Detection of RUNX2 gene expression in cumulus cells in women undergoing controlled ovarian stimulation

Reproductive Biology and Endocrinology

Dimitris Loutradis¹  Kostas Kallianidis¹  Elli Anagnostou¹  Ritsa Bletsa¹  Spyros Marinopoulos¹  Fotodotis Malamas¹  Haralampos Theofanakis¹  Vasiliki Dinopoulou¹  Despina Mavrogianni¹  Myrto Papamentzelopoulou¹ 

[1] Division of Human Reproduction, IVF Unit, 1st Department of Obstetrics and Gynaecology, Alexandra Hospital, Athens University Medical School, Athens, Greece

关键词: ICSI;    Estradiol levels;    Cumulus cells;    ART treatment;    RUNX2 expression;   

Others  :  1149717
DOI  :  10.1186/1477-7827-10-99

 received in 2012-06-28, accepted in 2012-11-24,  发布年份 2012

【 摘 要 】

Background

RUNX2 is a transcription factor, whose expression has been recently identified in the mouse ovary. Regulation of RUNX2 expression and its function in the human ovary have not been determined yet. The aim of the present study is the investigation of the possible correlation between RUNX2 gene expression in cumulus cells and controlled ovarian stimulation and pregnancy outcomes after ART treatment.

Methods

A total of 41 patients undergoing ICSI treatment for male factor infertility were enrolled into a specific ART program, during which cumulus cells were collected. The expression of RUNX2 gene in cumulus cells was examined by real-time PCR.

Results

Concerning RUNX2 gene expression, 12 out of 41 women were detected with RUNX2 expression, with ratios ranging from 0.84 to 1.00, while 28 out of 41 women had no expression (ratio = 0). Only 1 woman presented a weak RUNX2 gene expression (ratio = 0.52). From 8 women that proceeded to pregnancy, 7 of them did not express RUNX2 gene in cumulus cells, while one was the woman with weak gene expression that also achieved pregnancy. The group of women without RUNX2 expression presented higher number of follicles (p = 0.013), higher number of retrieved oocytes (p = 0.016), higher basal LH serum levels (p = 0.016) and higher peak estradiol levels (p = 0.013), while the number of fertilized oocytes differed marginally between the two groups (p = 0.089). Moreover, RUNX2 expression was negatively associated with LH levels (OR = 0.22, p = 0.021) and E2 levels (OR = 0.25, p = 0.026).

Conclusions

Consequently, based on the preliminary findings of the present pilot study a potential inhibitory mechanism of RUNX2 gene is observed in the ovary when high mRNA levels are detected, suggesting that RUNX2 could possibly be used as a candidate genetic marker in the monitoring of the outcome of an ART treatment.

【 授权许可】

   
2012 Papamentzelopoulou et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Devroey P, Fauser BCJM, Diedrich K: Approaches to improve the diagnosis and management of infertility. Hum Reprod Update 2009, 15(4):391-408.
• [2]Stock M, Schafer H, Fliegauf M, Otto F: Identification of novel target genes of the bone-specific transcription factor RUNX2. J Bone Miner Res 2004, 19:959-972.
• [3]Wang GX, Sun RP, Song FL: A novel RUNX2 mutation (T420I) in Chinese patients with cleidocranial dysplasia. Genet Mol Res 2010, 9(1):41-47.
• [4]Lou Y, Javed A, Hussain S, Colby J, Frederick D, Pratap J, Xie R, Gaur T, Wijnen AJ, Jones SN, et al.: A RUNX2 threshold for the cleidocranial dysplasia phenotype. Hum Mol Genet 2009, 18(3):556-568.
• [5]Hernandez-Gonzalez I, Gonzalez-Robayna I, Shimada M, Wayne CM, Ochsner SA, White L, Richards JS: Gene expression profiles of cumulus cell oocyte complexes during ovulation reveal cumulus cells express neuronal and immune-related genes: does this expand their role in the ovulation process? Mol Endocrinol 2006, 20(6):1300-1321.
• [6]Park ES, Choi S, Lind AK, Dahm-Kahler P, Brannstrom M, Carletti M, Christenson KL, Curry TE, Jo M: The LH surge-induced RUNX2 transcription factor regulates the expression of specific genes in luteinizing granulosa cells. Biol Reprod 2009, 81:357.
• [7]He N, Xiao Z, Yin T, Stubbs J, Li L, Quarles LD: Inducible expression of RUNX2 results in multiorgan abnormalities in mice. J Cell Biochem 2011, 112(2):653-665.
• [8]Fan HY, Liu Z, Johnson PF, Richards JS: CCAAT/enhancer-binding proteins (C/EBP)-α and -β are essential for ovulation, luteinization, and the expression of key target genes. Mol Endocrinol 2011, 25(2):253-268.
• [9]Alarcón-Riquelme ME: Role of RUNX in autoimmune diseases linking rheumatoid arthritis, psoriasis and lupus. Arthritis Res Ther 2004, 6:169-173. BioMed Central Full Text
• [10]McCarthy TL, Chang WZ, Liu Y, Centrella M: RUNX2 integrates estrogen activity in osteoblasts. J Biol Chem 2003, 278(44):43121-43129.
• [11]Jeong JH, Jung JK, Kim HJ, Jin JS, Kim HN, Kang SM, Kim SY, Wijnen AJ, Stein JL, Lian JB, et al.: The gene for aromatase, a rate-limiting enzyme for local estrogen biosynthesis, is a downstream target gene of RUNX2 in skeletal tissues. Mol Cell Biol 2010, 30(10):2365-2375.
• [12]Park ES, Lind AK, Dahm-Kähler P, Brännström M, Carletti MZ, Christenson LK, Curry TE, Jo M: RUNX2 transcription factor regulates gene expression in luteinizing granulosa cells of rat ovaries. Mol Endocrinol 2010, 24(4):846-858.
• [13]Palermo G, Joris H, Devroey P, Van Steirteghem AC: Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet 1992, 340(8810):17-18.
• [14]Patsoula E, Loutradis D, Drakakis P, Michalas L, Bletsa R, Michalas S: Messenger RNA expression for the follicle-stimulating hormone receptor and luteinizing hormone receptor in human oocytes and preimplantation-stage embryos. Fertil Steril 2003, 79(5):1187-1193.
• [15]Müller MC, Saglio G, Lin F, Pfeifer H, Press RD, Tubbs RR, Paschka P, Gottardi E, O’Brien SG, Ottmann OG, et al.: An international study to standardize the detection and quantitation of BCR-ABL transcripts from stabilized peripheral blood preparations by quantitative RT-PCR. Haematologica 2007, 92:970-973.
• [16]Choi S, Park ES, Jo M: The expression pattern of core binding factor during the periovulatory period in the rat ovary. Biol Reprod 2007, 77:97-c–98.
• [17]Park ES, Park J, Franceschi RT, Jo M: The role for runt related transcription factor 2 (RUNX2) as a transcriptional repressor in luteinizing granulosa cells. Mol Cell Endocrinol 2012, 362(1–2):165-175.
• [18]Liu J, Park ES, Curry TE, Jo M: Periovulatory expression of hyaluronan and proteoglycan link protein 1 (Hapln1) in the rat ovary: hormonal regulation and potential function. Mol Endocrinol 2010, 24:1203-1217.
• [19]Sun GW, Kobayashi H, Suzuki M, Kanayama N, Terao T: Link protein as an enhancer of cumulus cell-oocyte complex expansion. Mol Reprod Dev 2002, 63:223-231.
• [20]Loutradis D, Drakakis P, Kallianidis K, Milingos S, Dendrinos S, Michalas S: Oocyte morphology correlates with embryo quality and pregnancy rate after intracytoplasmic sperm injection. Fertil Steril 1999, 72(2):240-244.
• [21]Khalid O, Baniwal SK, Purcell DJ, Leclerc N, Gabet Y, Stallcup MR, Coetzee GA, Frenkel B: Modulation of RUNX2 activity by estrogen receptor-alpha: implications for osteoporosis and breast cancer. Endocrinology 2008, 149(12):5984-5995.
• [22]Chimge NO, Baniwal SK, Little GH, Chen YB, Kahn M, Tripathy D, Borok Z, Frenkel B: Regulation of breast cancer metastasis by Runx2 and estrogen signaling: the role of SNAI2. Breast Cancer Res 2011, 13(6):R127. BioMed Central Full Text
• [23]Chimge NO, Baniwal SK, Luo J, Coetzee S, Khalid O, Berman BP, Tripathy D, Ellis MJ, Frenkel B: Opposing effects of Runx2 and estradiol on breast cancer cell proliferation: in vitro identification of reciprocally regulated gene signature related to clinical letrozole responsiveness. Clin Cancer Res 2012, 18(3):901-911.