Regulation of Corticosteroidogenic Genes by MicroRNAs

Stacy Robertson, Louise A Diver, Samantha Alvarez-Madrazo, Craig Livie, Ayesha Ejaz, Robert Fraser, John M. Connell, Scott M. MacKenzie, Eleanor Davies (Lead / Corresponding author)

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    Abstract

    The loss of normal regulation of corticosteroid secretion is important in the development of cardiovascular disease. We previously showed that microRNAs regulate the terminal stages of corticosteroid biosynthesis. Here, we assess microRNA regulation across the whole corticosteroid pathway. Knockdown of microRNA using Dicer1 siRNA in H295R adrenocortical cells increased levels of CYP11A1, CYP21A1, and CYP17A1 mRNA and the secretion of cortisol, corticosterone, 11-deoxycorticosterone, 18-hydroxycorticosterone, and aldosterone. Bioinformatic analysis of genes involved in corticosteroid biosynthesis or metabolism identified many putative microRNA-binding sites, and some were selected for further study. Manipulation of individual microRNA levels demonstrated a direct effect of miR-125a-5p and miR-125b-5p on CYP11B2 and of miR-320a-3p levels on CYP11A1 and CYP17A1 mRNA. Finally, comparison of microRNA expression profiles from human aldosterone-producing adenoma and normal adrenal tissue showed levels of various microRNAs, including miR-125a-5p to be significantly different. This study demonstrates that corticosteroidogenesis is regulated at multiple points by several microRNAs and that certain of these microRNAs are differentially expressed in tumorous adrenal tissue, which may contribute to dysregulation of corticosteroid secretion. These findings provide new insights into the regulation of corticosteroid production and have implications for understanding the pathology of disease states where abnormal hormone secretion is a feature.

    Original languageEnglish
    Article number2021903
    Pages (from-to)1-11
    Number of pages11
    JournalInternational Journal of Endocrinology
    Volume2017
    DOIs
    Publication statusPublished - 9 Aug 2017

    Fingerprint

    MicroRNAs
    Adrenal Cortex Hormones
    Genes
    Cholesterol Side-Chain Cleavage Enzyme
    Aldosterone
    18-Hydroxycorticosterone
    Cytochrome P-450 CYP11B2
    Desoxycorticosterone
    Messenger RNA
    Corticosterone
    Computational Biology
    Adenoma
    Small Interfering RNA
    Hydrocortisone
    Cardiovascular Diseases
    Binding Sites
    Hormones
    Pathology

    Cite this

    Robertson, S., Diver, L. A., Alvarez-Madrazo, S., Livie, C., Ejaz, A., Fraser, R., ... Davies, E. (2017). Regulation of Corticosteroidogenic Genes by MicroRNAs. International Journal of Endocrinology, 2017, 1-11. [2021903]. https://doi.org/10.1155/2017/2021903
    Robertson, Stacy ; Diver, Louise A ; Alvarez-Madrazo, Samantha ; Livie, Craig ; Ejaz, Ayesha ; Fraser, Robert ; Connell, John M. ; MacKenzie, Scott M. ; Davies, Eleanor. / Regulation of Corticosteroidogenic Genes by MicroRNAs. In: International Journal of Endocrinology. 2017 ; Vol. 2017. pp. 1-11.
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    abstract = "The loss of normal regulation of corticosteroid secretion is important in the development of cardiovascular disease. We previously showed that microRNAs regulate the terminal stages of corticosteroid biosynthesis. Here, we assess microRNA regulation across the whole corticosteroid pathway. Knockdown of microRNA using Dicer1 siRNA in H295R adrenocortical cells increased levels of CYP11A1, CYP21A1, and CYP17A1 mRNA and the secretion of cortisol, corticosterone, 11-deoxycorticosterone, 18-hydroxycorticosterone, and aldosterone. Bioinformatic analysis of genes involved in corticosteroid biosynthesis or metabolism identified many putative microRNA-binding sites, and some were selected for further study. Manipulation of individual microRNA levels demonstrated a direct effect of miR-125a-5p and miR-125b-5p on CYP11B2 and of miR-320a-3p levels on CYP11A1 and CYP17A1 mRNA. Finally, comparison of microRNA expression profiles from human aldosterone-producing adenoma and normal adrenal tissue showed levels of various microRNAs, including miR-125a-5p to be significantly different. This study demonstrates that corticosteroidogenesis is regulated at multiple points by several microRNAs and that certain of these microRNAs are differentially expressed in tumorous adrenal tissue, which may contribute to dysregulation of corticosteroid secretion. These findings provide new insights into the regulation of corticosteroid production and have implications for understanding the pathology of disease states where abnormal hormone secretion is a feature.",
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    note = "This work was funded by the British Heart Foundation Project Grant PG/09/092, awarded to Eleanor Davies and Scott M. MacKenzie. Louise A. Diver was supported by the College of Medical, Veterinary and Life Sciences Medical Research Council Doctoral Training Grant Scholarship (Grant no. G0900185-1/1). Ayesha Ejaz was supported by the Society for Endocrinology Summer Studentship. Eleanor Davies is a member of COST Action BM1301 Aldosterone and Mineralocorticoid Receptor (ADMIRE). Eleanor Davies and Scott M. MacKenzie are participants in the EU-H2020 funded project ENSAT-HT.",
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    Robertson, S, Diver, LA, Alvarez-Madrazo, S, Livie, C, Ejaz, A, Fraser, R, Connell, JM, MacKenzie, SM & Davies, E 2017, 'Regulation of Corticosteroidogenic Genes by MicroRNAs', International Journal of Endocrinology, vol. 2017, 2021903, pp. 1-11. https://doi.org/10.1155/2017/2021903

    Regulation of Corticosteroidogenic Genes by MicroRNAs. / Robertson, Stacy; Diver, Louise A; Alvarez-Madrazo, Samantha; Livie, Craig; Ejaz, Ayesha; Fraser, Robert; Connell, John M.; MacKenzie, Scott M.; Davies, Eleanor (Lead / Corresponding author).

    In: International Journal of Endocrinology, Vol. 2017, 2021903, 09.08.2017, p. 1-11.

    Research output: Contribution to journalArticle

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    AU - Connell, John M.

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    AB - The loss of normal regulation of corticosteroid secretion is important in the development of cardiovascular disease. We previously showed that microRNAs regulate the terminal stages of corticosteroid biosynthesis. Here, we assess microRNA regulation across the whole corticosteroid pathway. Knockdown of microRNA using Dicer1 siRNA in H295R adrenocortical cells increased levels of CYP11A1, CYP21A1, and CYP17A1 mRNA and the secretion of cortisol, corticosterone, 11-deoxycorticosterone, 18-hydroxycorticosterone, and aldosterone. Bioinformatic analysis of genes involved in corticosteroid biosynthesis or metabolism identified many putative microRNA-binding sites, and some were selected for further study. Manipulation of individual microRNA levels demonstrated a direct effect of miR-125a-5p and miR-125b-5p on CYP11B2 and of miR-320a-3p levels on CYP11A1 and CYP17A1 mRNA. Finally, comparison of microRNA expression profiles from human aldosterone-producing adenoma and normal adrenal tissue showed levels of various microRNAs, including miR-125a-5p to be significantly different. This study demonstrates that corticosteroidogenesis is regulated at multiple points by several microRNAs and that certain of these microRNAs are differentially expressed in tumorous adrenal tissue, which may contribute to dysregulation of corticosteroid secretion. These findings provide new insights into the regulation of corticosteroid production and have implications for understanding the pathology of disease states where abnormal hormone secretion is a feature.

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    Robertson S, Diver LA, Alvarez-Madrazo S, Livie C, Ejaz A, Fraser R et al. Regulation of Corticosteroidogenic Genes by MicroRNAs. International Journal of Endocrinology. 2017 Aug 9;2017:1-11. 2021903. https://doi.org/10.1155/2017/2021903