMedCentral

26.

Takei M, Suzuki M, Kajiya H, Ishii Y, Tahara S, Miyakoshi T, Egashira N, Takekoshi S, Sanno N, Teramoto A, Osamura RY. Immunohistochemical detection of somatostatin receptor (SSTR) subtypes 2A and 5 in pituitary adenoma from acromegalic patients: good correlation with preoperative response to octreotide. Endocr Pathol. 2007;18(4):208–16. https://doi.org/10.1007/s12022-007-9004-0.CrossRefPubMed

27.

DeRycke MS, Andersen JD, Harrington KM, Pambuccian SE, Kalloger SE, Boylan KL, Argenta PA, Skubitz AP. S100A1 expression in ovarian and endometrial endometrioid carcinomas is a prognostic indicator of relapse-free survival. Am J Clin Pathol. 2009;132(6):846–56. https://doi.org/10.1309/AJCPTK87EMMIKPFS.CrossRefPubMedPubMedCentral

28.

Hajian-Tilaki K. Receiver operating characteristic (ROC) curve analysis for medical diagnostic test evaluation. Caspian J Intern Med. 2013;4(2):627–35.PubMedPubMedCentral

29.

Obuchowski NA, Bullen JA. Receiver operating characteristic (ROC) curves: review of methods with applications in diagnostic medicine. Phys Med Biol. 2018;63(7):07tr01.CrossRef

30.

Hoppe FM, Hoppe DJ, Walter SD. Explaining odds ratios as conditional risk ratios. J Clin Epidemiol. 2018;97:123–4. https://doi.org/10.1016/j.jclinepi.2017.10.009.CrossRefPubMed

31.

Gejman R, Swearingen B, Hedley-Whyte ET. Role of Ki-67 proliferation index and p53 expression in predicting progression of pituitary adenomas. Hum Pathol. 2008;39(5):758–66. https://doi.org/10.1016/j.humpath.2007.10.004.CrossRefPubMed

32.

Cuevas-Ramos D, Fleseriu M. Pasireotide: a novel treatment for patients with acromegaly. Drug Design Dev Ther. 2016;10:227–39.

33.

Brown R, Imran SA, Wilkinson M. Lipopolysaccharide (LPS) stimulates adipokine and socs3 gene expression in mouse brain and pituitary gland in vivo, and in N-1 hypothalamic neurons in vitro. J Neuroimmunol. 2009;209(1–2):96–103. https://doi.org/10.1016/j.jneuroim.2009.02.001.CrossRefPubMed

34.

Schally AV, Zhang X, Cai R, Hare JM, Granata R, Bartoli M. Actions and potential therapeutic applications of growth hormone-releasing hormone agonists. Endocrinology. 2019;160(7):1600–12. https://doi.org/10.1210/en.2019-00111.CrossRefPubMed

35.

Carreno G, Gonzalez-Meljem JM, Haston S, Martinez-Barbera JP. Stem cells and their role in pituitary tumorigenesis. Mol Cell Endocrinol. 2017;445:27–34. https://doi.org/10.1016/j.mce.2016.10.005.CrossRefPubMed

36.

Cox B, Roose H, Vennekens A, Vankelecom H. Pituitary stem cell regulation: who is pulling the strings? J Endocrinol. 2017;234(3):R135–r158. https://doi.org/10.1530/JOE-17-0083.CrossRefPubMed

37.

Kano M, Suga H, Kasai T, Ozone C, Arima H. Functional pituitary tissue generation from human embryonic stem cells. Curr Protoc Neurosci. 2018;83(1):e48. https://doi.org/10.1002/cpns.48.CrossRefPubMed

38.

Darido C, Buchert M, Pannequin J, Bastide P, Zalzali H, Mantamadiotis T, Bourgaux JF, Garambois V, Jay P, Blache P, Joubert D, Hollande F. Defective claudin-7 regulation by Tcf-4 and sox-9 disrupts the polarity and increases the tumorigenicity of colorectal cancer cells. Cancer Res. 2008;68(11):4258–68. https://doi.org/10.1158/0008-5472.CAN-07-5805.CrossRefPubMed

39.

Aleshcheva G, Wehland M, Sahana J, Bauer J, Corydon TJ, Hemmersbach R, Frett T, Egli M, Infanger M, Grosse J, Grimm D. Moderate alterations of the cytoskeleton in human chondrocytes after short-term microgravity produced by parabolic flight maneuvers could be prevented by up-regulation of BMP-2 and SOX-9. FASEB J. 2015;29(6):2303–14. https://doi.org/10.1096/fj.14-268151.CrossRefPubMed

40.

Raverot G, Burman P, McCormack A, Heaney A, Petersenn S, Popovic V, Trouillas J, Dekkers OM. European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas. Eur J Endocrinol. 2018;178(1):G1–g24. https://doi.org/10.1530/EJE-17-0796.CrossRefPubMed

41.

Zhang Y, Tang CL, Chen WJ, Zhang Q, Wang SL. Dynamic compression combined with exogenous SOX-9 promotes chondrogenesis of adipose-derived mesenchymal stem cells in PLGA scaffold. Eur Rev Med Pharmacol Sci. 2015;19(14):2671–8.PubMed

42.

Kadaja M, Keyes BE, Lin M, Pasolli HA, Genander M, Polak L, Stokes N, Zheng D, Fuchs E. SOX9: a stem cell transcriptional regulator of secreted niche signaling factors. Genes Dev. 2014;28(4):328–41. https://doi.org/10.1101/gad.233247.113.CrossRefPubMedPubMedCentral

43.

Kawai T, Yasuchika K, Ishii T, Miyauchi Y, Kojima H, Yamaoka R, Katayama H, Yoshitoshi EY, Ogiso S, Kita S, Yasuda K, Fukumitsu K, Komori J, Hatano E, Kawaguchi Y, Uemoto S. SOX9 is a novel cancer stem cell marker surrogated by osteopontin in human hepatocellular carcinoma. Sci Rep. 2016;6(1):30489. https://doi.org/10.1038/srep30489.CrossRefPubMedPubMedCentral

Title: Up-regulation of sex-determining region Y-box 9 (SOX9) in growth hormone-secreting pituitary adenomas
Authors: Farzad Izak Shirian
Mohammad Ghorbani
Mohammad E. Khamseh
Mehrnaz Imani
Mahshid Panahi
Alimohammad Alimohammadi
Mitra Nourbakhsh
Vahid Salimi
Masoumeh Tavakoli-Yaraki
Publication date: 01-12-2021
Publisher: BioMed Central
Keyword: Pituitary Adenoma
Published in: BMC Endocrine Disorders / Issue 1/2021
Electronic ISSN: 1472-6823
DOI: https://doi.org/10.1186/s12902-021-00720-x

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Up-regulation of sex-determining region Y-box 9 (SOX9) in growth hormone-secreting pituitary adenomas

Abstract

Background

Methods

Results

Conclusion

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