Iranian Society of Gynecology Oncology

Document Type : Review Article


1 Department of Obstetrics and Gynecology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

2 Fertility and Infertility Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran

3 Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran


Polycystic ovary syndrome (PCOS) is a hormonal disorder and a common health problem that affects women at the early to late reproductive stage. Several genetic and environmental factors such as obesity, liver diseases, imbalance of androgens, and menstrual dysfunction have contributed to the progression of PCOS. Research has shown a link between diabetes, hypertension, miscarriages, and cardiovascular disease with PCOS. Experimental discoveries have begun to evaluate the mechanisms involved in PCOS. Although various classical interventions are used in the treatment of PCOS, current medications are not able to control outcomes of PCOS and the management of this syndrome is still challenging. Accumulating evidence showed that dysregulation of long non-coding RNAs (lncRNAs) is essential to PCOS pathogenesis. LncRNAs are a class of transcripts that mediate the process of gene expressions at the level of transcription and post-transcription. It has been found that lncRNA metastasis‐associated lung adenocarcinoma transcript‐1 (MALAT1 or nuclear-enriched abundant transcript 2 (NEAT2)) presents a vital role in regulating PCOS. MALAT-1 as a competing endogenous RNA (ceRNA) can suppress microRNAs (miRNAs) and decrease granulosa cell proliferation, apoptosis, and pathogenesis. Abnormal expression of MALAT1 is one of the prognostic factors for cell autophagy, migration, and drug resistance. MALAT1 can be used as a potential biomarker for treatment of PCOS. However, the exact roles of MALAT1 in granulosa cells of women with PCOS remain largely unknown and further studies are required to confirm its action. In the present article, we summarize the functions of the lncRNA MALAT-1/miRNA axes in women with PCOS.


 Polycystic ovary syndrome (PCOS) is a hormonal disorder and a common health problem that affects women at the early to late reproductive stage. Several genetic and environmental factors such as obesity, liver diseases, imbalance of androgens, and menstrual dysfunction have contributed to the progression of PCOS


Main Subjects

1. Mu Y, Cheng D, Yin T-l, Yang J. Vitamin D and polycystic ovary syndrome: A narrative review. Reprod Sci. 2021;28(8):2110-7. [DOI:10.1007/s43032-020-00369-2] [PMID]
2. Joham AE, Piltonen T, Lujan ME, Kiconco S, Tay CT. Challenges in diagnosis and understanding of natural history of polycystic ovary syndrome. Clin Endocrinol. 2022;97(2):165-73. [DOI:10.1111/cen.14757] [PMID] [PMCID]
3. Zehravi M, Maqbool M, Ara I. Polycystic ovary syndrome and infertility: an update. Int J Adolesc Med Health. 2021;34(2):1-9. [DOI:10.1515/ijamh-2021-0073] [PMID]
4. Kshetrimayum C, Sharma A, Mishra VV, Kumar S. Polycystic ovarian syndrome: Environmental/occupational, lifestyle factors; an overview. J Turk Ger Gynecol Assoc. 2019;20(4):255-63. [DOI:10.4274/jtgga.galenos.2019.2018.0142] [PMID] [PMCID]
5. Ashraf S, Nabi M, Rasool SuA, Rashid F, Amin S. Hyperandrogenism in polycystic ovarian syndrome and role of CYP gene variants: a review. Egypt J Med Hum Genet. 2019;20(1):25. [DOI:10.1186/s43042-019-0031-4]
6. Liu Q, Xie Y-j, Qu L-h, Zhang M-x, Mo Z-c. Dyslipidemia involvement in the development of polycystic ovary syndrome. Taiwan J Obstet Gynecol. 2019;58(4):447-53. [DOI:10.1016/j.tjog.2019.05.003] [PMID]
7. Moghetti P, Tosi F. Insulin resistance and PCOS: chicken or egg? J Endocrinol Invest. 2021;44(2):233-44. [DOI:10.1007/s40618-020-01351-0] [PMID]
8. Thong EP, Lim SS, editors. Obesity, Diabetes and Reproductive Health. Seminars in Reproductive Medicine; 2021: Thieme Medical Publishers, Inc.
9. Mohammadi M. Oxidative stress and polycystic ovary syndrome: a brief review. Int J Prev Med. 2019;10(1):86. [DOI:10.4103/ijpvm.IJPVM_576_17] [PMID] [PMCID]
10. Barber TM, Hanson P, Weickert MO, Franks S. Obesity and polycystic ovary syndrome: implications for pathogenesis and novel management strategies. Clin Med Insights Reprod Health. 2019;13:1179558119874042. [DOI:10.1177/1179558119874042] [PMID] [PMCID]
11. Muhas C, Nishad K, Naseef P, Vajid KA. An Overview on Polycystic Ovary Syndrome (PCOS). Technol Innov Pharm Res. 2021;6:19-30. [DOI:10.9734/bpi/tipr/v6/9810D]
12. Asfari MM, Sarmini MT, Baidoun F, Al-Khadra Y, Ezzaizi Y, Dasarathy S, et al. Association of non-alcoholic fatty liver disease and polycystic ovarian syndrome. BMJ Open Gastroenterol. 2020;7(1):e000352. [DOI:10.1136/bmjgast-2019-000352] [PMID] [PMCID]
13. Shengir M, Chen T, Guadagno E, Ramanakumar AV, Ghali P, Deschenes M, et al. Non‐alcoholic fatty liver disease in premenopausal women with polycystic ovary syndrome: A systematic review and meta‐analysis. JGH Open. 2021;5(4):434-45. [DOI:10.1002/jgh3.12512] [PMID] [PMCID]
14. Krysiak R, Szkróbka W, Okopień B. The impact of atorvastatin on cardiometabolic risk factors in brothers of women with polycystic ovary syndrome. Pharmacol Rep. 2021;73(1):261-8. [DOI:10.1007/s43440-020-00135-w] [PMID] [PMCID]
15. Cooney LG, Dokras A. Cardiometabolic Risk in Polycystic Ovary Syndrome: Current Guidelines. Endocrinol Metab Clin. 2021;50(1):83-95. [DOI:10.1016/j.ecl.2020.11.001] [PMID]
16. De Leo V, Musacchio M, Cappelli V, Massaro M, Morgante G, Petraglia F. Genetic, hormonal and metabolic aspects of PCOS: an update. Reprod Biol Endocrinol. 2016;14(1):1-17. [DOI:10.1186/s12958-016-0173-x] [PMID] [PMCID]
17. Khan MJ, Ullah A, Basit S. Genetic basis of polycystic ovary syndrome (PCOS): current perspectives. Appl Clin Genet. 2019;12:249. [DOI:10.2147/TACG.S200341] [PMID] [PMCID]
18. Khan GH. The diagnostic and prognostic role of proteomics and metabolomics in Polycystic Ovary Syndrome: University of Nottingham; 2018.
19. de Melo AS, Dias SV, de Carvalho Cavalli R, Cardoso VC, Bettiol H, Barbieri MA, et al. Pathogenesis of polycystic ovary syndrome: multifactorial assessment from the foetal stage to menopause. Reproduction. 2015;150(1):R11-R24. [DOI:10.1530/REP-14-0499] [PMID]
20. Elkind-Hirsch KE, Chappell N, Seidemann E, Storment J, Bellanger D. Exenatide, dapagliflozin or phentermine/topiramate differentially affect metabolic profiles in polycystic ovary syndrome. J Clin Endocrinol Metab. 2021;06(10):3019-33. [DOI:10.1210/clinem/dgab408] [PMID]
21. Xu Y, Tang J, Guo Q, Xu Y, Yan K, Wu L, et al. Traditional Chinese Medicine formula FTZ protects against polycystic ovary syndrome through modulating adiponectin-mediated fat-ovary crosstalk in mice. J Ethnopharmacol. 2021;268:113587. [DOI:10.1016/j.jep.2020.113587] [PMID]
22. Zhang S-w, Zhou J, Gober H-J, Leung WT, Wang L. Effect and mechanism of berberine against polycystic ovary syndrome. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2021;138:111468. [DOI:10.1016/j.biopha.2021.111468] [PMID]
23. Saito S, Yamamoto M, Iwaizumi S, Yoshida H, Shigeta H. Laparoscopic surgery for massive ovarian edema during pregnancy: A case report. Case Rep Women's Health. 2021;31:e00318. [DOI:10.1016/j.crwh.2021.e00318] [PMID] [PMCID]
24. Tu M, Wu Y, Mu L, Zhang D. Long non-coding RNAs: novel players in the pathogenesis of polycystic ovary syndrome. Ann Transl Med. 2021;9(2). [DOI:10.21037/atm-20-5044] [PMID] [PMCID]
25. Wawrzkiewicz-Jałowiecka A, Kowalczyk K, Trybek P, Jarosz T, Radosz P, Setlak M, et al. In Search of New Therapeutics-Molecular Aspects of the PCOS Pathophysiology: Genetics, Hormones, Metabolism and Beyond. Int J Mol Sci. 2020;21(19):7054. [DOI:10.3390/ijms21197054] [PMID] [PMCID]
26. Jia L-Y, Feng J-X, Li J-L, Liu F-Y, Xie L-z, Luo S-J, et al. The Complementary and Alternative Medicine for Polycystic Ovary Syndrome: A Review of Clinical Application and Mechanism. Evid Based Complementary Altern Med. 2021;2021:1-2. [DOI:10.1155/2021/5555315] [PMID] [PMCID]
27. Che Q, Liu M, Zhang D, Lu Y, Xu J, Lu X, et al. Long noncoding RNA HUPCOS promotes follicular fluid androgen excess in PCOS patients via aromatase inhibition. J Clin Endocrinol Metab. 2020;105(4):1086-97. [DOI:10.1210/clinem/dgaa060] [PMID]
28. Anbiyaiee A, Ramazii M, Bajestani SS, Meybodi SM, Keivan M, Khoshnam SE, et al. The function of LncRNA-ATB in cancer. Clin Transl Oncol. 2022(1):1-9. [DOI:10.1007/s12094-022-02848-1] [PMID]
29. Sun L, Zhang P, Lu W. lncRNA MALAT1 Regulates Mouse Granulosa Cell Apoptosis and 17β-Estradiol Synthesis via Regulating miR-205/CREB1 Axis. Biomed Res Int. 2021;2021:1-9. [DOI:10.1155/2021/9140191] [PMID] [PMCID]
30. Pielok A, Marycz K. Non-coding RNAs as potential novel biomarkers for early diagnosis of hepatic insulin resistance. Int J Mol sci. 2020;21(11):4182. [DOI:10.3390/ijms21114182] [PMID] [PMCID]
31. Xu W-W, Jin J, Wu X-y, Ren Q-L, Farzaneh M. MALAT1-related signaling pathways in colorectal cancer. Cancer Cell Int. 2022;22(1):1-9. [DOI:10.1186/s12935-022-02540-y] [PMID] [PMCID]
32. Arun G, Aggarwal D, Spector DL. MALAT1 long non-coding RNA: Functional implications. Non-coding RNA. 2020;6(2):22. [DOI:10.3390/ncrna6020022] [PMID] [PMCID]
33. Wei Y, Niu B. Role of MALAT1 as a Prognostic Factor for Survival in Various Cancers: A Systematic Review of the Literature with Meta-Analysis. Dis Markers. 2015;2015:164635. [DOI:10.1155/2015/164635] [PMID] [PMCID]
34. Qiao F-H, Tu M, Liu H-Y. Role of MALAT1 in gynecological cancers: Pathologic and therapeutic aspects. OncolLett. 2021;21(4):1-8. [DOI:10.3892/ol.2021.12594] [PMID] [PMCID]
35. Lu X, Chen D, Yang F, Xing N. Quercetin inhibits epithelial-to-mesenchymal transition (EMT) process and promotes apoptosis in prostate cancer via downregulating lncRNA MALAT1. Cancer Manag Res. 2020;12:1741. [DOI:10.2147/CMAR.S241093] [PMID] [PMCID]
36. Dai Q, Zhang T, Li C. LncRNA MALAT1 regulates the cell proliferation and cisplatin resistance in gastric cancer via PI3K/AKT pathway. Cancer Manag Res. 2020;12:1929. [DOI:10.2147/CMAR.S243796] [PMID] [PMCID]
37. Li P, Zhang X, Wang H, Wang L, Liu T, Du L, et al. MALAT1 is associated with poor response to oxaliplatin-based chemotherapy in colorectal cancer patients and promotes chemoresistance through EZH2. Mol Cancer Ther. 2017;16(4):739-51. [DOI:10.1158/1535-7163.MCT-16-0591] [PMID]
38. Zhang H, Li W, Gu W, Yan Y, Yao X, Zheng J. MALAT1 accelerates the development and progression of renal cell carcinoma by decreasing the expression of miR‐203 and promoting the expression of BIRC5. Cell proliferation. 2019;52(5):e12640. [DOI:10.1111/cpr.12640] [PMID] [PMCID]
39. Ji D-G, Guan L-Y, Luo X, Ma F, Yang B, Liu H-Y. Inhibition of MALAT1 sensitizes liver cancer cells to 5-flurouracil by regulating apoptosis through IKKα/NF-κB pathway. Biochem Biophys Res Commun. 2018;501(1):33-40. [DOI:10.1016/j.bbrc.2018.04.116] [PMID]
40. Sun R, Qin C, Jiang B, Fang S, Pan X, Peng L, et al. Down-regulation of MALAT1 inhibits cervical cancer cell invasion and metastasis by inhibition of epithelial-mesenchymal transition. Mol Biosyst. 2016;12(3):952-62. [DOI:10.1039/C5MB00685F] [PMID]
41. Fu S, Wang Y, Li H, Chen L, Liu Q. Regulatory Networks of LncRNA MALAT-1 in Cancer. Cancer Manag Res. 2020;12:10181. [DOI:10.2147/CMAR.S276022] [PMID] [PMCID]
42. Li Q, Dai Y, Wang F, Hou S. Differentially expressed long non-coding RNAs and the prognostic potential in colorectal cancer. Neoplasma. 2016;63(6):977-83. [DOI:10.4149/neo_2016_617] [PMID]
43. Chen Y, Chen Y, Cui X, He Q, Li H. Down-regulation of MALAT1 aggravates polycystic ovary syndrome by regulating MiR-302d-3p-mediated leukemia inhibitory factor activity. Life sciences. 2021;277:119076. [DOI:10.1016/j.lfs.2021.119076] [PMID]
44. Ma Y, Ma L, Cao Y, Zhai J. Construction of a ceRNA-based lncRNA-mRNA network to identify functional lncRNAs in polycystic ovarian syndrome. Aging (Albany NY). 2021;13(6):8481. [DOI:10.18632/aging.202659] [PMID] [PMCID]
45. Chen H, Cheng S, Xiong W, Tan X. The lncRNA-miRNA-mRNA ceRNA network in mural granulosa cells of patients with polycystic ovary syndrome: an analysis of Gene Expression Omnibus data. Ann Transl Med. 2021;9(14). [DOI:10.21037/atm-21-2696] [PMID] [PMCID]
46. Ratti M, Lampis A, Ghidini M, Salati M, Mirchev MB, Valeri N, et al. MicroRNAs (miRNAs) and Long Non-Coding RNAs (lncRNAs) as New Tools for Cancer Therapy: First Steps from Bench to Bedside. Target Oncol. 2020;15(3):261-78. [DOI:10.1007/s11523-020-00717-x] [PMID] [PMCID]
47. Ying H, Ebrahimi M, Keivan M, Khoshnam SE, Salahi S, Farzaneh M. miRNAs; a novel strategy for the treatment of COVID‐19. Cell Biol Int. 2021;45(10):2045-53. [DOI:10.1002/cbin.11653] [PMID] [PMCID]
48. Zhang X, Hamblin MH, Yin K-J. The long noncoding RNA Malat1: Its physiological and pathophysiological functions. RNA Biol. 2017;14(12):1705-14. [DOI:10.1080/15476286.2017.1358347] [PMID] [PMCID]
49. Amodio N, Raimondi L, Juli G, Stamato MA, Caracciolo D, Tagliaferri P, et al. MALAT1: a druggable long non-coding RNA for targeted anti-cancer approaches. J Hematol Oncol. 2018;11(1):1-19. [DOI:10.1186/s13045-018-0606-4] [PMID] [PMCID]
50. Donlic A, Zafferani M, Padroni G, Puri M, Hargrove AE. Regulation of MALAT1 triple helix stability and in vitro degradation by diphenylfurans. Nucleic Acids Res. 2020;48(14):7653-64. [DOI:10.1093/nar/gkaa585] [PMID] [PMCID]
51. Brown JA, Valenstein ML, Yario TA, Tycowski KT, Steitz JA. Formation of triple-helical structures by the 3′-end sequences of MALAT1 and MENβ noncoding RNAs. Proc Natl Acad Sci. 2012;109(47):19202-7. [DOI:10.1073/pnas.1217338109] [PMID] [PMCID]
52. McCown PJ, Wang MC, Jaeger L, Brown JA. Secondary structural model of human MALAT1 reveals multiple structure-function relationships. Int J Mol sci. 2019;20(22):5610. [DOI:10.3390/ijms20225610] [PMID] [PMCID]
53. Song Z, Lin J, Li Z, Huang C. The nuclear functions of long noncoding RNAs come into focus. Non-coding RNA Res. 2021. [DOI:10.1016/j.ncrna.2021.03.002] [PMID] [PMCID]
54. Zeber-Lubecka N, Hennig EE. Genetic Susceptibility to Joint Occurrence of Polycystic Ovary Syndrome and Hashimoto's Thyroiditis: How Far Is Our Understanding? Front Immunol. 2021;12:71. [DOI:10.3389/fimmu.2021.606620] [PMID] [PMCID]
55. Kim SH, Kim SH, Yang WI, Kim SJ, Yoon SO. Association of the long non-coding RNA MALAT1 with the polycomb repressive complex pathway in T and NK cell lymphoma. Oncotarget. 2017;8(19):31305. [DOI:10.18632/oncotarget.15453] [PMID] [PMCID]
56. Zhang X-Z, Liu H, Chen S-R. Mechanisms of Long Non-Coding RNAs in Cancers and Their Dynamic Regulations. Cancers (Basel). 2020;12(5):1245. [DOI:10.3390/cancers12051245] [PMID] [PMCID]
57. Zhao K, Jin S, Wei B, Cao S, Xiong Z. Association study of genetic variation of lncRNA MALAT1 with carcinogenesis of colorectal cancer. Cancer Manag Res. 2018;10:6257-61. [DOI:10.2147/CMAR.S177244] [PMID] [PMCID]
58. Li Y, Liu Y-d, Chen S-l, Chen X, Ye D-s, Zhou X-y, et al. Down-regulation of long non-coding RNA MALAT1 inhibits granulosa cell proliferation in endometriosis by up-regulating P21 via activation of the ERK/MAPK pathway. Basic sci reprod med. 2019;25(1):17-29. [DOI:10.1093/molehr/gay045] [PMID]
59. Tu M, Wu Y, Wang F, Huang Y, Qian Y, Li J, et al. Effect of lncRNA MALAT1 on the Granulosa Cell Proliferation and Pregnancy Outcome in Patients With PCOS. Front Endocrinol. 2022;13:825431-. [DOI:10.3389/fendo.2022.825431] [PMID] [PMCID]
60. Zhang D, Tang HY, Tan L, Zhao DM. MALAT1 is involved in the pathophysiological process of PCOS by modulating TGFβ signaling in granulosa cells. Molecular and cellular endocrinology. 2020;499:110589. [DOI:10.1016/j.mce.2019.110589] [PMID]
61. Raja-Khan N, Urbanek M, Rodgers RJ, Legro RS. The role of TGF-β in polycystic ovary syndrome. Reprod Sci. 2014;21(1):20-31. [DOI:10.1177/1933719113485294] [PMID] [PMCID]
62. Li Y, Xiang Y, Song Y, Zhang D, Tan L. MALAT1 downregulation is associated with polycystic ovary syndrome via binding with MDM2 and repressing P53 degradation. Molecular and cellular endocrinology. 2022;543:111528. [DOI:10.1016/j.mce.2021.111528] [PMID]
63. Zhang P, Wang J, Lang H, Wang W, Liu X, Liu H, et al. Knockdown of CREB1 promotes apoptosis and decreases estradiol synthesis in mouse granulosa cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2018;105:1141-6. [DOI:10.1016/j.biopha.2018.06.101] [PMID]
64. Zhang P, Wang J, Lang H, Wang W, Liu X, Liu H, et al. MicroRNA‐205 affects mouse granulosa cell apoptosis and estradiol synthesis by targeting CREB1. J Cell Biochem. 2019;120(5):8466-74. [DOI:10.1002/jcb.28133] [PMID]