ISSN: 1301-2193 E-ISSN: 1308-9846
  • Turkish Journal of
    Endocrinology and Metabolism
ORIGINAL ARTICLE

Role of AGR2 Expression in Specimens from Pituitary Adenoma Tissue on Tumor Behavior
Hipofiz Adenom Doku Örneklerinde AGR2 Ekspresyonunun Tümör Davranışı Üzerine Etkisi
Received Date : 10 Jun 2020
Accepted Date : 25 Sep 2020
Available Online : 16 Oct 2020
Doi: 10.25179/tjem.2020-76663 - Makale Dili: EN
Turk J Endocrinol Metab. 2020;24:293-299
Bu makale, CC BY-NC-SA altında lisanslanmış açık erişim bir makaledir.
ABSTRACT
Objective: To investigate the anterior gradient 2 (AGR2) mRNA expression, which performs various cellular functions such as cell migration, differentiation, and proliferation in tissue specimens from pituitary adenomas. Material and Methods: A total of 44 pituitary adenoma specimens (20 female/24 male) from patients, and ten normal brain tissues (5 female/5 male) operated for epilepsy surgery (control group) were included in the study. Specimens were stored at -80 °C throughout the study. Molecular assessment of pituitary adenomas and control brain tissues was performed to quantify mRNA expression of AGR2using real-time PCR. Distribution of AGR2 mRNA expression levels was evaluated according to pituitary adenoma subtypes, tumor aggressiveness, or invasiveness. Results: Expression levels of AGR2 mRNA in corticotroph (n=5) and somatotroph adenomas (n=14) were higher compared to control brain tissues (p=0.045 and p=0.005, respectively); however, expression levels of AGR2 mRNA in lactotroph (n=3), gonadotroph (n=14), and non-secretory adenomas (n=7) were similar to the control brain tissues. The thyrotroph adenoma (n=1) was not included in the analysis. Expression levels of AGR2 mRNA were similar in female and male patients. The expression levels of the AGR2 mRNA were higher in non-invasive tumors (n=20) than invasive tumors (n=24) (p=0.001), and in the nonaggressive tumors (n=27) than aggressive tumors (n=17) (p=0.018). A negative correlation between expression levels of AGR2 mRNA and Ki-67 labeling index (r=-0.328; p=0,029) was obtained. However, no correlation was found between the expression levels of AGR2 mRNA and age or maximum tumor diameter. Conclusion: AGR2 expression is inversely correlated to invasiveness and aggressiveness, independently from age and sex in pituitary adenomas.
ÖZET
Amaç: Migrasyon, farklılaşma ve proliferasyon gibi çeşitli hücresel görevleri olan anterior gradient 2 (AGR2) expresyonunun hipofiz adenom doku örneklerinde değerlendirilmesi. Gereç ve Yöntemler: Bu çalışmaya, 44 hastanın (20 kadın/24 erkek) hipofiz adenom doku örnekleri ve epilepsi cerrahisi uygulanan 10 hastanın (5 kadın/5 erkek) da normal beyin dokusu örnekleri kontrol grubu olarak kabul edilerek dâhil edilmiştir. Tüm doku örnekleri çalışılana kadar -80°C’de saklanmıştır. Dokularda AGR2 mRNA ekspresyonu real-time PCR kullanılarak kullanılarak değerlendirilmiştir. Hipofizer adenomunun subtipi, tümörün agresifliği ve invazivliğine göre AGR2 mRNA ekspresyonunun dağılımına bakılmıştır. Bulgular: AGR2 mRNA ekspresyonu kortikotrop adenomlarda (n=5) ve somatotrop adenomlarda (n=14), kontrol beyin dokusundan daha yüksekti (sırasıyla, p=0,045 ve p=0,005), bununla birlikte lactotrop adenomlarda (n=3), gonadotrop adenomalarda (n=14) ve nonsekretuar adenomlarda (n=7) kontrol beyin dokusuna göre benzer idi, tirotrop adenomlar ise (n=1) hesaplamalara dâhil edilmemiştir. AGR2 mRNA ekspresyonu kadın ve erkeklerde benzerdir. İnvaziv olmayanlarda (n=20), invasiv tümörlerden (n=24), agresif olmayanlarda (n=27) ise agresif tümörlerden (n=17) AGR2 mRNA ekspresyonu anlamlı derecede yüksekti (sırasıyla, p=0,001 ve p=0,018). AGR2 mRNA ekspresyonu ile Ki-67 labeling index arasında bir negatif korelasyon (r=-0,328; p=0,029) saptanırken yaş ve maksimum tümör boyutu arasında bir korelasyon saptanmadı. Sonuç: AGR2 ekspresyonu yaş ve cinsiyetten bağımsız olarak hipofiz adenomlarının agresifliği ve invazivliği ile ters orantılıdır.
KAYNAKLAR
  1. Molitch ME. Diagnosis and treatment of pituitary adenomas: a review. JAMA. 2017;317:516-524. [Crossref] 
  2. Cooper O, Melmed S. Subclinical hyperfunctioning pituitary adenomas: the silent tumors. Best Pract Res Clin Endocrinol Metab. 2012;26:447-460. [Crossref] 
  3. Di Ieva A, Rotondo F, Syro LV, Cusimano MD, Kovacs K. Aggressive pituitary adenomas--diagnosis and emerging treatments. Nat Rev Endocrinol. 2014;10:423-435. [Crossref]  [PubMed] 
  4. Raverot G, Burman P, McCormack A, Heaney A, Petersenn S, Popovic V, Trouillas J, Dekkers OM; European Society of Endocrinology. European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas. Eur J Endocrinol. 2018;178:G1-G24. [Crossref]  [PubMed] 
  5. Melmed S. Pathogenesis of pituitary tumors. Nat Rev Endocrinol. 2011;7:257-266. [Crossref]  [PubMed] 
  6. Higa A, Mulot A, Delom F, Bouchecareilh M, Nguyên DT, Boismenu D, Wise MJ, Chevet E. Role of pro-oncogenic protein disulfide isomerase (PDI) family member anterior gradient 2 (AGR2) in the control of endoplasmic reticulum homeostasis. J Biol Chem. 2011;286:44855-44868. [Crossref]  [PubMed]  [PMC] 
  7. Brychtova V, Vojtesek B, Hrstka R. Anterior gradient 2: a novel player in tumor cell biology. Cancer Lett. 2011;304:1-7. [Crossref]  [PubMed] 
  8. Tian SB, Tao KX, Hu J, Liu ZB, Ding XL, Chu YN, Cui JY, Shuai XM, Gao JB, Cai KL, Wang JL, Wang GB, Wang L, Wang Z. The prognostic value of AGR2 expression in solid tumours: a systematic review and meta-analysis. Sci Rep. 2017;7:15500. [Crossref]  [PubMed]  [PMC] 
  9. Tohti M, Li J, Ma C, Li W, Lu Z, Hu Y. Expression of AGR2 in pituitary adenomas and its association with tumor aggressiveness. Oncol Lett. 2015;10:2878-2882. [Crossref]  [PubMed] 
  10. Tohti M, Li J, Tang C, Wen G, Abdujilil A, Yizim P, Ma C. Serum AGR2 as a useful biomarker for pituitary adenomas. Clin Neurol Neurosurg. 2017;154:19-22. [Crossref]  [PubMed] 
  11. Hardy J, Vezina JL. Transsphenoidal neurosurgery of intracranial neoplasm. Adv Neurol. 1976;15:261-273. [PubMed] 
  12. Knosp E, Steiner E, Kitz K, Matula C. Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery. 1993;33:610-617. [Crossref]  [PubMed] 
  13. Fessart D, Domblides C, Avril T, Eriksson LA, Begueret H, Pineau R, Malrieux C, Dugot-Senant N, Lucchesi C, Chevet E, Delom F. Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties. Elife. 2016;5:e13887. [Crossref]  [PubMed]  [PMC] 
  14. Delom F, Nazaraliyev A, Fessart D. The role of protein disulphide isomerase AGR2 in the tumour niche. Biol Cell. 2018;110:271-282. [Crossref]  [PubMed] 
  15. Fritzsche FR, Dahl E, Pahl S, Burkhardt M, Luo J, Mayordomo E, Gansukh T, Dankof A, Knuechel R, Denkert C, Winzer KJ, Dietel M, Kristiansen G. Prognostic relevance of AGR2 expression in breast cancer. Clin Cancer Res. 2006;12:1728-1734. [Crossref]  [PubMed] 
  16. Fritzsche FR, Dahl E, Dankof A, Burkhardt M, Pahl S, Petersen I, Dietel M, Kristiansen G. Expression of AGR2 in non small cell lung cancer. Histol Histopathol. 2007;22:703-708. [Crossref]  [PubMed] 
  17. Riener MO, Thiesler T, Hellerbrand C, Amann T, Cathomas G, Fritzsche FR, Dahl E, Bahra M, Weichert W, Terracciano L, Kristiansen G. Loss of anterior gradient-2 expression is an independent prognostic factor in colorectal carcinomas. Eur J Cancer. 2014;50:1722-1730. [Crossref]  [PubMed] 
  18. Lee E, Lee DH. Emerging roles of protein disulfide isomerase in cancer. BMB Rep. 2017;50:401-410. [Crossref]  [PubMed]  [PMC] 
  19. Chevet E, Fessart D, Delom F, Mulot A, Vojtesek B, Hrstka R, Murray E, Gray T, Hupp T. Emerging roles for the pro-oncogenic anterior gradient-2 in cancer development. Oncogene. 2013;32:2499-2509. [Crossref]  [PubMed] 
  20. Wilson CL, Sims AH, Howell A, Miller CJ, Clarke RB. Effects of oestrogen on gene expression in epithelium and stroma of normal human breast tissue. Endocr Relat Cancer. 2006;13:617-628. [Crossref]  [PubMed] 
  21. Zhang JS, Gong A, Cheville JC, Smith DI, Young CY. AGR2, an androgen-inducible secretory protein overexpressed in prostate cancer. Genes Chromosomes Cancer. 2005;43:249-259. [Crossref]  [PubMed] 
  22. Salmans ML, Zhao F, Andersen B. The estrogen-regulated anterior gradient 2 (AGR2) protein in breast cancer: a potential drug target and biomarker. Breast Cancer Res. 2013;15:204. [Crossref]  [PubMed]  [PMC] 
  23. Bu H, Bormann S, Schäfer G, Horninger W, Massoner P, Neeb A, Lakshmanan VK, Maddalo D, Nestl A, Sültmann H, Cato AC, Klocker H. The anterior gradient 2 (AGR2) gene is overexpressed in prostate cancer and may be useful as a urine sediment marker for prostate cancer detection. Prostate. 2011;71:575-587. [Crossref]  [PubMed] 
  24. Hong XY, Wang J, Li Z. AGR2 expression is regulated by HIF-1 and contributes to growth and angiogenesis of glioblastoma. Cell Biochem Biophys. 2013;67:1487-1495. [Crossref]  [PubMed] 
  25. Xiao Z, Liu Q, Zhao B, Wu J, Lei T. Hypoxia induces hemorrhagic transformation in pituitary adenomas via the HIF-1α signaling pathway. Oncol Rep. 2011;26:1457-1464. [Crossref]  [PubMed]  [PMC]