open access

Vol 93, No 4 (2022)
Research paper
Early publication date: 2022-03-30
Get Citation

Comparison of MED 12 gene mutation and microRNA-124 expression in leiomyoma and myometrium of Turkish patients

Cagdas Demiroglu1, Ozge Komurcu Karuserci2, Sadrettin Pence3, Halime Hanım Pence3, Burcu Çaykara3, Seyhun Sucu2, Mete Gürol Ugur2
DOI: 10.5603/GP.a2021.0102
·
Pubmed: 35419790
·
Ginekol Pol 2022;93(4):290-295.
Affiliations
  1. SANKO University, Gaziantep Gazi Muhtarpaşa Bulvarı, Gaziantep, Turkey
  2. Deparment of Obstetrics and Gynecology, Gaziantep Univercity, Medical Medicine, Turkey
  3. Department of Biochemistry, Health Science University,Bakırkoy Sadi Konuk, Training and Research Hospital, Istanbul, Turkey

open access

Vol 93, No 4 (2022)
ORIGINAL PAPERS Gynecology
Early publication date: 2022-03-30

Abstract

Objectives: It is believed that there are still unclear areas in the formation mechanism of leiomyomas. In our study, it
was aimed to investigate the formation mechanisms of leiomyomas due to local MED 12 gene exon 2 mutation and local
microRNA-124 expression in a Turkish population.
Material and methods: Thirty patients who underwent hysterectomy for leiomyoma uteri at Gaziantep University between
January 2013 and January 2016 were included in our study. In the pathology specimens of these patients, the patient’s
myometrium tissue and her own leiomyoma tissue were analysed via quantitative Realtime PCR in association with MED
12 exon 2 mutation and microRNA-124 expression.
Results: The average age of the 30 patients included in our study is 46.67 ± 5.42 and 13 patients had single leiomyoma;
17 patients had more than one leiomyoma. There were significantly higher c.130G> T (p.G44C) mutation and c.131G> A
(p.G44A) mutation of MED 12 gene exon in leiomyoma tissues than healthy myometrium tissues of same patients. There
was a 3.7-fold decrease in the expression of microRNA-124 in leiomyoma tissues compared to intact eutopic myometrium
tissues, but this difference was not statistically significant.
Conclusions: In recent studies, it has been suggested that MED 12 gene may play an active role in the formation of
fibroids. MED12 and β-catenin / Wnt pathway were emphasized, and alternative genetic pathways are sought in fibroid
formation. Also, tumour suppressor and oncogenesis effects of microRNAs have been demonstrated in many different
studies. Since it is involved in the Wnt pathway, microRNA-124 has been blamed by some previous studies for the formation
of fibroids. This study demonstrates that MED12 exon 2 mutations and probably microRNA-124 gene expressions might
contribute to uterine leiomyoma pathology.

Abstract

Objectives: It is believed that there are still unclear areas in the formation mechanism of leiomyomas. In our study, it
was aimed to investigate the formation mechanisms of leiomyomas due to local MED 12 gene exon 2 mutation and local
microRNA-124 expression in a Turkish population.
Material and methods: Thirty patients who underwent hysterectomy for leiomyoma uteri at Gaziantep University between
January 2013 and January 2016 were included in our study. In the pathology specimens of these patients, the patient’s
myometrium tissue and her own leiomyoma tissue were analysed via quantitative Realtime PCR in association with MED
12 exon 2 mutation and microRNA-124 expression.
Results: The average age of the 30 patients included in our study is 46.67 ± 5.42 and 13 patients had single leiomyoma;
17 patients had more than one leiomyoma. There were significantly higher c.130G> T (p.G44C) mutation and c.131G> A
(p.G44A) mutation of MED 12 gene exon in leiomyoma tissues than healthy myometrium tissues of same patients. There
was a 3.7-fold decrease in the expression of microRNA-124 in leiomyoma tissues compared to intact eutopic myometrium
tissues, but this difference was not statistically significant.
Conclusions: In recent studies, it has been suggested that MED 12 gene may play an active role in the formation of
fibroids. MED12 and β-catenin / Wnt pathway were emphasized, and alternative genetic pathways are sought in fibroid
formation. Also, tumour suppressor and oncogenesis effects of microRNAs have been demonstrated in many different
studies. Since it is involved in the Wnt pathway, microRNA-124 has been blamed by some previous studies for the formation
of fibroids. This study demonstrates that MED12 exon 2 mutations and probably microRNA-124 gene expressions might
contribute to uterine leiomyoma pathology.

Get Citation

Keywords

anormal uterin bleeding; leiomyoma; MED 12; microRNA-124

About this article
Title

Comparison of MED 12 gene mutation and microRNA-124 expression in leiomyoma and myometrium of Turkish patients

Journal

Ginekologia Polska

Issue

Vol 93, No 4 (2022)

Article type

Research paper

Pages

290-295

Early publication date

2022-03-30

Page views

155

Article views/downloads

77

DOI

10.5603/GP.a2021.0102

Pubmed

35419790

Bibliographic record

Ginekol Pol 2022;93(4):290-295.

Keywords

anormal uterin bleeding
leiomyoma
MED 12
microRNA-124

Authors

Cagdas Demiroglu
Ozge Komurcu Karuserci
Sadrettin Pence
Halime Hanım Pence
Burcu Çaykara
Seyhun Sucu
Mete Gürol Ugur

References (56)
  1. Stewart EA. Uterine fibroids. Lancet. 2001; 357: 293–298.
  2. Marshall LM, Spiegelman D, Goldman MB, et al. A prospective study of reproductive factors and oral contraceptive use in relation to the risk of uterine leiomyomata. Fertil Steril. 1998; 70(3): 432–439.
  3. Jacobson GF, Shaber RE, Armstrong MA, et al. Hysterectomy rates for benign indications. Obstet Gynecol. 2006; 107(6): 1278–1283.
  4. De La Cruz MS, Buchanan EM. Uterine Fibroids: Diagnosis and Treatment. Am Fam Physician. 2017; 95(2): 100–107.
  5. Kurose K, Mine N, Doi D, et al. Novel gene fusion ofCOX6C at 8q22-23 toHMGIC at 12q15 in a uterine leiomyoma. Genes, Chromosomes and Cancer. 2000; 27(3): 303–307, doi: 10.1002/(sici)1098-2264(200003)27:3<303::aid-gcc11>3.0.co;2-3.
  6. Laganà AS, Vergara D, Favilli A, et al. Epigenetic and genetic landscape of uterine leiomyomas: a current view over a common gynecological disease. Arch Gynecol Obstet. 2017; 296(5): 855–867.
  7. Mäkinen N, Mehine M, Tolvanen J, et al. MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas. Science. 2011; 334(6053): 252–255.
  8. Markowski DN, Bartnitzke S, Loning T, et al. MED12 mutations in uterine fibroids the irrelations hiptocytogenetic subgroups. International Journal of Cancer. 2012.
  9. Mello JBH, Barros-Filho MC, Abreu FB, et al. MicroRNAs involved in the HMGA2 deregulation and its co-occurrence with MED12 mutation in uterine leiomyoma. Mol Hum Reprod. 2018; 24(11): 556–563.
  10. Hashimoto K, Azuma C, Kamiura S, et al. Clonal determination of uterine leiomyomas by analyzing differential inactivation of the X-chromosome-linked phosphoglycerokinase gene. Gynecol Obstet Invest. 1995; 40(3): 204–208.
  11. Flynn M, Jamison M, Datta S, et al. Health care resource use for uterine fibroid tumors in the United States. Am J Obstet Gynecol. 2006; 195(4): 955–964.
  12. Je EMi, Kim MR, Min KiO, et al. Mutational analysis of MED12 exon 2 in uterine leiomyoma and other common tumors. Int J Cancer. 2012; 131(6): E1044–E1047.
  13. Kittelmann S, McGregor AP. Modulation and Evolution of Animal Development through microRNA Regulation of Gene Expression. Genes (Basel). 2019; 10(4).
  14. Alsaadoni H, Çaykara B, Pençe S, et al. The expression levels of miR-655-3p, miR127-5p, miR-369-3p, miR-544a in gastric cancer. Turkish Journal of Biochemistry. 2019; 44(4): 487–491.
  15. Zhao X, Wang Y, Sun X. The functions of microRNA-208 in the heart. Diabetes Res Clin Pract. 2020; 160: 108004.
  16. Króliczewski J, Sobolewska A, Lejnowski D, et al. microRNA single polynucleotide polymorphism influences on microRNA biogenesis and mRNA target specificity. Gene. 2018; 640: 66–72.
  17. Zhang B, Pan X, Cobb GP, et al. microRNAs as oncogenes and tumor suppressors. Dev Biol. 2007; 302(1): 1–12.
  18. Marsh EE, Lin Z, Yin P, et al. Differential expression of microRNA species in human uterine leiomyoma versus normal myometrium. Fertil Steril. 2008; 89(6): 1771–1776.
  19. Hu H, Wang G, Li C. miR-124 suppresses proliferation and invasion of nasopharyngeal carcinoma cells through the Wnt/β-catenin signaling pathway by targeting Capn4. Onco Targets Ther. 2017; 10: 2711–2720.
  20. Pençe H. Investigation of LFA-1 rs2230433 variation in renal cell carcinoma tissues. Haydarpasa Numune Training and Research Hospital Medical Journal. 2019; 59(3): 216–219.
  21. Alsaadoni H, Caykara B, Pence S, et al. Analysis of the BACE1 and Clusterin Genes Expression Levels in Alzheimer’s Disease. Journal of Academic Research in Medicine. 2019; 9(1): 45–49.
  22. Dogan H, Can H, Otu HH. Whole genome sequence of a Turkish individual. PLoS One. 2014; 9(1): e85233.
  23. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001; 25(4): 402–408.
  24. Di Tommaso S, Massari S, Malvasi A, et al. Selective genetic analysis of myoma pseudocapsule and potential biological impact on uterine fibroid medical therapy. Expert Opin Ther Targets. 2015; 19(1): 7–12.
  25. Di Tommaso S, Massari S, Malvasi A, et al. Gene expression analysis reveals an angiogenic profile in uterine leiomyoma pseudocapsule. Mol Hum Reprod. 2013; 19(6): 380–387.
  26. Serrat N, Sebastian C, Pereira-Lopes S, et al. The response of secondary genes to lipopolysaccharides in macrophages depends on histone deacetylase and phosphorylation of C/EBPβ. J Immunol. 2014; 192(1): 418–426.
  27. Tanoğlu EG, Pençe H, Karuserci ÖK, et al. Uterin leiomyomda  Wnt, β-katenin, TGF–β, Siklin D1’in ekspresyon seviyelerinin  belirlenmesi. Zeynep Kamil Tıp Bülteni. 2019; 50(3): 138–141.
  28. Chegini N. Uterine microRNA Signature and Consequence of Their Dysregulation in Uterine Disorders. Anim Reprod. 2010; 7(3): 117–128.
  29. Park MJu, Shen H, Spaeth JM, et al. Oncogenic exon 2 mutations in Mediator subunit MED12 disrupt allosteric activation of cyclin C-CDK8/19. J Biol Chem. 2018; 293(13): 4870–4882.
  30. Graaff Mde, Cleton-Jansen AM, Szuhai K, et al. Mediator complex subunit 12 exon 2 mutation analysis in different subtypes of smooth muscle tumors confirms genetic heterogeneity. Human Pathology. 2013; 44(8): 1597–1604.
  31. Pérot G, Croce S, Ribeiro A, et al. MED12 alterations in both human benign and malignant uterine soft tissue tumors. PLoS One. 2012; 7(6): e40015.
  32. Zhang B, Pan X, Cobb GP, et al. microRNAs as oncogenes and tumor suppressors. Dev Biol. 2007; 302(1): 1–12.
  33. Subramanian S, Lui WO, Lee CH, et al. MicroRNA expression signature of human sarcomas. Oncogene. 2008; 27(14): 2015–2026.
  34. Marsh EE, Lin Z, Yin P, et al. Differential expression of microRNA species in human uterine leiomyoma versus normal myometrium. Fertil Steril. 2008; 89(6): 1771–1776.
  35. Wang T, Zhang X, Obijuru L, et al. A micro-RNA signature associated with race, tumor size, and target gene activity in human uterine leiomyomas. Genes Chromosomes Cancer. 2007; 46(4): 336–347.
  36. Zhang G, Song K, Yan H. MicroRNA-124 represses wound healing by targeting SERP1 and inhibiting the Wnt/β-catenin pathway. Adv Clin Exp Med. 2019; 28(6): 711–718.
  37. Zhang X, Cai D, Meng L, et al. MicroRNA-124 inhibits proliferation, invasion, migration and epithelial-mesenchymal transition of cervical carcinoma cells by targeting astrocyte-elevated gene-1. Oncol Rep. 2016; 36(4): 2321–2328.
  38. Yuan Li, Li S, Zhou Qi, et al. MiR-124 inhibits invasion and induces apoptosis of ovarian cancer cells by targeting programmed cell death 6. Oncol Lett. 2017; 14(6): 7311–7317.
  39. Lu ML, Zhang y, Li J, et al. MicroRNA-124 Inhibits Colorectal Cancer Cell Proliferation and Suppresses Tumor Growth by Interacting With PLCB1 and Regulating Wnt/β-catenin Signaling Pathway. Eur Rev Med Pharmacol Sci. 2019; 23(1): 121–136.
  40. Du S, Li H, Sun X, et al. MicroRNA-124 inhibits cell proliferation and migration by regulating SNAI2 in breast cancer. Oncol Rep. 2016; 36(6): 3259–3266.
  41. Yu Bo, Jiang K, Zhang J. MicroRNA-124 suppresses growth and aggressiveness of osteosarcoma and inhibits TGF-β-mediated AKT/GSK-3β/SNAIL-1 signaling. Mol Med Rep. 2018; 17(5): 6736–6744.
  42. Cui Z, Hu Y. MicroRNA-124 Suppresses Slug-mediated Lung Cancer Metastasis. Eur Rev Med Pharmacol Sci. 2016; 20(18): 3802–3811.
  43. Xiao HJ, Ji Q, Yang L, et al. In vivo and in vitro effects of microRNA-124 on human gastric cancer by targeting JAG1 through the Notch signaling pathway. J Cell Biochem. 2018; 119(3): 2520–2534.
  44. Wilting SM, van Boerdonk RAA, Henken FE, et al. Methylation-mediated silencing and tumour suppressive function of hsa-miR-124 in cervical cancer. Mol Cancer. 2010; 9: 167.
  45. Banno K, Yanokura M, Iida M, et al. Carcinogenic mechanisms of endometrial cancer: involvement of genetics and epigenetics. J Obstet Gynaecol Res. 2014; 40(8): 1957–1967.
  46. Chegini N. Proinflammatory and Profibrotic Mediators: Principal Effectors of Leiomyoma Development as a Fibrotic Disorder. Seminars in Reproductive Medicine. 2010; 28(04): 345–346.
  47. Nair S, Al-Hendy A. Adipocytes enhance the proliferation of human leiomyoma cells via TNF-α proinflammatory cytokine. Reprod Sci. 2011; 18(12): 1186–1192.
  48. Wang T, Zhang X, Obijuru L, et al. A micro-RNA signature associated with race, tumor size, and target gene activity in human uterine leiomyomas. Genes Chromosomes Cancer. 2007; 46(4): 336–347.
  49. Zhang G, Song K, Yan H. MicroRNA-124 represses wound healing by targeting SERP1 and inhibiting the Wnt/β-catenin pathway. Adv Clin Exp Med. 2019; 28(6): 711–718.
  50. Santamaria X, Taylor H. Micro RNA and gynecologicalr eproductive diseases. Fertility and Sterility. 2014; 101(6): 1545–1551.
  51. Chegini N. Uterine microRNA signature and consequence of their dysregulation in uterine disorders. Anim Reprod. 2010; 7(3): 117–128.
  52. Sun Y, Li Qi, Gui H, et al. MicroRNA-124 mediates the cholinergic anti-inflammatory action through inhibiting the production of pro-inflammatory cytokines. Cell Res. 2013; 23(11): 1270–1283.
  53. Ponomarev ED, Veremeyko T, Barteneva N, et al. MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α-PU.1 pathway. Nat Med. 2011; 17(1): 64–70.
  54. Hu H, Wang G, Li C. miR-124 suppresses proliferation and invasion of nasopharyngeal carcinoma cells through the Wnt/β-catenin signaling pathway by targeting Capn4. Onco Targets Ther. 2017; 10: 2711–2720.
  55. Zhang C, Hu Y, Wan J, et al. MicroRNA-124 suppresses the migration and invasion of osteosarcoma cells via targeting ROR2-mediated non-canonical Wnt signaling. Oncol Rep. 2015; 34(4): 2195–2201.
  56. Long QZ, Du YF, Liu XG, et al. miR-124 represses FZD5 to attenuate P-glycoprotein-mediated chemo-resistance in renal cell carcinoma. Tumour Biol. 2015; 36(9): 7017–7026.

Regulations

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

By "Via Medica sp. z o.o." sp.k., ul. Świętokrzyska 73, 80–180 Gdańsk
tel.:+48 58 320 94 94, faks:+48 58 320 94 60, e-mail:  viamedica@viamedica.pl