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 Table of Contents  
Year : 2021  |  Volume : 5  |  Issue : 2  |  Page : 107-118

MicroRNA-543 in systemic diseases and possible applications in gynecologic tumors

1 Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200090, China
2 Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200090; Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai 200032; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200090, China

Date of Submission03-Jul-2020
Date of Decision13-Oct-2020
Date of Acceptance04-Dec-2020
Date of Web Publication08-Jul-2021

Correspondence Address:
Xiao-Yong Zhu
Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200090
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2096-2924.320879

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In recent years, an increasing number of young women have been diagnosed with cancer, including some nulliparous women. Therefore, many young patients with early-stage cancer desire to preserve fertility after cytotoxic oncological treatments. It is important to develop a multidisciplinary approach to achieve the best outcomes for each patient. On the other hand, there has been a sharp increase in microRNAs (miRNAs) as potential biomarkers for the diagnosis, prognosis, and evaluation of treatment efficacy of several diseases. MiR-543 has been reported to affect the pathogenesis and progression of diseases via complex mechanisms. Understanding the regulatory role of miR-543 may aid comprehension of the pathogenesis and treatment of a broad range of diseases. Therefore, we provide an overview of the biogenesis, function, and role of miR-543 in various systems. These results shed light on the anticancer and endometrial protection role of miR-543 in young patients with gynecologic tumors and highlight the clinical potential of miR-543-based applications and related challenges.

Keywords: Endometrial Receptivity; Gynecological Oncology; MicroRNA-543; Pathway; Target

How to cite this article:
Sheng YR, Hu WT, Wei CY, Liu YK, Liu YY, Zhu XY. MicroRNA-543 in systemic diseases and possible applications in gynecologic tumors. Reprod Dev Med 2021;5:107-18

How to cite this URL:
Sheng YR, Hu WT, Wei CY, Liu YK, Liu YY, Zhu XY. MicroRNA-543 in systemic diseases and possible applications in gynecologic tumors. Reprod Dev Med [serial online] 2021 [cited 2021 Jul 31];5:107-18. Available from: https://www.repdevmed.org/text.asp?2021/5/2/107/320879

  Introduction Top

According to Cancer Statistics in China, 2015, approximately 202,900 women aged 30–44 years are newly diagnosed with cancer each year in China, although the mortality rate is relatively low (52,800).[1] This means over 70% of those cancer patients will become long-term survivors and some of them will be nulliparous because the mean age for women having their first child has delayed from 26.31 to 29.13 years old from 2000 to 2010.[2] Most young women undergoing cancer treatment strongly desire to have healthy children in the future. Cancer treatment increases rates of diminished fertility and pregnancy complications in survivors. Therefore, an efficient and multidisciplinary approach to achieve the best outcome for each patient is worthy of thorough exploration.

MicroRNAs (miRNAs) are a class of highly conserved noncoding and short RNA molecules (20–30 nt),[3] which are considered master posttranscriptional regulators of gene expression. They perform distinct roles in the physiological functions and pathological states of illnesses, including cancer, infections, metabolic diseases, and cachexia.[4],[5] They exert translational inhibition and mRNA destabilization by hybridizing to complementary sequences in the 3'-untranslated region (3'-UTR) of target RNA transcripts. Over the last few years, numerous studies and databases have been developed to predict or experimentally validate miRNA-disease associations. The miRCancer website (http://mircancer.ecu.edu/) has identified 8,131 relationships between 57,984 miRNAs and 196 human cancers by processing 6,422 published papers until October 31, 2019. In addition, the effects of miRNAs on different cancers depend on the target genes and the intracellular and extracellular microenvironments. They can act as either tumor oncogenes or suppressors by regulating cell proliferation, apoptosis, adhesion, invasion, angiogenesis, and other cellular behaviors. In this review, we summarize the current knowledge about the location of imprinted genes, the synthesis process of miR-543, and its association with diseases in various systems and provide future directions for the promising clinical transformation and challenges of applying miR-543 to preserve the fertility of young patients with cancer.

  The Biogenesis and Function of MicroRNA-543 Top

miR-543 is a member of the miR379–410 cluster, which is the largest known placental mammal-specific miRNA cluster, containing 39 miRNA genes expressed only from the maternal allele, and is mainly involved in neurodevelopmental processes and diverse neuronal functions.[6],[7] These miRNAs are encoded by a sequence on chromosome 14q32.31 in humans and chromosome 12qF1 in mice, and it is highly conserved between them.[8],[9] This coding sequence is called the DLK1-DIO3-imprinted region, spanning ~ 850 kb. This region contains the paternally expressed protein-coding genes, delta-like homolog 1 (DLK1 in human and Dlk1 in mice), retrotransposon-like gene 1 (RTL1 in human and Rtl1 in mice), and type 3 deiodinase (DIO3 in human and Dio3 in mice), and maternally expressed genes MEG3 (Gtl2 in mice), MEG8 (Rian in mice), and antisense RTL1 (RTL1as). Both MEG3 and MEG8 are nonprotein-coding RNAs including miRNAs and C/D small nucleolar RNA (snoRNA) genes.[8] The miR379–410 cluster is encoded by the genes situated in the region between MEG8 and DIO3.

These miRNA genes frequently and autonomously undergo RNA polymerase II (polII)-dependent transcription and later produce a primary-miRNA (pri-miRNA). Then, the pri-miRNA is cleaved and processed into the precursor miRNA (pre-miRNA) by the microprocessor complex, which consists of a ribonuclease enzyme Drosha and RNA-binding protein DGCR8. The pre-miRNA is then transported to the cytoplasm by exportin 5 and is further processed by Dicer, a ribonuclease III enzyme that produces a transient 19–24 nt miRNA–miRNA duplex. Finally, only one strand of the mature miRNA duplex is incorporated into the RNA-induced silencing complex to mediate RNA degradation or posttranslational inhibitory action. Moreover, the mature miRNAs are released from cells into the extracellular space. These miRNAs released from cells into the extracellular space are particularly stable due to microvesicles such as exosomes or apoptotic bodies,[10] as well as subcellular vesicle-free particles such as protein complexes.[11] These extracellular vesicle miRNAs are presumed to be involved in cell-to-cell communication, and they act as effective biomarkers because their aberrant expression is detectable in pathological tissues and in various body fluids such as blood, saliva, urine, and even cerebrospinal fluid.[12] A schematic representation of the DLK1-DIO3-imprinted region in mice and in humans along with the biogenesis and function of miRNA (taking miR-543 as an example) is shown in [Figure 1]. Specifically, the has-miR-543 is in Homo sapiens, mmu-miR-543-3p is in Mus musculus, and rno-miR-543-5p is in Rattus norvegicus. They are all mature miRNAs, but with different annotations.[13]
Figure 1: The schematic representation of the DLK1-DIO3-imprinted region in mice and in humans along with the biogenesis and function of microRNA (taking miR-543 as an example). Genes, snoRNAs, and miRNAs expressed from the paternal and maternally inherited chromosomes are noted by blue and purple, respectively. IG-DMR: Intergenic differentially methylated regions; DLK1: Delta-like homolog 1; DIO3: Type 3-iodothyronine deiodinase; RTL1: Retrotransposon-like gene 1; RTL1as: Antisense; MEG3 (Gtl2): Maternally expressed 3; MEG8 (Rian): Maternally expressed 8; Drosha: Ribonuclease enzyme; DGCR8: RNA binding protein; Dicer: A ribonuclease III enzyme; RISC: RNA-induced silencing complex; snoRNAs: Small nucleolar RNAs.

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In 2013, the research team of Nidadavolu identified the miRNAs dysregulated in the cellular senescence driven by endogenous genotoxic stress. They found that eight miRNAs (including miR-543) were downregulated in the liver of progeroid Ercc1−/Δ and old WT mice compared with young adult WT mice.[14] Since then, there have been many published papers focusing on the interrelationship between miR-543 and the nervous,[15] respiratory, and digestive systems,[16],[17] as well as gynecologic and obstetric diseases.[18],[19],[20] miR-543 could affect the pathogenesis and progression of diseases via a complex functional long noncoding RNA (lncRNA)-miRNA-mRNA-signaling pathway regulatory network.

  The Role of MicroRNA-543 in Systemic Diseases Top

miR-543 has been most studied in the nervous, digestive, and respiratory systems. Due to a variety of target genes and the complexity of the microenvironment in each system, the functions of miR-543 in different systems are varied, including regulating the biological characteristics of cells, promoting or delaying the progress of diseases, and modulating the cellular sensitivity to chemotherapeutics. The relevant information is shown in [Figure 2], [Figure 3] and [Table 1]. The following is a detailed elaboration according to each system.
Figure 2: The role of miR-543 in systemic diseases. The red color indicates genes that are highly expressed or promote disease progression, and the blue color represents genes that are low in expression or relieve disease progression. EN2: Engrailed homeobox 2; Smad7: SMAD family member 7; DNAJB1: Heat shock protein 40; ATXN3: Ataxin-3; SCA3: Spinocerebellar ataxia type 3; GH: Growth hormone; KLF4: Kruppel-like factor 4; KRAS: GTPase; MTA1: Metastasis-associated 1; HMGA2: High mobility group AT-hook 2; PTEN: Phosphatase and tensin homolog; 5-FU: 5-Fluorouracil; DCA: Dichloroacetate; PLA2G4A: Phospholipase A2 group IVA; SIRT1: Sirtuin 1; SPOP: Speckle type BTB/POZ protein; PAQR3: Progestin and adipoQ receptor family member 3; NSCLC: Nonsmall cell lung cancer; ONECUT2: One cut homeobox 2; TWIST1: Twist-related protein 1; ET-1: Endothelin; IL-33: Interleukin-33; COPD: Chronic obstructive pulmonary disease; Angpt2: Angiopoietin 2; PRMT9: Protein arginine methyltransferase 9; HIF-1α: Hypoxia inducible factor 1 subunit alpha; TRT1/2: Ten-eleven translocation 1/2; YAF2: Transcriptional repressor protein Yy1 associated factor 2; KLF6: Kruppel-like factor 6; DKK1: Dickkopf1; RKIP: Raf kinase inhibitor, putative; TSP1: Tumor suppressor region 1; TGFβ: Transforming growth factor beta 1.

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Figure 3: The role of miR-543 in the female reproductive system. FAK: Focal adhesion kinase; TWIST1: Twist-related protein 1; MMP7: Matrix metalloproteinase 7; EN2: Engrailed homeobox 2; ZEB1/2: Zinc finger E-box binding homeobox 1/2; TRPM7: Transient receptor potential melastatin 7; CDH2: N-cadherin; COL16A1: Collagen16A1.

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Table 1: The role of miR.543 in systemic diseases

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The role of microRNA-543 in the nervous system

Several studies have demonstrated the association between miR-543 and neuronal function. The expression levels of miR-543 in six human glioma cell lines (A172, U251, U87, LN229, T98G, and U343) were all downregulated compared with primary normal human astrocytes. In addition, the qRT-PCR results from the glioma specimens showed markedly reduced expression of miR-543 compared with the results from normal brain tissues. Moreover, in high-grade (grades III and IV) gliomas, miR-543 expression was significantly decreased compared with low-grade (grades I and II) gliomas. Therefore, miR-543 may act as a glioma suppressor and is inversely associated with the progression of glioma. Subsequent experiments in vitro and in vivo confirmed this hypothesis. They found that miR-543 could induce apoptosis and inhibit proliferation, cell cycle progression, migration, and invasion of glioma cells to suppress the growth of glioma xenografts. Furthermore, 339 proteins and multiple pathways were predicted to be involved in miR-543-mediated tumorigenesis, such as pyrimidine metabolism, base excision repair, RNA degradation, inositol phosphate metabolism, and adipocytokine signaling pathways, and many other biological processes.[15] Based on the above discoveries, Ebrahimkhani et al.[21] demonstrated the predictive power of miR-543. They selected miR-543 as one of the most stable markers among seven miRNAs for the classification of glioblastoma through random forest modeling and data partitioning results. Moreover, Zeng et al.[22] provided a novel strategy for glioblastoma treatment. Their results emphasized that a competitive endogenous lncRNA LEF1-AS1 facilitates the progression of glioblastoma by sponging miR-543 to upregulate engrailed homeobox 2 (EN2) expression, which has been found to be a novel biomarker in epithelial ovarian cancer.[23] Moreover, EN2 may be a candidate oncogene, which activates the PI3K/AKT pathway and inhibits phosphatase and tensin homolog (PTEN) in bladder cancer.[24]

In addition to its antioncogenic effect in malignant glioma, miR-543 is also oncogenic in benign pituitary adenomas (PAs).[25] miR-543 was upregulated in the PA tissues compared to noninvasive PA tissues. Moreover, the overexpression of miR-543 in the human PA cell line HP75 increased cell proliferation, migration, and invasion and decreased cell apoptosis via the negative regulation of SMAD family member 7 (Smad7), followed by the activation of the Wnt/β-catenin pathway.

A handful of studies have reported the relationship between miR-543 and some less common diseases and processes, for example, pediatric posterior fossa ependymoma,[26] neuronal differentiation of human Wharton's jelly mesenchymal stem cells,[27] and the spinocerebellar ataxia type 3 (SCA3).[28] One study indicated that miR-543 might contribute to the pathogenesis of SCA3, which is caused by a mutation in the polyglutamine (polyQ) protein ataxin-3 (ATXN3). Inhibition of miR-543 along with miR-370 could upregulate the co-chaperone DnaJ homolog subfamily B member 1 (DNAJB1 or heat shock protein 40), which could minimize the toxicity of the polyQ protein ATXN3 and then ease SCA3 disease.[28] This is an interesting mechanism because miR-543 does not normally inhibit the mRNA of ATXN3 but affects the folding of ATXN3 through the molecular chaperone, DNAJB1.

In an experimental rat model of spinal cord injury, miR-543-3p and miR-543-5p can promote nerve regeneration and locomotor function recovery by inhibiting the NF-κB pathway and the subsequent inflammatory factors.[29],[30] On the contrary, miR-543-5p could inhibit the expression of growth hormone 1 mRNA and reduce the secretion of growth hormone in the rat anterior pituitary cells and the GH3 cell line,[31] which is adverse to the growth and development of the organism. These studies lack evidence from human samples.

The role of microRNA-543 in the digestive system

Multiple studies have reported the significant role of miR-543 in the progression of colorectal cancer and the sensitivity to anticancer drugs between different individuals. miR-543 not only suppresses tumor growth and metastasis by targeting the GTPase KRAS, metastasis-associated 1 (MTA1), and high mobility group AT-hook 2 (HMGA2)[32] but also promotes proliferation and metastasis by targeting Kruppel-like factor 4.[16] Moreover, experiments on HCT8/FU colon cancer cell line in vitro showed that an miR-543 inhibitor or mimic could increase the sensitivity of colon cancer cells to 5-fluorouracil (5-FU) through the PTEN/PI3K/AKT pathway.[33] Another study found that dichloroacetate, a pyruvate dehydrogenase kinase inhibitor, can downregulate miR-543 and then overcome oxaliplatin chemoresistance in colorectal cancer cells through the miR-543/PTEN/Akt/mTOR pathway.[34] In the future, miR-543 may be used as a potential marker or therapeutic target in colorectal cancer.

It has been proven that miR-543 acts as an oncogene in gastric cancer by targeting sirtuin 1 (SIRT1)[35] or speckle-type BTB/POZ protein (SPOP)[36] and in hepatocellular carcinoma by targeting progestin and adipoQ receptor family member 3 (PAQR3),[37] while suppressing liver cancer via the JAK2/STAT3 signaling pathway.[38] In esophageal cancer, miR-543 tends to promote migration, invasion, and epithelial–mesenchymal transition (EMT) of cancer cells by targeting phospholipase A2 group IVA,[39] and lncRNA p53-induced transcript (LINC-PINT) acts as a tumor suppressor by sponging miR-543.[40]

The role of microRNA-543 in the respiratory system

Of all malignancies, lung cancer is the leading cause of death worldwide, and 80%–85% of all lung cancers are nonsmall cell lung cancer (NSCLC). Two lncRNA-miRNA-mRNA-signaling pathways have been shown to be involved in the pathogenesis and progression of NSCLC. Through a rigorous series of experiments on NSCLC epithelial cell lines (A549 and H1299 cells) NSCLC tissues, Hu et al. indicated that lncRNA THUMPD3-AS1 (THUMPD3 antisense RNA1) could function as an endogenous sponge of miR-543 to affect cell proliferation and self-renewal by targeting one cut homeobox 2.[41] This novel molecular mechanism could provide a molecular basis for the progression of NSCLC, and miR-543 may be a new biomarker and therapy target for this serious malignant tumor. However, a study found that miR-543 promoted the proliferation and invasion of NSCLC cells by inhibiting the expression of PTEN.[42] Recently, an LINC-PINT has been reported to alleviate lung cancer progression by sponging miR-543 and inducing PTEN, which was proven by in vitro (A549 and H1299 cells) and in vivo experiments.[43] Due to the lack of relevant literature, more experiments are needed to confirm these results. In a basic study of pulmonary arterial hypertension,[44] the researchers found that hypoxia-inducible factor-1α (HIF-1α) could regulate endothelin (ET-1) expression via miRNA-543 and its targeting of twist-related protein-1 (TWIST1). The miR-543/TWIST signal pathway has also been shown to suppress tumorigenesis and metastasis in endometrial cancer[20] as well as in ovarian cancer.[18] Clinical trials have found that the decrease of miR-543 in the plasma and lung tissues may enhance the progression of chronic obstructive pulmonary disease by targeting interleukin-33 (IL-33),[45] the “alarmin” in response to cellular damage, tissue injury, or viral infection.

The role of microRNA-543 in the skeletal system

miR-543 has been reported to be dysregulated in osteosarcoma, which is the most common primary solid bone tumor. Both in vitro and in vivo models were used to determine that miR-543 could inhibit the expression of angiopoietin 2 (Angpt2), which is a key regulator in angiogenesis of tumors, facilitating the growth and metastasis of osteosarcoma. Moreover, connective tissue growth factor (also known as CCN2) could promote osteosarcoma angiogenesis by negatively regulating miR-543 expression and stabilizing the expression of Angpt2 via the phospholipase C (PLC)/protein kinase C (PKCδ) signaling pathway,[46] while miR-543 was found to promote osteosarcoma cell proliferation and glycolysis by partially suppressing the protein arginine methyltransferase 9 (PRMT9) and stabilizing the HIF-1α protein.[47]

In myeloproliferative neoplasm myelofibrosis (MF), which did not respond to ruxolitinib treatment, miR-543 expression was increased. The underlying molecular mechanism of miR-543-related resistance is that the JAK inhibitor, ruxolitinib, could inactivate STAT3. The inhibition of STAT3 in the promoter region of miR-543 was removed and the expression level of miR-543 was elevated, followed by changes in the epigenetic landscape of MF. Specifically, the downregulated expression of dioxygenases ten-eleven translocation 1 and 2 targeted by miR-543 could then decrease the acetylation of histone 3, STAT3, and tumor protein p53, while promoting the expression of global 5-methylcytosine and CYP3A4, which are involved in ruxolitinib metabolism.[48] Moreover, miRNA-543 promoted ovariectomy-induced osteoporosis in rats by targeting the transcriptional repressor protein Yy1 associated factor 2 and then inhibiting the AKT/p38 MAPK signaling pathway.[49]

The role of microRNA-543 in the male urinary system

miRNA-543 promotes the proliferation and metastasis of renal cell carcinoma by targeting Kruppel-like factor 6[50] and dickkopf 1 through the Wnt/β-catenin signaling pathway.[51] In addition, the miR-543/Wnt/β-catenin signaling pathway was found to promote growth and stem cell-like phenotype in bladder cancer.[52] miR-543 acts as an oncogene in prostate cancer by targeting the raf kinase inhibitor, putative[53] and AKT/mTOR pathway. lncRNA HCG11 could control prostate cancer development by sponging endogenous miR-543.[54] A recent study demonstrated that lncRNA RNF7 promoted cardiac fibrosis progression in a rat model by sponging miR-543 and promoting tumor suppressor region 1 protein and transforming growth factor beta 1 activation.[55]

The role of microRNA-543 in gynecological tumors

Breast cancer is one of the most common malignant tumors in women, and its morbidity has increased in recent years. A previous study showed that miR-543 could inhibit breast cancer metastasis by downregulating the zinc finger transcription factor ZNF281. ZNF281 is an inducer of EMT and transactivates the expression of zinc finger E-box binding homeobox 1 (ZEB1) and Snail. Furthermore, the latter two can suppress miR-543 expression transcriptionally. This ZNF281-miR-543 feedback loop participates in regulating breast cancer metastasis.[56]

In 2014, the expression of miR-543 and its ability to impact the proliferation, migration, and invasion of endometrial cancer cell lines as well as tissue samples from patients were investigated.[20] Compared with hTERT immortalized endometrial fibroblast cell T-HESC, human endometrial carcinoma cell lines ECC-1, RL95-2, and AN3 CA expressed lower levels of miR-543. Likewise, tissues from the endometrial cancer specimens expressed lower levels of miR-543 compared with those from normal endometrium tissues. miR-543 suppressed endometrial cancer oncogenicity by targeting focal adhesion kinase (FAK) and TWIST1 expression in RL95-2 and AN3 CA cell lines. In addition, it was discovered that miR-543 was inversely correlated with FAK and TWIST1 mRNA levels in clinical samples from endometrial cancer.

Over the past decade, miR-543 has been identified as a classical onco-miRNA or tumor suppressor. For instance, Song et al. demonstrated the elevated expression of the placental growth factor (PGF) as well as matrix metalloproteinase 7 (MMP7) in ovarian cancer tissues, while miR-543 expression was downregulated.[57] miR-543 inhibits the translation of MMP7 through binding to the 3'-UTR of MMP7 mRNA in ovarian cancer. In addition, PGF could promote the invasion of ovarian cancer cells by inhibiting the miR-543-regulated MMP7[57] but also by MAPK-p38-dependent activation of zinc finger E-box binding homeobox 2,[58] which is a critical transcription factor for EMT induction. Recent research has shown that the anticancer effect of miR-543 on ovarian cancer cells was attenuated by the lncRNA PVT1.[59] In the light of the present research, miR-543 might act as a suppressor in endometrial cancer and ovarian cancer.

However, some groups of cervical cancer researchers have reported different results. Ma et al. reported that lncRNA PCAT6 could accelerate the progression and chemoresistance of cervical cancer by upregulating ZEB1 by sponging miR-543.[19] Liu et al. confirmed that miR-543 could inhibit cervical cancer growth and metastasis by targeting transient receptor potential melastatin 7 (TRPM7) and that the PI3K/AKT and p38/MAPK signaling pathways were involved in miR-543/TRPM7 axis-mediated cervical cancer progression.[60] Both proved these conclusions with in vivo and in vitro experiments. Another in vitro study demonstrated that miR-543 could exert its oncogene function by directly targeting BRCA1-interacting protein 1 in cervical cancer.[61] However, a recent study revealed that miR-543 downregulation could promote the aggressive phenotype of cervical cancer cells.[62] Therefore, miR-543 is likely to have an anticervical cancer effect. In general, compared with other systemic diseases, miR-543 plays a role in inhibiting tumor progression in gynecological tumors.

Except for cancer, the analysis of endometrial tissues from patients with endometriosis-related infertility showed a complicated and dysregulated miRNA-mRNA regulatory network, and miR-543 was the top core miRNA and might be associated with the progression and metastases of endometriosis and impaired endometrial receptivity.[63] In addition, an integrated dataset of miRNA and mRNA profiles in severe intrauterine adhesion showed the downregulation of miR-543 and their corresponding target genes, N-cadherin (CDH2), and collagen16A1.[64] Moreover, the upregulation of miR-543 expression could suppress early growth response-1 expression and inhibit collagen synthesis in human keloid fibroblasts.[65] These results led us to speculate that miR-543 has a beneficial effect on endometrial receptivity, as well as the repair and growth of the uterus. Therefore, we performed some analyses using the GeneMANIA website (http://genemania.org). We found that some target genes of miR-543 are predicted to be associated with known decidualization factors, such as PROK1,[66],[67] F3,[68] INHBE,[69] IL-11,[70] PRL,[71] and IGFBP-1.[72] [Figure 4] shows the prediction results. As is well known, favorable decidualization is a key factor at the beginning of pregnancy. In addition, Yang et al. revealed that miR-543 plays an important role during the embryo implantation process and is associated with endometrial receptivity. Downregulation of miR-543 may affect embryo implantation, resulting in the pathogenesis of endometriosis-related infertility.[63] Moreover, our unpublished results showed that miR-543 is associated with endometrial receptivity by targeting IL-33, which is critical for the proliferation and invasiveness of decidual stromal cells and the function of NK cells and macrophages in the first trimester.[73],[74],[75] Therefore, we speculated that manufacturing surface-engineered gold nanoparticles for miR-543 mimics or anti-miR-543 delivery into the uterine cavity can offer the opportunity for future clinical applications to maintain endometrial receptivity in young women with cancer. This shows potential as an interesting and meaningful research field.
Figure 4: The predicted results from the GeneMANIA website (http://genemania.org).

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  The Signal Pathways Involved with MicroRNA-543 and Their Roles in Gynecological Oncology Top

Like other miRNAs, miR-543 has redundancy and its various target genes are involved in intricate signal pathways. We summit role in these pathways in this section. [Figure 5] displays the relevant signaling pathways and target genes.
Figure 5: The signal pathways involved with miR-543. Smad7: SMAD family member 7; EN2: Engrailed homeobox 2; PTEN: Phosphatase and tensin homolog; HIF-1α: Hypoxia inducible factor 1 subunit alpha; TWIST1: Twist-related protein 1; ET-1: Endothelin; PRMT9: Protein arginine methyltransferase 9.

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PI3K/Akt/mTOR signal pathway

The PI3K/Akt/mTOR signaling pathway is well known as a tumor-related pathway. Compared with other signaling pathways, the components of the PI3K/AKT/mTOR signal pathway are complicated and are associated with other signaling pathways (e.g., NF-κB and p38/MAPK signaling pathways). As mentioned above, the miR-543/PTEN/PI3K/AKT/mTOR pathway is involved in the regulation of sensitivity of colon cancer cells to chemotherapy drugs (e.g., 5-FU[29] and oxaliplatin[30]). Moreover, the target gene EN2 was reported to activate the PI3K/AKT pathway and inhibit PTEN in bladder cancer cells.[22] Furthermore, the PI3K/AKT/mTOR signaling pathway has been reported to be associated with endometrial cancer,[76] ovarian cancer,[77] and cervical cancer.[78] In addition, the PI3K/AKT/mTOR pathway could regulate the sensitivity of endometrial cancer cell lines to PARP inhibitors (e.g., olaparib and BMN-673), shedding light on the personalized treatment of endometrial cancer patients with PTEN mutations.[79]

Wnt/β-catenin signal pathway

The Wnt/β-catenin signaling pathway is thought to be involved in EMT, one of the pathogenic factors of tumors. miR-543 activates the Wnt/β-catenin pathway through negative regulation of Smad7 in PAs[25] and promotes growth and stem cell-like phenotype through this signaling pathway in bladder cancer.[51] In addition, the Wnt/β-catenin pathway was also found to be related to endometrial cancer,[80] ovarian cancer,[81] and cervical cancer[82] and might play an active role in chemoresistance in epithelial ovarian cancer.[83]

JAK/STAT3 and phospholipase C/protein kinase C δ signal pathway

The JAK/STAT3 and PLC/PKCδ signaling pathways were shown to inhibit miR-543 to regulate the progression of osteosarcoma[46] and chemoresistance to ruxolitinib in myelofibrosis.[48] The JAK/STAT3 signaling pathway was demonstrated to affect the growth of endometrial cancer[84] and ovarian cancer,[85],[86] while we have not found research on the PLC/PKCδ signal pathway with three cancers of the female reproductive system. We suppose that miR-543 might be a bridge between these two signaling pathways and the three cancers of the female reproductive system.

Negative feedback loop involved with hypoxia-inducible factor-1α

In the basic research on the mechanism of pulmonary arterial hypertension, the HIF-1α/miR-543/TWIST/ET-1 axis has been found to participate in the contraction and dilation of pulmonary blood vessels to maintain steady blood pressure,[44] which is also found in endometrial cancer,[20] as well as in ovarian cancer.[18] In osteosarcoma, miR-543 could in return stabilize the HIF-1α protein by partially suppressing PRMT9.[47] HIF-1α has also been shown to be required for normal endometrial repair during menstruation,[87] be associated with different stages of cervical cancer,[88] and regulate cisplatin efficacy in ovarian cancer,[89] which leads us to believe that miR-543 is also needed to maintain homeostasis of the uterine microenvironment through a negative feedback loop including miR-543 and HIF-1α.

  Applications and Related Challenges of MicroRNA-543 in Young Patients with Gynecologic Tumors Top

As is well known, interest has been increasing rapidly toward the use of miRNA for early diagnosis, treatment, and understanding the pathogenesis of systemic diseases and cancers ever since the first report on the association of miRNA dysregulation with various diseases. Most studies mentioned previously have shown that miR-543 is not only a tumor suppressor gene but also an oncogene in several cancers. However, in the three tumors of the female reproductive system, high expression and enrichment of miR-543 are demonstrated to relieve the progress of cancers; only one in vitro study of cervical cancer concluded the opposite. In addition, it has potential benefits for endometriosis-related infertility and severe intrauterine adhesion. Therefore, miR-543 might have a promising clinical application prospect for fertility preservation in young patients with cancer. Some exciting avenues of research related to miRNAs are underway. There are many potential miRNA-based applications [Figure 6]: (1) miRNA-based biosensors to detect miRNA profiles in pathological tissue or even body fluids (circulating miRNAs) in patients have gained immense clinical significance. miRNAs might be used as biological markers in conjunction with other clinical examinations for cancer diagnosis, prognosis, and survival prediction.[90] (2) Anti-miRNA agents, such as anti-miRNA oligonucleotides, specifically inhibiting the function of miRNA, could be used for the treatment of diseases.[91] (3) Mimic miRNAs that can be processed by cells and form the active miRNA molecule to target specific mRNAs, aiming to relieve or cure diseases.[91] (4) Nanoparticles carrying miRNA oligos that can affect the tumor tissues sensitive to specific drugs, and allow the healthy tissues to grow normally through targeting specific cells, or regulate intracellular trafficking of target miRNA.[92]
Figure 6: Implications on the fertility preservation in young patients with cancer.

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In young patients with cancer, many treatments are now recognized as negatively impacting fertility and thereby impacting their quality of life. A recent study found that the uterus and endometrium matter equally in fertility-preserving treatments, except for the ovary.[92] The female reproductive system needs to be treated in its entirety. We speculate that miR-543 might be effective in maintaining endometrial receptivity at the same time as treating cancer. First, the patients with cancer could undergo investigation using miRNA-based biosensors to obtain the expression of miR-543 for prognosis and diagnosis. After fertility-sparing surgery, these patients could receive the combinational therapy to increase the future rate of conception. For instance, nanoparticles containing miR-543 could be placed in the uterine cavity to improve endometrial receptivity and reduce intrauterine adhesion at the same time to prevent cancer recurrence. In addition, it can also be used to maintain the homeostasis of the uterine cavity in patients with induced abortion surgery and polycystic ovary syndrome.[93] If these visions are realized, it can be a breakthrough for cancer patient shopping to preserve their fertility after surgery.

However, considering the large number of articles published every year along with commercialized or near-to-be-marketed miRNA diagnostic platforms, there are several biological and methodological challenges: (1) miRNAs in lesions are generally unstable due to endogenous and exogenous RNases, making it difficult to diagnose at earlier stages of diseases. Although circulating miRNAs contained in exosomes are more stable, the abundance of disease or cancer-specific circulating miRNAs is quite low. The existing methods are unable to separate disease or cancer-specific exosomes effectively from various bodily fluids because of size overlapping with lipoproteins, chylomicrons, and microvesicles.[12] (2) The presence of homologous miRNA sequences, and other biomolecules, such as lipids and proteins, jeopardizes the reliability of specific miRNA detection due to nonspecific interactions with each other or with the various components of detection platforms. Considering the physiological variation in humans, a large cohort of individuals should be recruited to counteract this issue. (3) Neither the conventional miRNA detection approaches (e.g., qRT-PCR, RNA sequencing, miRNA microarray, and northern blotting) nor the emerging techniques (e.g., nanopore, optical and electrochemical readout techniques[94]) are suitable for outpatient services because of the expensive equipment cost, complex detection processes, and the required expertise in bioinformatics. (4) miRNAs and anti-miRNA agents are still in preclinical studies, and in vivo toxicity studies are underway. Moreover, nanotechnology is very expensive and difficult for ordinary families to afford. (5) Diseases in humans are the combined result of multigene and multistep processes. Combination therapy is more effective than single therapy. The individualized strategy of combination therapy needs to be further explored.

  Conclusions Top

Here, we have briefly introduced the biogenesis and function of miR-543. We have systematically reviewed the various roles of miR-543 in the nervous, digestive, respiratory, and skeletal systems, as well as gynecologic tumors. We hypothesized that miR-543 can promote endometrial receptivity and uterine repair while inhibiting gynecologic tumor progression. Finally, the potential clinical applications of miR-543 and its challenges have also been discussed. With the development of new technologies over the past few years, the clinical potential of miR-543-based applications will likely continue to increase.

Financial support and sponsorship

This work was supported by grants from the National Basic Research Program of China (2015CB943304) and National Natural Science Foundation of China (81671457 and 81871143 to X.Y.Z., 31800768 to W.T.H.).

Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]

  [Table 1]


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