Hostname: page-component-78c5997874-xbtfd Total loading time: 0 Render date: 2024-11-10T10:59:32.520Z Has data issue: false hasContentIssue false

The expression profile of WNT/β-catanin signalling genes in human oocytes obtained from polycystic ovarian syndrome (PCOS) patients

Published online by Cambridge University Press:  31 March 2022

Aya Badeea Ismail
Affiliation:
Department of Medical Biology, Faculty of Medicine, Near East University, Nicosia, Cyprus
Marwan ’Mohammad Saeed’ Naji
Affiliation:
Department of Medical Biology, Faculty of Medicine, Near East University, Nicosia, Cyprus
İnci Nebih
Affiliation:
Department of Medical Biology, Faculty of Medicine, Near East University, Nicosia, Cyprus
Gulten Tuncel
Affiliation:
DESAM Institute, Near East University, Nicosia, Cyprus
Burcu Ozbakir
Affiliation:
DESAM Institute, Near East University, Nicosia, Cyprus Department of Obstetrics and Gynecology, Faculty of Medicine, Near East University, Nicosia, Cyprus
Sehime Gulsun Temel
Affiliation:
Department of Medical Genetics, Faculty of Medicine, Bursa Uludag University, BursaTurkey
Pinar Tulay
Affiliation:
DESAM Institute, Near East University, Nicosia, Cyprus Department of Medical Genetics, Faculty of Medicine, Near East University, Nicosia, Cyprus
Gamze Mocan
Affiliation:
Department of Medical Pathology, Faculty of Medicine, Near East University, Nicosia, Cyprus
Mahmut Cerkez Ergoren*
Affiliation:
Department of Medical Genetics, Faculty of Medicine, Near East University, Nicosia, Cyprus
*
Author for correspondence: M.C. Ergoren. Near East University, Faculty of Medicine, Department of Medical Genetics, 99138 Nicosia, Cyprus. E-mail: mahmutcerkez.ergoren@neu.edu.tr

Summary

Polycystic ovarian syndrome (PCOS) is a chronic hormonal turmoil that is demonstrated in 2.2−27% of women of pre-menopausal age. This disease is a complex multigenic disorder that results from the interaction between excess androgen expression, genetic susceptibility and environmental influences. PCOS is associated with 40% of female infertility and endometrial cancer. The WNT/β-catenin signalling transduction pathway regulates aspects of cell proliferation, migration and cell fate determination in the tissue along with early embryonic development and controls the proper activation of the female reproductive system, along with regulating hormonal activity in ovarian granulosa cells. In the current study, we investigated the expression profiles of WNT/β-catenin signalling pathway genes (AXIN2, FZD4, TCF4, WNT3, WNT4, WNT5A, WNT7A, WNT1, APC, GSK3B and β-catenin) in a total of 13 oocyte samples. Seven of these samples were from polycystic women and six were from healthy women. The results of this study displayed the absence of expression of AXIN2, FZD4, TCF4, WNT5A, WNT3, WNT4 and WNT7A genes in ovaries from women with PCOS and from healthy women. While APC and β-catenin expression levels were similar in the oocytes of both patients and controls, conversely, WNT1 and GSK3β genes both showed elevated expression in the oocytes of patients with PCOS, therefore suggesting an association between aberrant expression of WNT1 and GSK3β and the pathogenesis of PCOS. The observations of the current study could be helpful to provide evidence regarding the pathogenesis of PCOS and its treatment.

Type
Research Article
Copyright
© The Author(s), 2022. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Amato, M. C., Galluzzo, A., Finocchiaro, S., Criscimanna, A. and Giordano, C. (2008). The evaluation of metabolic parameters and insulin sensitivity for a more robust diagnosis of the polycystic ovary syndrome. Clinical Endocrinology, 69(1), 5260. doi: 10.1111/j.1365-2265.2007.03145.x CrossRefGoogle ScholarPubMed
Asuni, A. A., Hooper, C., Reynolds, C. H., Lovestone, S., Anderton, B. H. and Killick, R. (2006). GSK3alpha exhibits beta-catenin and tau directed kinase activities that are modulated by Wnt. European Journal of Neuroscience, 24(12), 33873392. doi: 10.1111/j.1460-9568.2006.05243.x CrossRefGoogle ScholarPubMed
Azziz, R. (2006). Controversy in clinical endocrinology: Diagnosis of polycystic ovarian syndrome: The Rotterdam criteria are premature. Journal of Clinical Endocrinology and Metabolism, 91(3), 781785. doi: 10.1210/jc.2005-2153 CrossRefGoogle ScholarPubMed
Ben-Salem, A., Ajina, M., Suissi, M., Daher, H. S., Almawi, W. Y. and Mahjoub, T. (2014). Polymorphisms of transcription factor-7-like 2 (TCF7L2) gene in Tunisian women with polycystic ovary syndrome (PCOS). Gene, 533(2), 554557. doi: 10.1016/j.gene.2013.09.104 CrossRefGoogle Scholar
Cadigan, K. M. and Nusse, R. (1997) Wnt signaling: A common theme in animal development. Genes and Development, 11(24), 32863305. doi: 10.1101/gad.11.24.3286 CrossRefGoogle ScholarPubMed
Castrop, J., van Norren, K. and Clevers, H. (1992) A gene family of HMG-box transcription factors with homology to TCF-1. Nucleic Acids Research, 20(3), 611. doi: 10.1093/nar/20.3.611 CrossRefGoogle ScholarPubMed
Christopoulos, P., Mastorakos, G., Gazouli, M., Panidis, D., Deligeoroglou, E., Katsikis, I., Papadias, K., Diamandi-Kandarakis, E. and Creatsas, G. (2008). Genetic variants in TCF7L2 and KCNJ11 genes in a Greek population with polycystic ovary syndrome. Gynecological Endocrinology: the Official Journal of the International Society of Gynecological Endocrinology, 24(9), 486490. doi: 10.1080/09513590802196379 CrossRefGoogle Scholar
Coleman, W. B. (2018). Molecular pathogenesis of prostate cancer. Chapter 25. In Coleman, W. B. and Tsongalis, G. J. (eds), Molecular Pathology: The Molecular Basis of Human Disease. (2nd ed.) (pp. 555568). Academic Press. doi: 10.1016/B978-0-12-802761-5.00025-0 CrossRefGoogle Scholar
Coviello, A. D., Sam, S., Legro, R. S. and Dunaif, A. (2009). High prevalence of metabolic syndrome in first-degree male relatives of women with polycystic ovary syndrome is related to high rates of obesity. Journal of Clinical Endocrinology and Metabolism, 94(11), 43614366. doi: 10.1210/jc.2009-1333 CrossRefGoogle ScholarPubMed
Dahlgren, E., Friberg, L. G., Johansson, S., Lindström, B., Odén, A., Samsioe, G. and Janson, P. O. (1991). Endometrial carcinoma; ovarian dysfunction—A risk factor in young women. European Journal of Obstetrics, Gynecology and Reproductive Biology, 41(2), 143150. doi: 10.1016/0028-2243(91)90092-y CrossRefGoogle ScholarPubMed
Doble, B. W. and Woodgett, J. R. (2003). GSK-3: Tricks of the trade for a multi-tasking kinase. Journal of Cell Science, 116(7), 11751186. doi: 10.1242/jcs.00384 CrossRefGoogle ScholarPubMed
Facchinello, N., Tarifeño-Saldivia, E., Grisan, E., Schiavone, M., Peron, M., Mongera, A., Ek, O., Schmitner, N., Meyer, D., Peers, B., Tiso, N. and Argenton, F. (2017). Tcf7l2 plays pleiotropic roles in the control of glucose homeostasis, pancreas morphology, vascularization and regeneration. Scientific Reports, 7(1), 9605. doi: 10.1038/s41598-017-09867-x CrossRefGoogle ScholarPubMed
Gluecksohn-Schoenheimer, S. (1949). the effects of a lethal mutation responsible for duplications and twinning in mouse embryos. Journal of Experimental Zoology, 110(1), 4776. doi: 10.1002/jez.1401100105 CrossRefGoogle ScholarPubMed
Gupta, P. S., Folger, J. K., Rajput, S. K., Lv, L., Yao, J., Ireland, J. J. and Smith, G. W. (2014). Regulation and regulatory role of WNT signaling in potentiating FSH action during bovine dominant follicle selection. PLoS ONE, 9(6), e100201. doi: 10.1371/journal.pone.0100201 CrossRefGoogle Scholar
Habas, R. and Dawid, I. B. (2005). Dishevelled and Wnt signaling: Is the nucleus the final frontier? Journal of Biology, 4(1), 2. doi: 10.1186/jbiol22 CrossRefGoogle ScholarPubMed
Hsieh, M., Boerboom, D., Shimada, M., Lo, Y., Parlow, A. F., Luhmann, U. F., Berger, W. and Richards, J. S. (2005). Mice null for Frizzled4 (Fzd4−/−) are infertile and exhibit impaired corpora lutea formation and function. Biology of Reproduction, 73(6), 11351146. doi: 10.1095/biolreprod.105.042739 CrossRefGoogle ScholarPubMed
Iozzo, R. V., Eichstetter, I. and Danielson, K. G. (1995). aberrant expression of the growth factor Wnt-5A in human malignancy. Cancer Research, 55(16), 34953499. Jho, EH, Zhang, T, Domon, C, Joo, CK.Google ScholarPubMed
Jho, E. H., Zhang, T., Domon, C., Joo, C. K., Freund, J. N. and Costantini, F. (2002). Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Molecular and Cellular Biology, 22(4), 11721183. doi: 10.1128/MCB.22.4.1172-1183.2002 CrossRefGoogle ScholarPubMed
Jin, T. and Liu, L. (2008). The Wnt signaling pathway effector TCF7L2 and type 2 diabetes mellitus. Molecular Endocrinology, 22(11), 23832392. doi: 10.1210/me.2008-0135 CrossRefGoogle ScholarPubMed
Knochenhauer, E. S., Key, T. J., Kahsar-Miller, M., Waggoner, W., Boots, L. R. and Azziz, R. (1998). Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: A prospective study. Journal of Clinical Endocrinology and Metabolism, 83(9), 3078–3082. doi: 10.1210/jcem.83.9.5090 Google ScholarPubMed
Kobayashi, A. and Behringer, R. R. (2003). Developmental genetics of the female reproductive tract in mammals. Nature Reviews. Genetics, 4(12), 969980. doi: 10.1038/nrg1225 CrossRefGoogle ScholarPubMed
Leibel, N. I., Baumann, E. E., Kocherginsky, M. and Rosenfield, R. L. (2006). Relationship of adolescent polycystic ovary syndrome to parental metabolic syndrome. Journal of Clinical Endocrinology and Metabolism, 91(4), 12751283. doi: 10.1210/jc.2005-1707 CrossRefGoogle ScholarPubMed
Leung, J. Y., Kolligs, F. T., Wu, R., Zhai, Y., Kuick, R., Hanash, S., Cho, K. R. and Fearon, E. R. (2002) Activation of AXIN2 expression by beta-catenin-T cell factor. A feedback repressor pathway regulating Wnt signaling. Journal of Biological Chemistry, 277(24), 2165721665. doi: 10.1074/jbc.M200139200 CrossRefGoogle ScholarPubMed
Mai, M., Qian, C., Yokomizo, A., Smith, D. I. and Liu, W. (1999). Cloning of the human homolog of conductin (AXIN2), a gene mapping to chromosome 17q23-q24. Genomics, 55(3), 341344. doi: 10.1006/geno.1998.5650 CrossRefGoogle Scholar
Mehdinejadiani, S., Amidi, F., Mehdizadeh, M., Barati, M., Safdarian, L., Aflatoonian, R., Alyasin, A., Aghahosseini, M., Pazhohan, H., P., Mohammad Zadeh Kazorgah, F. and Sobhani, A. (2018). The effects of letrozole and clomiphene citrate on ligands expression of Wnt3, Wnt7a, and Wnt8b in proliferative endometrium of women with polycystic ovarian syndrome. Gynecological Endocrinology: the Official Journal of the International Society of Gynecological Endocrinology, 34(9), 775780. doi: 10.1080/09513590 CrossRefGoogle ScholarPubMed
Milhem, R. M., Ben-Salem, S., Al-Gazali, L. and Ali, B. R. (2014). Identification of the cellular mechanisms that modulate trafficking of frizzled family receptor 4 (FZD4) missense mutants associated with familial exudative vitreoretinopathy. Investigative Ophthalmology and Visual Science, 55(6), 34233431. doi: 10.1167/iovs.14-13885 CrossRefGoogle ScholarPubMed
Mohamed, N. E., Hay, T., Reed, K. R., Smalley, M. J. and Clarke, A. R. (2019). APC2 is critical for ovarian WNT signalling control, fertility and tumour suppression. BMC Cancer, 19(1), 677. doi: 10.1186/s12885-019-5867-y CrossRefGoogle ScholarPubMed
Moon, R. T., Bowerman, B., Boutros, M. and Perrimon, N. (2002). The promise and perils of Wnt signaling through beta-catenin. Science, 296(5573), 16441646. doi: 10.1126/science.1071549 CrossRefGoogle ScholarPubMed
Nishita, M., Enomoto, M., Yamagata, K. and Minami, Y. (2010). Cell/tissue-tropic functions of Wnt5a signaling in normal and cancer cells. Trends in Cell Biology, 20(6), 346354. doi: 10.1016/j.tcb.2010.03.001 CrossRefGoogle ScholarPubMed
Peifer, M. (1999). Signal transduction: Neither straight nor narrow. Nature, 400(6741), 213215. doi: 10.1038/22214 CrossRefGoogle ScholarPubMed
Prabhu, Y. D., Sekar, N. and Abilash, V. G. (2018). Screening of Polymorphisms of transcription factor 7-like 2 gene in polycystic ovary syndrome using polymerase chain reaction–restriction fragment length polymorphism Analysis. Journal of Human Reproductive Sciences, 11(2), 137141. doi: 10.4103/jhrs.JHRS_123_15 Google ScholarPubMed
Rebar, R., Judd, H. L., Yen, S. S. C., Rakoff, J., Vandenberg, G. and Naftolin, F. (1976). Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome. Journal of Clinical Investigation, 57(5), 13201329. doi: 10.1172/JCI108400 CrossRefGoogle ScholarPubMed
Robitaille, J. M., Zheng, B., Wallace, K., Beis, M. J., Tatlidil, C., Yang, J., Sheidow, T. G., Siebert, L., Levin, A. V., Lam, W. C., Arthur, B. W., Lyons, C. J., Jaakkola, E., Tsilou, E., Williams, C. A., Weaver, R. G., Shields, C. L. and Guernsey, D. L. (2011). The role of Frizzled-4 mutations in familial exudative vitreoretinopathy and Coats disease. British Journal of Ophthalmology, 95(4), 574579. doi: 10.1136/bjo.2010.190116 CrossRefGoogle ScholarPubMed
Sam, S., Legro, R. S., Bentley-Lewis, R. and Dunaif, A. (2005). Dyslipidemia and metabolic syndrome in the sisters of women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism, 90(8), 47974802. doi: 10.1210/jc.2004-2217 CrossRefGoogle ScholarPubMed
Sanchez, A. M., Viganò, P., Quattrone, F., Pagliardini, L., Papaleo, E., Candiani, M. and Panina-Bordignon, P. (2014). The WNT/b-catenin signaling pathway and expression of survival promoting genes in luteinized granulosa cells: Endometriosis as a paradigm for a dysregulated apoptosis pathway. Fertility and Sterility, 101(6), 16881696. doi: 10.1016/j.fertnstert.2014.02.040 CrossRefGoogle Scholar
Strauss, J. F., 3rd (2003). Some new thoughts on the pathophysiology and genetics of polycystic ovary syndrome. Annals of the New York Academy of Sciences, 997, 4248. doi: 10.1196/annals.1290.005 CrossRefGoogle ScholarPubMed
Teede, H., Deeks, A. and Moran, L. (2010). Polycystic ovary syndrome: A complex conditions with psychological, reproductive and metabolic manifestations that impact on health across the lifespan. BMC Medicine, 8(1), 41. doi: 10.1186/1741-7015-8-41 CrossRefGoogle ScholarPubMed
Toomes, C., Bottomley, H. M., Jackson, R. M., Towns, K. V., Scott, S., Mackey, D. A., Craig, J. E., Jiang, L., Yang, Z., Trembath, R., Woodruff, G., Gregory-Evans, C. Y., Gregory-Evans, K., Parker, M. J., Black, G. C., Downey, L. M., Zhang, K. and Inglehearn, C. F. (2004). Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. American Journal of Human Genetics, 74(4), 721730. doi: 10.1086/383202 CrossRefGoogle ScholarPubMed
Tulay, P., Naja, R. P., Cascales-Roman, O., Doshi, A., Serhal, P. and SenGupta, S. B. (2015). Investigation of microRNA expression and DNA repair gene transcripts in human oocytes and blastocysts. Journal of Assisted Reproduction and Genetics, 32(12), 17571764. doi: 10.1007/s10815-015-0585-0 CrossRefGoogle ScholarPubMed
Vainio, S., Heikkilä, M., Kispert, A., Chin, N. and McMahon, A. P. (1999). Female development in mammals is regulated by Wnt-4 signalling. Nature, 397(6718), 405409. doi: 10.1038/17068 CrossRefGoogle ScholarPubMed
Wang, Y., Huso, D., Cahill, H., Ryugo, D. and Nathans, J. (2001). Progressive cerebellar, auditory, and esophageal dysfunction caused by targeted disruption of the frizzled-4 gene. Journal of Neuroscience, 21(13), 47614771. doi: 10.1523/JNEUROSCI.21-13-04761.2001 CrossRefGoogle ScholarPubMed
Wu, X. Q., Wang, Y. Q., Xu, S. M., Liu, J. F., Bi, X. Y., Wang, Z. Q. and Zhang, J. P. (2017) The WNT/β-catenin signaling pathway may be involved in granulosa cell apoptosis from patients with PCOS in North China. Journal of Gynecology Obstetrics and Human Reproduction, 46(1), 9399. doi: 10.1016/j.jgyn.2015.08.013 CrossRefGoogle ScholarPubMed
Wu, X. K., Zhou, S. Y., Liu, J. X., Pöllänen, P., Sallinen, K., Mäkinen, M. and Erkkola, R. (2003). Selective ovary resistance to insulin signaling in women with polycystic ovary syndrome. Fertility and Sterility, 80(4), 954965. doi: 10.1016/s0015-0282(03)01007-0 CrossRefGoogle ScholarPubMed
Xiong, W. J., Hu, L. J., Jian, Y. C., Wang, L. J., Jiang, M., Li, W. and He, Y. (2012). Wnt5a participates in hepatic stellate cell activation observed by gene expression profile and functional assays. World Journal of Gastroenterology, 18(15), 17451752. doi: 10.3748/wjg.v18.i15.1745 CrossRefGoogle ScholarPubMed
Xu, P., Che, Y., Cao, Y., Wu, X., Sun, H., Liang, F., Sun, J., Ke, L., Yi, L. and Wang, Y. (2010). Polymorphisms of TCF7L2 and HHEX genes in Chinese women with polycystic ovary syndrome. Journal of Assisted Reproduction and Genetics, 27(1), 2328. doi: 10.1007/s10815-009-9377-8 CrossRefGoogle ScholarPubMed
Yamaguchi, T. P., Bradley, A., McMahon, A. P. and Jones, S. (1999). A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. Development, 126(6), 12111223. doi: 10.1242/dev.126.6.1211 CrossRefGoogle ScholarPubMed
Zeng, L., Fagotto, F., Zhang, T., Hsu, W., Vasicek, T. J., Perry, W. L., 3rd, Lee, J. J., Tilghman, S. M., Gumbiner, B. M. and Costantini, F. (1997). The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation. Cell, 90(1), 181192. doi: 10.1016/s0092-8674(00)80324-4 CrossRefGoogle ScholarPubMed
Zhao, Y., Zhang, C., Huang, Y., Yu, Y., Li, R., Li, M., Liu, N., Liu, P. and Qiao, J. (2015). Unregulated expression of WNT5a increases inflammation and oxidative stress via PI3K/AKT/NF-kB signaling in the granulosa cells of PCOS patients. Journal of Clinical Endocrinology and Metabolism, 100(1), 201211. doi: 10.1210/jc.2014-2419 CrossRefGoogle Scholar