Exp Clin Endocrinol Diabetes 2021; 129(08): 593-600
DOI: 10.1055/a-1185-9121
Article

SNPs of miR-23b, miR-107 and HMGA2 and their Relations with the Response to Medical Treatment in Acromegaly Patients

Derya Metin Armagana
1   Department of Medical Biology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
,
Ayse Seda Akdemir
1   Department of Medical Biology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
,
Hande Mefkure Ozkaya
2   Department of Endocrinology and Metabolism, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
,
Ozge Polat Korkmaz
2   Department of Endocrinology and Metabolism, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
,
Nurperi Gazioglu
3   Department of Neurosurgery, Faculty of Medicine, T.C Demiroglu Bilim University, Istanbul, Turkey
,
Pinar Kadioglu
2   Department of Endocrinology and Metabolism, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
6   Pituitary Center, Istanbul University-Cerrahpasa, Istanbul, Turkey
,
Necmettin Tanriover
4   Department of Neurosurgery, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
6   Pituitary Center, Istanbul University-Cerrahpasa, Istanbul, Turkey
,
Kaya-Fatma Dagistanli
1   Department of Medical Biology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
,
Ahmet Dirican
5   Department of Biostatistic, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
,
1   Department of Medical Biology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
› Author Affiliations
Funding: The study was supported by the Research Fund of the Istanbul University, Istanbul, Turkey, project number TSA-2016–20129, THZ-2017–27454.

Abstract

Introduction Acromegaly is a chronic disease of increased growth hormone (GH) secretion and elevated insulin-like growth factor-I (IGF-I) levels induced by a pituitary adenoma. HMGA2 (high mobility group A2) and AIP (aryl hydrocarbon receptor-interacting protein) expression levels are related to GH-secreting adenomas, and also a response to Somatostatin Analogs (SSAs). We studied SNPs in miR-107 and miR-23b that related with AIP and HMGA2 genes respectively and control their expression, and also SNP in the 3'UTR of HMGA2 gene. Our aim was to investigate genotype distributions of the studied SNPs, as well as the possible relationship between disease and/or response to SSAs treatment in patients with acromegaly.

Material and Methods Genotypes were determined by qRT-PCR method from DNA materials obtained blood samples of acromegaly patients (141) and healthy individuals (99). The genotype distributions of patients and healthy groups, as well as the relationship between the clinical data of the disease and genotypes were statistically compared.

Results In acromegaly patients with T-allele, p53 expression (p=0.049) was significantly higher. In patients with CT+TT genotype and T-allele who were responder to SSA-treatment Ki-67 index (respectively p=0.019, p=0.020 respectively) was higher. We did not observe the genotypes for miR-23b and miR-107 polymorphisms in the patients and control group of Turkish population.

Conclusion The genetic variations of the miRNAs genes related with HMGA2 and AIP genes were not seen in our study. Although there is no relationship between HMGA2-rs1351394 polymorphism and acromegaly disease, T allele was associated with some clinical features related to adenoma in patients with acromegaly.

a Derya Metin Armagan was affiliated with the Department of Medical Biology, Cerrahpasa Faculty of Medicine at Istanbul University-Cerrahpasa at the time of the study and is currently affliated with Department of Medicine at Cedars-Sinai Medical Center, Los Angeles, CA, USA.




Publication History

Received: 24 February 2020
Received: 07 May 2020

Accepted: 22 May 2020

Article published online:
24 August 2020

© 2020. Thieme. All rights reserved.

© Georg Thieme Verlag KG
Stuttgart · New York

 
  • References

  • 1 Colao A, Grasso LFS, Giustina A. et al. Acromegaly. Nat Rev Dis Prim 2019; 5: 20
  • 2 Melmed S, Bronstein MD, Chanson P. et al. A Consensus Statement on acromegaly therapeutic outcomes. Nat Rev Endocrinol 2018; 14: 552-561
  • 3 Colao A, Auriemma RS, Lombardi G. et al. Resistance to somatostatin analogs in acromegaly. Endocr Rev 2011; 32: 247-271
  • 4 Cuevas-Ramos D, Carmichael JD, Cooper O. et al. A structural and functional acromegaly classification. J Clin Endocrinol Metab 2015; 100: 122-131
  • 5 Cuevas-Ramos D, Fleseriu M. Somatostatin receptor ligands and resistance to treatment in pituitary adenomas. J Mol Endocrinol 2014; 52: R223-R240
  • 6 Gadelha MR, Wildemberg LE, Bronstein MD. et al. Somatostatin receptor ligands in the treatment of acromegaly. Pituitary 2017; 20: 100-108
  • 7 Fabian MR, Sonenberg N, Filipowicz W. Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem 2010; 79: 351-379
  • 8 Van Schooneveld E, Wildiers H, Vergote I. et al. Dysregulation of microRNAs in breast cancer and their potential role as prognostic and predictive biomarkers in patient management. Breast Cancer Res 2015; 17: 21
  • 9 Jin Y, Lee CGL. Single nucleotide polymorphisms associated with microRNA regulation. Biomolecules 2013; 3: 287-302
  • 10 Gao Y, Diao L, Li H. et al. Single nucleotide polymorphisms of microRNA processing genes and outcome of non-hodgkin’s lymphoma. Onco Targets Ther 2015; 8: 1735-1741
  • 11 Sivapragasam M, Rotondo F, Lloyd RV. et al. MicroRNAs in the human pituitary. Endocr Pathol 2011; 22: 134-143
  • 12 Ozkaya HM, Comunoglu N, Sayitoglu M. et al. Germline mutations of aryl hydrocarbon receptor-interacting protein (AIP) gene and somatostatin receptor 1–5 and AIP immunostaining in patients with sporadic acromegaly with poor versus good response to somatostatin analogues. Pituitary 2018; 21: 335-346
  • 13 Chahal HS, Trivellin G, Leontiou CA. et al. Somatostatin analogs modulate AIP in somatotroph adenomas: The role of the ZAC1 pathway. J Clin Endocrinol Metab 2012; 97: E1411-E1420
  • 14 Kasuki L, Neto LV, Wildemberg LEA. et al. AIP expression in sporadic somatotropinomas is a predictor of the response to octreotide LAR therapy independent of SSTR2 expression. Endocr Relat Cancer 2012; 19: L25-L29
  • 15 Trivellin G, Butz H, Delhove J. et al. MicroRNA miR-107 is overexpressed in pituitary adenomas and inhibits the expression of aryl hydrocarbon receptor-interacting protein in vitro. Am J Physiol - Endocrinol Metab 2012; 303: E708-E719
  • 16 Di Ieva A, Butz H, Niamah M. et al. MicroRNAs as biomarkers in pituitary tumors. Neurosurgery 2014; 75: 181-188
  • 17 Zhang S, Mo Q, Wang X. Oncological role of HMGA2 (Review). Int J Oncol 2019; 55: 775-778
  • 18 Fedele M, Battista S, Kenyon L. et al. Overexpression of the HMGA2 gene in transgenic mice leads to the onset of pituitary adenomas. Oncogene 2002; 21: 3190-3198
  • 19 Fedele M, Pentimalli F, Baldassarre G. et al. Transgenic mice overexpressing the wild-type form of the HMGA1 gene develop mixed growth hormone/prolactin cell pituitary adenomas and natural killer cell lymphomas. Oncogene 2005; 24: 3427-3435
  • 20 D’Angelo D, Palmieri D, Mussnich P. et al. Altered microRNA expression profile in human pituitary GH adenomas: Down-regulation of miRNA targeting HMGA1, HMGA2, and E2F1. J Clin Endocrinol Metab 2012; 97: E1128-E1138
  • 21 Fedele M, De Martino I, Pivonello R. et al. SOM230, a new somatostatin analogue, is highly effective in the therapy of growth hormone/prolactin-secreting pituitary adenomas. Clin Cancer Res 2007; 13: 2738-2744
  • 22 D’Angelo D, Esposito F, Fusco A. Epigenetic mechanisms leading to overexpression of HMGA proteins in human pituitary adenomas. Front Med 2015; 2: 39
  • 23 Qian ZR, Asa SL, Siomi H. et al. Overexpression of HMGA2 relates to reduction of the let-7 and its relationship to clinicopathological features in pituitary adenomas. Mod Pathol 2009; 22: 431-441
  • 24 Palmieri D, D’Angelo D, Valentino T. et al. Downregulation of HMGA-targeting microRNAs has a critical role in human pituitary tumorigenesis. Oncogene 2012; 31: 3857-3865
  • 25 Leone V, Langella C, D’Angelo D. et al. MiR-23b and miR-130b expression is downregulated in pituitary adenomas. Mol Cell Endocrinol 2014; 390: 1-7
  • 26 Federico A, Forzati F, Esposito F. et al. Hmga1/Hmga2 double knock-out mice display a “superpygmy” phenotype. Biol Open 2014; 3: 372-378
  • 27 Battista S, Fidanza V, Fedele M. et al. The expression of a truncated HMGI-C gene induces gigantism associated with lipomatosis. Cancer Res 1999; 59: 4793-4797
  • 28 Ligon AH, Moore SDP, Parisi MA. et al. Constitutional rearrangement of the architectural factor HMGA2: A novel human phenotype including overgrowth and lipomas. Am J Hum Genet 2005; 76: 340-348
  • 29 Weedon MN, Lettre G, Freathy RM. et al. A common variant of HMGA2 is associated with adult and childhood height in the general population. Nat Genet 2007; 39: 1245-1250
  • 30 Kamat MA, Blackshaw JA, Young R. et al. PhenoScanner V2: An expanded tool for searching human genotype-phenotype associations. Bioinformatics 2019; 35: 4851-4853
  • 31 Staley JR, Blackshaw J, Kamat MA. et al. PhenoScanner: A database of human genotype-phenotype associations. Bioinformatics 2016; 32: 3207-3209
  • 32 Alaylioglu M, Gezen-Ak D, Dursun E. et al. The association between clusterin and APOE polymorphisms and late-onset Alzheimer disease in a Turkish cohort. J Geriatr Psychiatry Neurol 2016; 29: 221-226
  • 33 Moszyńska A, Gebert M, Collawn JF. et al. SNPs in microRNA target sites and their potential role in human disease. Open Biol 2017; 7: 170019
  • 34 Niu Y, Zhou H, Liu Y. et al. MiR-16 regulates proliferation and apoptosis of pituitary adenoma cells by inhibiting HMGA2. Oncol Lett 2019; 17: 2491-2497
  • 35 Li XH, Wang EL, Zhou HM. et al. MicroRNAs in human pituitary adenomas. Int J Endocrinol 2014; 2014: 435171
  • 36 De Pinho LKJ, Neto LV, Wildemberg LEA. et al. Low aryl hydrocarbon receptor-interacting protein expression is a better marker of invasiveness in somatotropinomas than Ki-67 and p53. Neuroendocrinology 2011; 94: 39-48
  • 37 Yong SL, Dutta A. The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev 2007; 21: 1025-1030
  • 38 Yates AD, Achuthan P, Akanni W. et al. Ensembl 2020. Nucleic Acids Res 2020; 48: D682-D688
  • 39 Fedele M, Palmieri D, Fusco A. HMGA2: A pituitary tumour subtype-specific oncogene?. Mol Cell Endocrinol 2010; 326: 19-24
  • 40 Amirjmshidi A, Alimohamadi M, Ownagh V. et al. The impact of immunohistochemical markers of Ki-67 and p53 on the long-term outcome of growth hormone-secreting pituitary adenomas: A cohort study. Asian J Neurosurg 2014; 9: 130-136
  • 41 Selek A, Cetinarslan B, Canturk Z. et al. The effect of somatostatin analogues on Ki-67 levels in GH-secreting adenomas. Growth Horm IGF Res 2019; 45: 1-5
  • 42 Fusco A, Zatelli MC, Bianchi A. et al. Prognostic significance of the Ki-67 labeling index in growth hormone-secreting pituitary adenomas. J Clin Endocrinol Metab 2008; 93: 2746-2750
  • 43 Kasuki L, Wildemberg LEA, Neto LV. et al. Ki-67 is a predictor of acromegaly control with octreotide LAR independent of SSTR2 status and relates to cytokeratin pattern. Eur J Endocrinol 2013; 169: 217-223
  • 44 Liu B, Pang B, Hou X. et al. Expression of high-mobility group AT-hook protein 2 and its prognostic significance in malignant gliomas. Hum Pathol 2014; 45: 1752-1758