Emerging Role of the ceRNA-Based MALAT-1-miRNA Network in Polycystic Ovary Syndrome

ABSTRACT


Introduction
Polycystic ovary syndrome (PCOS) is an important endocrine problem and a heterogeneous disorder that develops in reproductive-aged women (1, 2).This multifactorial disease with a prevalence between 5% to 15% can disrupt ovarian and reproductive function, and cause infertility (3).PCOS symptoms can be divided into a few PCOS-linked, mild, severe, or all PCOSlinked symptoms (4).PCOS is commonly associated with hormonal imbalance or hyperandrogenism (5), dyslipidemia (6), insulin resistance  Accumulating evidence has found the important roles of MALAT1 in controlling PCOS (43).MALAT1 as a competitive endogenous RNA (ceRNA) can inhibit microRNAs (miRNAs) and control granulosa cell (GCs) proliferation, apoptosis, and pathogenesis (44, 45).miRNAs are a class of ncRNAs with 20-22 lengths that regulate key genes at the level of transcription and post-transcription (46, 47).In the present article, we summarize the role of the lncRNA MALAT1/miRNA axis in PCOS.

Biogenesis of MALAT1
MALAT1 or nuclear-enriched abundant transcript 2 (NEAT2) is a well-known nuclear-retained lncRNA with more than 8-kb in nuclear speckles (the sites of pre-mRNA splicing) (48).This lncRNA is transcribed via the enzyme RNA polymerase II (49) and contains a tRNA-like structure with a triple-helix element at the 3′-end known as MALAT1 associated with small cytoplasmic RNA (mascRNA) and a short poly (A) tail-like moiety (50).RNase P and RNase Z are two endonucleases that separate mascRNA and pre-mature MALAT1, respectively to produce mature-MALAT1 (51-53).MALAT1 can act as miRNA sponges and reduce the impact of miRNAs on target mRNAs (54).MALAT1 has been shown to involve in the alternative splicing of various oncogenes and the assembly of polycomb repressive complexes (PRC) such as EZH2 and SUZ12 (55).Abnormal expression of MALAT1 is one of the prognostic factors for cell autophagy, migration, and drug resistance (49, 56, 57).In the reproductive system, the abnormal expression of MALAT1 was observed in endometriosis, pregnancy loss, and PCOS (58).However, the exact function of MALAT1 in PCOS is still unclear (59).In GCs, MALAT1 has been shown to bind with miRNAs and regulate cell growth, proliferation, and apoptosis (58, 60).Table 1 and Figure 1 demonstrates a schematic of possible cross-linkages between MALAT1 and miRNAs in PCOS.Here, we summarized the functional roles of MALAT1 in GCs of patients with PCOS.A recent study reported that low expression of MALAT1 may contribute to the pathophysiology of patients with PCOS.In GCs, MALAT1 via targeting MDM2 and PARP1 reduced p53 protein levels.Therefore, low expression of MALAT1 inhibited cell proliferation and accelerated apoptosis (62).

Ref. MALAT-1 Function
The expression of MALAT1 was reported to be downregulated in ovarian tissue of PCOS.Chen et al. displayed that miR-302d-3p can suppress leukemia inhibitory factor (LIF) and increase ovarian tissue damage.MALAT1 by targeting miR-302d-3p, upregulated the expression of LIF and reduced mouse GCs proliferation.They found that knocking down of MALAT1 accelerated the activity of caspase-3/9 and promoted cellular apoptosis.In the PCOS rat, high expression of MALAT1 decreased the concentration of FSH and enhanced estradiol (E2), T, and LH.Therefore, MALAT1 by regulating the miR-302d-3p/LIF axis has a protective role in reducing endocrine disorder in PCOS (43).
Cyclic AMP response element-(CRE-) binding protein 1 (CREB1) is involved in the follicular growth and increased E2 and progesterone (P4) levels in mouse GCs.Also, the CREB1 knockdown enhanced cell proliferation and apoptosis, and decreased the expression of the Cyclin A1, Cyclin B1, and Cyclin D2 as cell cycle factors (63).miR-205 by targeting CREB1 can induce GC apoptosis (64).Sun et al. showed that MALAT1 by suppressing miR-205 positively regulates the expression of CREB1 and up-regulates the synthesis of E2 and P4.Knockdown of MALAT1 decreased estradiol synthesis, increased apoptosis and caspase-3/9 activities in mouse GCs.They also displayed that the expression of two steroidogenic enzymes such as cytochrome P450 1B1 (CYP1B1) and cytochrome P450 (CYP19A1) were decreased following MALAT1 depletion.Their results suggested that MALAT1 might be an important biomarker in the regulation of steroidogenesis in mGCs (29).Therefore, the ceRNA-based MALAT-1-miRNA network has a critical role in the pathogenesis of PCOS.

Conclusion
Considering the above-mentioned examples, we highlighted the recently reported function of MALAT1 in PCOS.Although the expression of MALAT1 was found to be decreased in women with PCOS, the exact roles of MALAT1 remain largely unknown and further studies are required to confirm this hypothesis.In GCs from patients with PCOS, MALAT1 by targeting several signaling pathways such as TGF-β, LIF, E2, P4 and some miRNAs such as miR-125b, miR-203a, miR-302d-3p, and miR-205 participates in controlling PCOS.Therefore, MALAT1 can be used as a potential biomarker for treatment of PCOS.

(32, 33). MALAT1
as an oncogene was reported to stimulate tumor cell proliferation and migration in various cancers such as breast ( ).LncRNAs have crucial roles in gene transcription, cellular proliferation, inflammation, and apoptosis (28).