Transcription factor‑microRNA synergistic regulatory network revealing the mechanism of polycystic ovary syndrome

Liu,Hai‑Ying; Huang,Yu‑Ling; Liu,Jian‑Qiao; Huang,Qing

doi:10.3892/mmr.2016.5019

Transcription factor‑microRNA synergistic regulatory network revealing the mechanism of polycystic ovary syndrome

Authors:
- Hai‑Ying Liu
- Yu‑Ling Huang
- Jian‑Qiao Liu
- Qing Huang
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Affiliations: Department of Reproductive Medicine Center, Key Laboratory for Reproductive Medicine of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510000, P.R. China
Published online on: March 21, 2016 https://doi.org/10.3892/mmr.2016.5019
Pages: 3920-3928
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Polycystic ovary syndrome (PCOS) is the most common type of endocrine disorder, affecting 5‑11% of women of reproductive age worldwide. Transcription factors (TFs) and microRNAs are considered to have crucial roles in the developmental process of several diseases and have synergistic regulatory actions. However, the effects of TFs and microRNAs, and the patterns of their cooperation in the synergistic regulatory network of PCOS, remain to be elucidated. The present study aimed to determine the possible mechanism of PCOS, based on a TF‑microRNA synergistic regulatory network. Initially, the differentially expressed genes (DEGs) in PCOS were identified using microarray data of the GSE34526 dataset. Subsequently, the TFs and microRNAs which regulated the DEGs of PCOS were identified, and a PCOS‑associated TF‑microRNA synergistic regulatory network was constructed. This network included 195 DEGs, 136 TFs and 283 microRNAs, and the DEGs were regulated by TFs and microRNAs. Based on topological and functional enrichment analyses, SP1, mir‑355‑5p and JUN were identified as potentially crucial regulators in the development of PCOS and in characterizing the regulatory mechanism. In conclusion, the TF‑microRNA synergistic regulatory network constructed in the present study provides novel insight on the molecular mechanism of PCOS in the form of synergistic regulated model.

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1	Sirmans SM and Pate KA: Epidemiology, diagnosis and management of polycystic ovary syndrome. Clin Epidemiol. 6:1–13. 2013. View Article : Google Scholar
2	Raja-Khan N, Stener-Victorin E, Wu X and Legro RS: The physiological basis of complementary and alternative medicines for polycystic ovary syndrome. American journal of physiology. Am J Physiol Endocrinol Metab. 301:E1–E10. 2011. View Article : Google Scholar : PubMed/NCBI
3	Trivax B and Azziz R: Diagnosis of polycystic ovary syndrome. Clin Obstet Gynecol. 50:168–177. 2007. View Article : Google Scholar : PubMed/NCBI
4	Joham AE, Ranasinha S, Zoungas S, Moran L and Teede HJ: Gestational diabetes and type 2 diabetes in reproductive-aged women with polycystic ovary syndrome. J Clin Endocrinol Metab. 99:447–452. 2014.
5	Nasrat H, Patra SK, Goswami B, Jain A and Raghunandan C: Study of association of leptin and insulin resistance markers in patients of PCOS. Indian J Clin Biochem. 31:104–107. 2016. View Article : Google Scholar : PubMed/NCBI
6	Kao YH, Chiu WC, Hsu MI and Chen YJ: Endothelial progenitor cell dysfunction in polycystic ovary syndrome: Implications for the genesis of cardiovascular diseases. Int J Fertil Steril. 6:208–213. 2013.
7	Chang AY, Oshiro J, Ayers C and Auchus RJ: Influence of race/ethnicity on cardiovascular risk factors in polycystic ovary syndrome, the Dallas Heart Study. Clin Endocrinol (Oxf). Nov 26–2015.Epub ahead of print. View Article : Google Scholar
8	Cheng C, Zhang H, Zhao Y, Li R and Qiao J: Paternal history of diabetes mellitus and hypertension affects the prevalence and phenotype of PCOS. J Assist Reprod Genet. 32:1731–1739. 2015. View Article : Google Scholar : PubMed/NCBI
9	Lee YJ, Jeong JE, Joo JK and Lee KS: A case of idiopathic intracranial hypertension associated with PCOS. Clin Exp Obstet Gynecol. 42:547–549. 2015.PubMed/NCBI
10	Bazarganipour F, Ziaei S, Montazeri A, Foroozanfard F, Kazemnejad A and Faghihzadeh S: Psychological investigation in patients with polycystic ovary syndrome. Health Qual Life Outcomes. 11:1412013. View Article : Google Scholar : PubMed/NCBI
11	Qi X, Pang Y and Qiao J: Role of Anti-Müllerian Hormone in the pathogenesis and pathophysiological characteristics of polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 199:82–87. 2016. View Article : Google Scholar : PubMed/NCBI
12	Ding L, Gao F, Zhang M, Yan W, Tang R, Zhang C and Chen ZJ: Higher PDCD4 expression is associated with obesity, insulin resistance, lipid metabolism disorders, and granulosa cell apoptosis in polycystic ovary syndrome. Fertil Steril. Feb 8–2016.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI
13	Palioura E and Diamanti-Kandarakis E: Polycystic ovary syndrome (PCOS) and endocrine disrupting chemicals (EDCs). Rev Endocr Metab Disord. Jan 29–2016.Epub ahead of print. PubMed/NCBI
14	Rajender S, Carlus SJ, Bansal SK, Negi MP, Sadasivam N, Sadasivam MN and Thangaraj K: Androgen receptor CAG repeats length polymorphism and the risk of polycystic ovarian syndrome (PCOS). PLoS One. 8:e757092013. View Article : Google Scholar : PubMed/NCBI
15	Gul OO, Cander S, Gul B, Acikgoz E, Sarandol E and Ersoy C: Evaluation of insulin resistance and plasma levels for visfatin and resistin in obese and non-obese patients with polycystic ovary syndrome. Eur Cytokine Netw. 26:73–78. 2015.
16	Rice S, Elia A, Jawad Z, Pellatt L and Mason HD: Metformin inhibits follicle-stimulating hormone (FSH) action in human granulosa cells: Relevance to polycystic ovary syndrome. J Clin Endocrinol Metab. 98:E1491–E1500. 2013. View Article : Google Scholar : PubMed/NCBI
17	Li D, Li C, Xu Y, Xu D, Li H, Gao L, Chen S, Fu L, Xu X, Liu Y, et al: Differential expression of microRNAs in the ovaries from letrozole-induced rat model of polycystic ovary syndrome. DNA Cell Biol. Jan 8–2016.Epub ahead of print. View Article : Google Scholar
18	Ojeda-Ojeda M, Murri M, Insenser M and Escobar-Morreale HF: Mediators of low-grade chronic inflammation in polycystic ovary syndrome (PCOS). Curr Pharm Des. 19:5775–5791. 2013. View Article : Google Scholar : PubMed/NCBI
19	Roth LW, McCallie B, Alvero R, Schoolcraft WB, Minjarez D and Katz-Jaffe MG: Altered microRNA and gene expression in the follicular fluid of women with polycystic ovary syndrome. J Assist Reprod Genet. 31:355–362. 2014. View Article : Google Scholar : PubMed/NCBI
20	Hossain MM, Cao M, Wang Q, Kim JY, Schellander K, Tesfaye D and Tsang BK: Altered expression of miRNAs in a dihydrotestosterone-induced rat PCOS model. J Ovarian Res. 6:362013. View Article : Google Scholar : PubMed/NCBI
21	Sang Q, Yao Z, Wang H, Feng R, Wang H, Zhao X, Xing Q, Jin L, He L and Wu L: Identification of microRNAs in human follicular fluid: Characterization of microRNAs that govern steroidogenesis in vitro and are associated with poly-cystic ovary syndrome in vivo. J Clin Endocrinol Metab. 98:3068–3079. 2013. View Article : Google Scholar : PubMed/NCBI
22	Chen YH, Heneidi S, Lee JM, Layman LC, Stepp DW, Gamboa GM, Chen BS, Chazenbalk G and Azziz R: miRNA-93 inhibits GLUT4 and is overexpressed in adipose tissue of polycystic ovary syndrome patients and women with insulin resistance. Diabetes. 62:2278–2286. 2013. View Article : Google Scholar : PubMed/NCBI
23	Hsu SD, Tseng YT, Shrestha S, Lin YL, Khaleel A, Chou CH, Chu CF, Huang HY, Lin CM, Ho SY, et al: miRTarBase update 2014: An information resource for experimentally validated miRNA-target interactions. Nucleic acids research. 42:D78–D85. 2014. View Article : Google Scholar :
24	Yang JH, Li JH, Jiang S, Zhou H and Qu LH: ChIPBase: A database for decoding the transcriptional regulation of long non-coding RNA and microRNA genes from ChIP-Seq data. Nucleic Acids Res. 41:D177–D187. 2013. View Article : Google Scholar :
25	Kaur S, Archer KJ, Devi MG, Kriplani A, Strauss JF III and Singh R: Differential gene expression in granulosa cells from polycystic ovary syndrome patients with and without insulin resistance: Identification of susceptibility gene sets through network analysis. J Clin Endocrinol Metab. 97:E2016–E2021. 2012. View Article : Google Scholar : PubMed/NCBI
26	Huang da W, Sherman BT and Lempicki RA: Bioinformatics enrichment tools: Paths toward the comprehensive functional analysis of large gene lists. Nucleic acids research. 37:1–13. 2009. View Article : Google Scholar
27	Yang JH, Li JH, Jiang S, Zhou H and Qu LH: ChIPBase: A database for decoding the transcriptional regulation of long non-coding RNA and microRNA genes from ChIP-Seq data. Nucleic Acids Res. 41:D177–D187. 2013. View Article : Google Scholar :
28	Raja-Khan N, Urbanek M, Rodgers RJ and Legro RS: The role of TGF-β in polycystic ovary syndrome. Reprod Sci. 21:20–31. 2014. View Article : Google Scholar
29	Uchimura K, Hayata M, Mizumoto T, Miyasato Y, Kakizoe Y, Morinaga J, Onoue T, Yamazoe R, Ueda M, Adachi M, et al: The serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signalling. Nat Commun. 5:34282014. View Article : Google Scholar : PubMed/NCBI
30	Solomon SS, Majumdar G, Martinez-Hernandez A and Raghow R: A critical role of Sp1 transcription factor in regulating gene expression in response to insulin and other hormones. Life Sci. 83:305–312. 2008. View Article : Google Scholar : PubMed/NCBI
31	Anjali G, Kaur S, Lakra R, Taneja J, Kalsey GS, Nagendra A, Shrivastav TG, Gouri Devi M, Malhotra N, Kriplani A and Singh R: FSH stimulates IRS-2 expression in human granulosa cells through cAMP/SP1, an inoperative FSH action in PCOS patients. Cell Signal. 27:2452–2466. 2015. View Article : Google Scholar : PubMed/NCBI
32	Jansen E, Laven JS, Dommerholt HB, Polman J, van Rijt C, van den Hurk C, Westland J, Mosselman S and Fauser BC: Abnormal gene expression profiles in human ovaries from polycystic ovary syndrome patients. Mol Endocrinol. 18:3050–3063. 2004. View Article : Google Scholar : PubMed/NCBI
33	Lee BS, Oh J, Kang SK, Park S, Lee SH, Choi D, Chung JH, Chung YW and Kang SM: Insulin protects cardiac myocytes from doxorubicin toxicity by Sp1-mediated transactivation of survivin. PLoS One. 10:e01354382015. View Article : Google Scholar : PubMed/NCBI
34	Huang X, Hao C, Shen X, Zhang Y and Liu X: RUNX2, GPX3 and PTX3 gene expression profiling in cumulus cells are reflective oocyte/embryo competence and potentially reliable predictors of embryo developmental competence in PCOS patients. Reprod Biol Endocrinol. 11:1092013. View Article : Google Scholar : PubMed/NCBI
35	Wang A, Al-Kuhlani M, Johnston SC, Ojcius DM, Chou J and Dean D: Transcription factor complex AP-1 mediates inflammation initiated by Chlamydia pneumoniae infection. Cell Microbiol. 15:779–794. 2013. View Article : Google Scholar :
36	Chazenbalk G, Chen YH, Heneidi S, Lee JM, Pall M, Chen YD and Azziz R: Abnormal expression of genes involved in inflammation, lipid metabolism and Wnt signaling in the adipose tissue of polycystic ovary syndrome. J Clin Endocrinol Metab. 97:E765–E770. 2012. View Article : Google Scholar : PubMed/NCBI
37	Saikumar P, Selvi VK, Prabhu K, Venkatesh P and Krishna P: Anti mullerian hormone: A potential marker for recruited non growing follicle of ovarian pool in women with polycystic ovarian syndrome. J Clin Diagn Res. 7:1866–1869. 2013.PubMed/NCBI