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Role and mechanism of miR-335-5p in the pathogenesis and treatment of polycystic ovary syndrome

  • Author Footnotes
    # Co-first authors: Zhang Shanshan, Liu Yajing, Mingming Wang contributed equally to this work.
    Shanshan Zhang
    Footnotes
    # Co-first authors: Zhang Shanshan, Liu Yajing, Mingming Wang contributed equally to this work.
    Affiliations
    State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
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  • Author Footnotes
    # Co-first authors: Zhang Shanshan, Liu Yajing, Mingming Wang contributed equally to this work.
    Yajing Liu
    Footnotes
    # Co-first authors: Zhang Shanshan, Liu Yajing, Mingming Wang contributed equally to this work.
    Affiliations
    State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China

    Hainan Yazhou Bay Seed Lab
    Search for articles by this author
  • Author Footnotes
    # Co-first authors: Zhang Shanshan, Liu Yajing, Mingming Wang contributed equally to this work.
    Mingming Wang
    Footnotes
    # Co-first authors: Zhang Shanshan, Liu Yajing, Mingming Wang contributed equally to this work.
    Affiliations
    State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
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  • Donata Ponikwicka-Tyszko
    Affiliations
    Department of Biology and Pathology of Human Reproduction, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland

    Institute of Biomedicine, Faculty of Medicine, University of Turku, Turku, Finland
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  • Wenqiang Ma
    Affiliations
    State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
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  • Anna Krentowska
    Affiliations
    Department of Internal Medicine and Metabolic Diseases, Medical University of Białystok, Bialystok, Poland
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  • Irina Kowalska
    Affiliations
    Department of Internal Medicine and Metabolic Diseases, Medical University of Białystok, Bialystok, Poland
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  • Ilpo Huhtaniemi
    Affiliations
    Institute of Biomedicine, Faculty of Medicine, University of Turku, Turku, Finland

    Institute of Reproductive and Developmental Biology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK
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  • Slawomir Wolczynski
    Affiliations
    Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, 15276, Poland
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  • Nafis A Rahman
    Affiliations
    Institute of Biomedicine, Faculty of Medicine, University of Turku, Turku, Finland

    Institute of Reproductive and Developmental Biology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK
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  • Xiangdong Li
    Correspondence
    Reprint requests: Xiangdong Li, State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China; Beijing 100193, China.
    Affiliations
    State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China

    Hainan Yazhou Bay Seed Lab

    Institute of Reproductive and Developmental Biology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK

    Department of Nutrition and Health, China Agricultural University, Beijing, China
    Search for articles by this author
  • Author Footnotes
    # Co-first authors: Zhang Shanshan, Liu Yajing, Mingming Wang contributed equally to this work.
Published:August 01, 2022DOI:https://doi.org/10.1016/j.trsl.2022.07.007
      Polycystic ovary syndrome (PCOS) is a common endocrine disorder of unknown etiology that occurs in women of reproductive age. Despite being considered to affect up to one-fifth of women in this cohort, the condition lacks generally accepted diagnostic biomarkers and options for targeted therapy. Hereby, we analyzed the diagnostic, therapeutic, and functional potential of a recently discovered miR-335-5p that was observed to be reduced in the follicular fluid (FF) of PCOS patients as compared with healthy women. We found miR-335-5p to be significantly decreased in the serum and FF samples of PCOS patients (n = 40) vs healthy women (n = 30), as well as in primary human granulosa cells (hGCs), and in 3 different hormonally induced PCOS-like murine models vs. wild-type (WT) mice. The level of circulating miR-335-5p was found to significantly correlate with the impaired endocrine and clinical features associated with PCOS in human patients. Ovarian intrabursal injection of the miR-335-5p antagomir in WT mice ovaries induced a PCOS-like reproductive phenotype. Treatment with the miR-335-5p agomir rescued the dihydrotestosterone-induced PCOS-phenotype in mice, thereby providing a functional link between miR-335-5p and PCOS. We identified SP1 as a miR-335-5p target gene by using the dual-luciferase reporter assay. Both the luciferase reporter assay and chromatin immunoprecipitation assay showed that SP1 bound to the promoter region of human CYP19A1 and inhibited its transcription. miR-335-5p increased the production of estradiol via the SP1/CYP19A1 axis in hGCs, thereby suggesting its mechanistic pathway of action. In conclusion, these results provide evidence that miR-335-5p may function as a mediator in the etiopathogenesis of PCOS, as well as has the potential as both a novel diagnostic biomarker and therapeutic target for PCOS.

      Abbreviation:

      AFC (antral follicle count), AMH (anti-Mullerian hormone), AREs (androgen response elements), AUC (area under the curve), BMI (body mass index), CMC (carboxymethylcellulose), CI (confidence interval), DHEA (dehydroepiandrosterone), DHEA-S (dehydroepiandrosterone sulfate), DHT (dihydrotestosterone), E2 (estradiol), FF (follicular fluid), FSH (follicle-stimulating hormone), HDL (high-density lipoprotein), HOMA-IR (homeostatic model assessment of insulin resistance), hGCs (human granulosa cells), IR (insulin resistance), LDL (low-density lipoprotein), LH (luteinizing hormone), mGCs (mouse granulosa cells), miRNAs (microRNAs), NC (negative control), PCOS (polycystic ovary syndrome), PI (propidium iodide), PRL (prolactin), P4 (progesterone), qPCR (quantitative real-time PCR), ROC (receiver operating characteristic), SHBG (sex hormone-binding globulin), TC (total cholesterol), TFs (transcription factors), TG (triglyceride), TT (total testosterone), UTR (untranslated region), WT (wild-type)
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