GAMZE EVKURAN DAL, Eray ALÇIĞIR, İBRAHİM MERT POLAT, Sevil ATALAY VURAL, Hatice Esra CANATAN, MEHMET RIFAT VURAL, ŞÜKRÜ KÜPLÜLÜ

Granulosa theca cell tumor in an Arabian mare: Are immunohistochemically loss of GDF-9 and BMP-6 proteins associated with high GATA-4, inhibin-α, AMH expressions?

Bir Arap kısrağında granuloza-teka hücre tümörü (GTHT); klinik, patomorfolojik ve immunohistokimyasal (İHK) incelemelerle teşhis edildi. İmmunohistokimyasal olarak GTHTde; Transforming Growth factor-β ailesi [GDF-9 Growth Diff erentiation Factor-9 (GDF-9), Bone Morphogenetic Protein-6 (BMP-6), anti-Müllerian Hormone (AMH) ve inhibin-α], GATA ailesi (GATA-4 ve GATA-6) ve Insulin-like Growth Factor ailesi (IGF-1 and IGF-2) üyelerinin olası rolleri ortaya konmaya çalışıldı ve bulgular iki negatif kontrol ovaryum dokusuyla karşılaştırıldı. Neoplastik ovaryum dokusunda AMH, inhibin-α, IGF-2, GATA-4 orta derecede, IGF-1, GATA-6 ise hafif derecede pozitif sonuç verirken GDF-9 ve BMP-6 pozitifl ik göstermedi. Ayrıca kontrol grubu dokuların boyamalarında tüm belirteçler ile orta derecede pozitif sonuçlar elde edildi. Kısraklarda GTHT tümörogenezisinde yüksek GATA-4, AMH ve İnhibin-α düzeylerinin, GDF-9 ve BMP-6 eksikliğindeki önemli rolünü belirlemede mitojenik ve stres sinyallerine yanıttaki genlerin aktivasyonundan sorumlu transkripsiyon faktörlerinin de yeni moleküler çalışmalar ile incelenmesi gerekliliğini ortaya koymuştur.

Arap kısrakta granuloza-teka hücre tümörü: İmmunohistokimyasal olarak GDF-9 ve BMP-6 protein kayıpları yüksek GATA-4, inhibin-α ve AMH ekspresyonları ile ilişkili mi?

Granulosa-theca cell tumor (GTCT) in an Arabian mare was diagnosed by clinical, pathomorphological and immunohistochemical (IHC) examinations. Immunohistochemically, it was tried to clarify the possible roles of Transforming Growth Factorβ superfamily members [Growth Diff erentiation Factor-9 (GDF-9), Bone Morphogenetic Protein-6 (BMP-6), anti-Müllerian Hormone (AMH) and inhibin-α], GATA family members (GATA-4 and GATA-6) and Insulin-like Growth Factor family (IGF-1 and IGF-2) on GTCT and results was compared with two negative control ovarian tissues. Moderate positivities with AMH, inhibin-α, IGF-2, GATA-4, and mild positivities with IGF-1, GATA-6 were obtained whereas no positivity could be shown with GDF-9 and BMP-6 in neoplastic ovarian tissue. Additionally, mild positivities were obtained with all markers in control stainings. Further molecular studies for transcription factors regulating activation of genes in response to mitogenic and stress signals in equine GTCT tumorigenesis are needed to elucidate whether the high GATA-4, AMH, and inhibin-α immunopositivities play a significant role on GDF-9 and BMP-6 deficiency.

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1. Charman RE, Mckinnon AO: A granulosa-theca cell tumour in a 15-month-old Thoroughbred filly. Aust Vet J, 85, 124-125, 2007.
2. Frederico LM, Gerard MP, Pinto CRF, Gradil CM: Bilateral occurance of granulosa-theca cell tumors in an Arabian mare. Can Vet, 48, 502-505, 2007.
3. Hoque MS, Derar RI, Senba H, Osawa T, Kano K, Taya K, Miyake YI: Localization of inhibin α-, βA- and βB-subunits and aromatase in ovarian follicles with granulosa-theca cell tumor (GTCT) in 6 mares. J Vet. Med Sci, 65 (6): 713-717, 2003.
4. Hoque MS, Senba H, Tsunoda N, Derar RI, Watanabe G, Taya K, Osawa T, Miyake YI: Endocrinological changes before and after removal of the granulosa theca cell tumor (GTCT) aff ected ovary in 6 mares. J Vet Med Sci, 65 (8): 887-891, 2003.
5. Yoshida G, Tsunoda N, Miyake YI, Hoque MS, Osawa T, Nagamine N, Taniyama H, Nambo Y, Watanabe G, Taya K: Endocrinological studies of mares with granulosa-theca cell tumor. J Equine Sci, 11 (2): 35- 43, 2000.
6. Zelli R, Sylla L, Monaci M, Stradaioli G, Sibley LE, Roser JF, Munro C, Liu IKM: Gonadotropin secretion and pituitary responsiveness to GnRH in mares with granulosa-theca cell tumor. Theriogenology, 66, 1210-1218, 2006.
7. Maurice KT: Diagnosis and surgical removal of a granulosa-theca cell tumor in a mare. Can Vet J, 46, 644-646, 2005.
8. Tunca R, Serin G, Epikmen ET, Aydoğan A, Avcı H: İki köpekte granüloza hücre tümörü. Kafkas Univ Vet Fak Derg, 17 (4): 675-678, 2011.
9. Fırat İ, Sönmez K: Fibrothecoma in a trough bred mare with unilateral ovariectomy: A case report. Kafkas Univ Vet Fak Derg, 17 (2): 329-332, 2011.
10. Silvestri C, Bose R, Attisano L, Wrana JL: TGFβ Signal Transduction. In, Bradshaw RA, Dennis EA (Eds): Handbook of Cell Signaling, 2nd ed., pp. 521-532, Academic Press, San Diego, California, USA, 2010.
11. Knight P, Clister C: TGF beta superfamily members and ovarian follicle development. Reproduction, 132, 191-206, 2006.
12. Juengel JL, McNatty KP: The role of protein of the transforming growth factor-β superfamily in the intraovarian regulation of follicular development. Hum Reprod Update 11 (2): 144-161, 2005.
13. Stenvers KL, Findlay JK: Inhibins: From reproductive hormones to tumor suppressors. Trends Endocrin Met, 21 (3): 174-180, 2009.
14. Anttonen M, Unkila-Kallio L, Leminen A, Butzow R, Heikinheimo M: High GATA-4 expression associates with aggressive behaviour, whereas low anti-müllerian hormone expression associates with growth potential of ovarian granulosa cell tumors. J Clin Endocr Metab, 90 (12): 6529-6535, 2005.
15. LaVoie HA, McCoy GL, Blake CA: Expression of the GATA-4 and GATA-6 transcription factors in the fetal rat gonad and in the ovary during postnatal development and pregnancy. Mol Cell Endocrinol. 227, 31-40, 2004.
16. Wakana K, Akiyama Y, Aso T, Yuasa Y: Involvement of GATA-4/-5 transcription factors in ovarian carcinogenesis. Cancer Lett, 241, 281-288, 2006.
17. Rey F, Rodriguez FM, Salvetti NR, Palomar MM, Barbeito CG, Alfaro NS, Ortega HH: Insulin-like growth factor-II and insulin-like growth factor binding proteins in bovine cystic ovarian disease. J Comp Pathol, 142, 193-204, 2010.
18. Ball BA, Conley AJ, MacLaughlin DT, Grundy SA. Sabeur K, Liu IKM: Expression of anti-Müllerian hormone (AMH) in equine granulosacell tumors and in normal equine ovaries. Theriogenology, 70, 968-977, 2008.
19. Chen Y, Zhao S, Qiao J, Liu P, Lian Y, Zheng X: Expression of bone morphogenetic protein-15 in human oocyte and cumulus granulosa cells primed with recombinant follicle-stimulating hormone followed by human chorionic gonadotropin. Fertil Steril, 92 (6): 2045-2046, 2009.
20. Shi J, Yoshino O, Osuga Y, Koga K, Hirota Y, Hirota T, Yano T, Nishii O, Taketani Y: Bone morphogenetic protein-6 stimulates gene expression of follicle-stimulating hormon receptor, inhibin/activin β subunits, and anti-Müllerian hormone in human granulosa cells. Fertil Steril, 92 (5): 1794-1798, 2009.
21. Zhao SY, Qiao J, Chen YJ, Liu P, Li J, Yan J: Expression of growth differentiation factor-9 and bone morphogenetic protein-15 in oocytes and cumulus cells of patients with polycystic ovary syndrome. Fertil Steril, 94 (1): 261-267, 2010.
22. Almedia J, Ball BA, Conley AJ, Place NJ, Liu LKM, Scholtz EL, Mathewson L, Stanley SD, Moellere BC: Biological and clinical significance of anti-Muellerian hormone determination in blood serum of the mare. Theriogenology, 76, 1393-1403, 2011.
23. Matzuk MM, Finegold MJ, Su JJ, Hsueh AJW, Bradley A: Α-inhibin is a tumour suppressor gene with gonadal specificity in mice. Nature, 360, 313-319, 1992.
24. Robert NM, Miyamota Y, Taniguchi H, Viger R: LRH-1/NR5A2 cooperates with GATA factors to regulate inhibin-α subunit promoter activity. Mol Cell Endocrinol, 257-258, 65-74, 2006.
25. Tremblay JJ, Viger R: Novel roles for GATA transcription factors in the regulation of steriodogenesis. J Steroid Biochem, 85, 291-298, 2003.
26. Vuorenoja S, Muller AR, Kiiveri S, Bieluska M, Heikinheimo M, Wilson D, Huhtaniemi T, Rahmin NA: Adrenocortical tumorigenesis, luteinizing hormone receptor and transcription factors GATA-4 and GATA- 6. Mol Cell Endocrinol, 269, 38-45, 2007.
27. Silva JRV, Figueiredo JR, van den Hurk R: Involvement of growth hormone (GH) and insulin-like growth factor (IGF) system in ovarian folliculogenesis. Theriogenology, 71, 1193-1208, 2009.