PCOS serum-derived exosomal miR-27a-5p stimulates endometrial cancer cells migration and invasion

in Journal of Molecular Endocrinology

Correspondence should be addressed to W Feng: fww12066@rjh.com.cn

*(X Che and F Jian contributed equally to this work)

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Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-age women. Women with PCOS have a 2.7-fold increased risk for developing endometrial cancer (EC). This study was performed to investigate the potential stimulatory effects of serum exosomes isolated from patients with PCOS on EC cell lines and to explore the underlying mechanism. EC cell lines exposed to exosomes derived from PCOS patients serum exhibited an enhanced migration and invasion phenotype. Next, sequence-based analysis of exosomal miRNA was conducted to screen the differentially expressed miRNAs in serum exosomes from PCOS patients and normal controls. The levels of 55 mature miRNAs significantly differed in serum exosomes from PCOS patients compared with those from normal controls. Real-time PCR was used to verify the expression of eight of these miRNAs, among which miR-27a-5p was the most significantly elevated in PCOS patients serum exosomes. The role of miR-27a-5p in EC migration and invasion was further investigated via miR-27a-5p mimics or inhibitor transfection in Ishikawa and HEC-1A EC cell lines. In addition, the SMAD4 gene was identified as the target of miR-27a-5p by several target prediction databases and was validated by a luciferase assay. SMAD4 mRNA and protein levels were downregulated in EC cells transfected with the miR-27a-5p mimics, but upregulated in cells transfected with the miR-27a-5p inhibitor. Furthermore, in vitro experiments results confirmed that miR-27a-5p prohibited migration and invasion via SMAD4 downregulation. Thus, serum exosomal miR-27a-5p may play a role in EC development in PCOS patients.

 

      Society for Endocrinology

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  • BaSXuanYLongZWChenHYZhengSS 2017 MicroRNA-27a promotes the proliferation and invasiveness of colon cancer cells by targeting SFRP1 through the Wnt/beta-catenin signaling pathway. Cellular Physiology and Biochemistry 1920–1933. (https://doi.org/10.1159/000479610)

    • Search Google Scholar
    • Export Citation
  • BartelDP 2004 MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 281–297. (https://doi.org/10.1016/s0092-8674(04)00045-5)

  • ChaeDKBanEYooYSKimEEBaikJHSongEJ 2017 MIR-27a regulates the TGF-beta signaling pathway by targeting SMAD2 and SMAD4 in lung cancer. Molecular Carcinogenesis 1992–1998. (https://doi.org/10.1002/mc.22655)

    • Search Google Scholar
    • Export Citation
  • DumesicDALoboRA 2013 Cancer risk and PCOS. Steroids 782–785. (https://doi.org/10.1016/j.steroids.2013.04.004)

  • HaMKimVN 2014 Regulation of microRNA biogenesis. Nature Reviews: Molecular Cell Biology 509–524. (https://doi.org/10.1038/nrm3838)

  • HuangXYuanTLiangMDuMXiaSDittmarRWangDSeeWCostelloBAQuevedoF,, 2015 Exosomal miR-1290 and miR-375 as prognostic markers in castration-resistant prostate cancer. European Urology 33–41. (https://doi.org/10.1016/j.eururo.2014.07.035)

    • Search Google Scholar
    • Export Citation
  • IrelanJTWuMJMorganJKeNXiBWangXXuXAbassiYA 2011 Rapid and quantitative assessment of cell quality, identity, and functionality for cell-based assays using real-time cellular analysis. Journal of Biomolecular Screening 313–322. (https://doi.org/10.1177/1087057110397359)

    • Search Google Scholar
    • Export Citation
  • JiangYDuanYZhouH 2015 MicroRNA-27a directly targets KRAS to inhibit cell proliferation in esophageal squamous cell carcinoma. Oncology Letters 471–477. (https://doi.org/10.3892/ol.2014.2701)

    • Search Google Scholar
    • Export Citation
  • KahlertCKalluriR 2013 Exosomes in tumor microenvironment influence cancer progression and metastasis. Journal of Molecular Medicine 431–437. (https://doi.org/10.1007/s00109-013-1020-6)

    • Search Google Scholar
    • Export Citation
  • KosakaNYoshiokaYHagiwaraKTominagaNKatsudaTOchiyaT 2013 Trash or treasure: extracellular microRNAs and cell-to-cell communication. Frontiers in Genetics 173. (https://doi.org/10.3389/fgene.2013.00173)

    • Search Google Scholar
    • Export Citation
  • KumarBLupoldSE 2016 MicroRNA expression and function in prostate cancer: a review of current knowledge and opportunities for discovery. Asian Journal of Andrology 559–567. (https://doi.org/10.4103/1008-682X.177839)

    • Search Google Scholar
    • Export Citation
  • LazarIClementEDauvillierSMilhasDDucoux-PetitMLeGonidecSMoroCSoldanVDalleSBalorS,, 2016 Adipocyte exosomes promote melanoma aggressiveness through fatty acid oxidation: a novel mechanism linking obesity and cancer. Cancer Research 4051–4057. (https://doi.org/10.1158/0008-5472.CAN-16-0651)

    • Search Google Scholar
    • Export Citation
  • LiMHanYZhouHLiXLinCZhangEChiXHuJXuH 2018 Transmembrane protein 170B is a novel breast tumorigenesis suppressor gene that inhibits the Wnt/beta-catenin pathway. Cell Death and Disease 91. (https://doi.org/10.1038/s41419-017-0128-y)

    • Search Google Scholar
    • Export Citation
  • LiBLLuWQuJJYeLDuGQWanXP 2019a Loss of exosomal miR-148b from cancer-associated fibroblasts promotes endometrial cancer cell invasion and cancer metastasis. Journal of Cellular Physiology 2943–2953. (https://doi.org/10.1002/jcp.27111)

    • Search Google Scholar
    • Export Citation
  • LiXXuMDingLTangJ 2019b MiR-27a: a novel biomarker and potential therapeutic target in tumors. Journal of Cancer 2836–2848. (https://doi.org/10.7150/jca.31361)

    • Search Google Scholar
    • Export Citation
  • LiuYGuYCaoX 2015 The exosomes in tumor immunity. OncoImmunology e1027472. (https://doi.org/10.1080/2162402X.2015.1027472)

  • LivakKJSchmittgenTD 2001 Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 402–408. (https://doi.org/10.1006/meth.2001.1262)

    • Search Google Scholar
    • Export Citation
  • MeloSASugimotoHO’ConnellJTKatoNVillanuevaAVidalAQiuLVitkinEPerelmanLTMeloCA,, 2014 Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 707–721. (https://doi.org/10.1016/j.ccell.2014.09.005)

    • Search Google Scholar
    • Export Citation
  • MeloSALueckeLBKahlertCFernandezAFGammonSTKayeJLeBleuVSMittendorfEAWeitzJRahbariN,, 2015 Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 177–182. (https://doi.org/10.1038/nature14581)

    • Search Google Scholar
    • Export Citation
  • PapaioannouSTzafettasJ 2010 Anovulation with or without PCO, hyperandrogenaemia and hyperinsulinaemia as promoters of endometrial and breast cancer. Best Practice and Research: Clinical Obstetrics and Gynaecology 19–27. (https://doi.org/10.1016/j.bpobgyn.2008.11.010)

    • Search Google Scholar
    • Export Citation
  • PatrasLBanciuM 2019 Intercellular crosstalk via extracellular vesicles in tumor milieu as emerging therapies for cancer progression. Current Pharmaceutical Design 1980–2006. (https://doi.org/10.2174/1381612825666190701143845)

    • Search Google Scholar
    • Export Citation
  • SunBLiJShaoDPanYChenYLiSYaoXLiHLiuWZhangM,, 2015 Adipose tissue-secreted miR-27a promotes liver cancer by targeting FOXO1 in obese individuals. OncoTargets and Therapy 735–744. (https://doi.org/10.2147/OTT.S80945)

    • Search Google Scholar
    • Export Citation
  • ValadiHEkstromKBossiosASjostrandMLeeJJLotvallJO 2007 Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biology 654–659. (https://doi.org/10.1038/ncb1596)

    • Search Google Scholar
    • Export Citation
  • WuQBShengXZhangNYangMWWangF 2018 Role of microRNAs in the resistance of colorectal cancer to chemoradiotherapy. Molecular and Clinical Oncology 528–532. (https://doi.org/10.3892/mco.2018.1578)

    • Search Google Scholar
    • Export Citation
  • WuDMWenXHanXRWangSWangYJShenMFanSHZhangZFShanQLiMQ,, 2019 Bone marrow mesenchymal stem cell-derived exosomal MicroRNA-126-3p inhibits pancreatic cancer development by targeting ADAM9. Molecular Therapy: Nucleic Acids 229–245. (https://doi.org/10.1016/j.omtn.2019.02.022)

    • Search Google Scholar
    • Export Citation
  • YanokuraMBannoKIidaMIrieHUmeneKMasudaKKobayashiYTominagaEAokiD 2015 MicroRNAs in endometrial cancer: recent advances and potential clinical applications. Excli Journal 190–198. (https://doi.org/10.17179/excli2014-590)

    • Search Google Scholar
    • Export Citation