MicroRNAs and Adrenocortical Tumors: Where do we Stand on Primary Aldosteronism?

Abstract

MicroRNAs, the endogenous mediators of RNA interference, interact with the renin-angiotensin-aldosterone system, regulate aldosterone secretion and aldosterone effects. Some novel data show that the expression of some microRNAs is altered in primary aldosteronism, and some of these appear to have pathogenic relevance, as well. Differences in the circulating microRNA expression profiles between the two major forms of primary aldosteronism, unilateral aldosterone-producing adenoma and bilateral adrenal hyperplasia have also been shown. Here, we present a brief synopsis of these findings focusing on the potential relevance of microRNA in primary aldosteronism.

Key words

primary aldosteronism - microRNA - target gene - pathogenesis - biomarker

Publication History

Received: 24 November 2019

Accepted: 29 January 2020

Article published online:
13 March 2020

• References

• 1 Treiber T, Treiber N, Meister G. Regulation of microRNA biogenesis and its crosstalk with other cellular pathways. Nat Rev Mol Cell Biol 2019; 20: 5-20
• 2 Garzon R, Fabbri M, Cimmino A. et al. MicroRNA expression and function in cancer. Trends Mol Med 2006; 12: 580-587
• 3 Wijnhoven BPL, Michael MZ, Watson DI. MicroRNAs and cancer. Br J Surg 2007; 94: 23-30
• 4 Barbarotto E, Schmittgen TD, Calin GA. MicroRNAs and cancer: Profile, profile, profile. Int J Cancer 2007; 122: 969-977
• 5 Özata DM, Caramuta S, Velázquez-Fernández D. et al. The role of microRNA deregulation in the pathogenesis of adrenocortical carcinoma. Endocr Relat Cancer 2011; 18: 643-655
• 6 Patterson EE, Holloway AK, Weng J. et al. MicroRNA profiling of adrenocortical tumors reveals miR-483 as a marker of malignancy. Cancer 2011; 117: 1630-1639
• 7 Soon PSH, Tacon LJ, Gill AJ. et al. MiR-195 and miR-483-5p identified as predictors of poor prognosis in adrenocortical cancer. Clin Cancer Res 2009; 15: 7684-7692
• 8 Tömböl Z, Szabó PM, Molnár V. et al. Integrative molecular bioinformatics study of human adrenocortical tumors: MicroRNA, tissue-specific target prediction, and pathway analysis. Endocr Relat Cancer 2009; 16: 895-906
• 9 Igaz P, Igaz I, Nagy Z. et al. MicroRNAs in adrenal tumors: Relevance for pathogenesis, diagnosis, and therapy. Cell Mol Life Sci 2015; 72: 417-428
• 10 Chabre O, Libé R, Assie G. et al. Serum miR-483-5p and miR-195 are predictive of recurrence risk in adrenocortical cancer patients. Endocr Relat Cancer 2013; 20: 579-594
• 11 Szabó DR, Luconi M, Szabó PM. et al. Analysis of circulating microRNAs in adrenocortical tumors. Lab Investig 2014; 94: 331-339
• 12 Perge P, Butz H, Pezzani R. et al. Evaluation and diagnostic potential of circulating extracellular vesicle-associated microRNAs in adrenocortical tumors. Sci Rep 2017; 7: 5474
• 13 Decmann A, Perge P, Nyírő G. et al. MicroRNA expression profiling in adrenal myelolipoma. J Clin Endocrinol Metab 2018; 103: 3522-3530
• 14 Burrello J, Gai C, Tetti M. et al. Characterization and gene expression analysis of serum-derived extracellular vesicles in primary aldosteronism. Hypertension 2019; 74: 359-367
• 15 Butterworth MB. MicroRNAs and the regulation of aldosterone signaling in the kidney. Am J Physiol Cell Physiol 2015; 308: C521-C527
• 16 Butterworth MB. Role of microRNAs in aldosterone signaling. Curr Opin Nephrol Hypertens 2018; 27: 390-394
• 17 Klimczak D, Jazdzewski K, Kuch M. Regulatory mechanisms in arterial hypertension: Role of microRNA in pathophysiology and therapy. Blood Press 2017; 26: 2-8
• 18 Marques FZ, Campain AE, Tomaszewski M. et al. Gene expression profiling reveals renin mRNA overexpression in human hypertensive kidneys and a role for microRNAs. Hypertens 2011; 58: 1093-1098
• 19 Morris BJ. Renin, genes, microRNAs, and renal mechanisms involved in hypertension. Hypertension 2015; 65: 956-962
• 20 Kemp JR, Unal H, Desnoyer R. et al. Angiotensin II-regulated microRNA 483-3p directly targets multiple components of the renin-angiotensin system. J Mol Cell Cardiol 2014; 75: 25-39
• 21 Boettger T, Beetz N, Kostin S. et al. Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster. J Clin Invest 2009; 119: 2634-2647
• 22 Chen L-J, Xu R, Yu H-M. et al. The ACE2/Apelin signaling, microRNAs, and hypertension. Int J Hypertens 2015; 1-6
• 23 Pan J, Zhang J, Zhang X. et al. Role of microRNA-29b in angiotensin II-induced epithelial-mesenchymal transition in renal tubular epithelial cells. Int J Mol Med 2014; 34: 1381-1387
• 24 Robertson S, MacKenzie SM, Alvarez-Madrazo S. et al. MicroRNA-24 is a novel regulator of aldosterone and cortisol production in the human adrenal cortex. Hypertension 2013; 62: 572-578
• 25 Lin Z, Murtaza I, Wang K. et al. MiR-23a functions downstream of NFATc3 to regulate cardiac hypertrophy. Proc Natl Acad Sci USA 2009; 106: 12103-12108
• 26 Rezaei M, Andrieu T, Neuenschwander S. et al. Regulation of 11β-hydroxysteroid dehydrogenase type 2 by microRNA. Hypertens 2014; 64: 860-866
• 27 Shang Y, Yang X, Zhang R. et al. Low amino acids affect expression of 11β-HSD2 in BeWo cells through leptin-activated JAK-STAT and MAPK pathways. Amino Acids 2012; 42: 1879-1887
• 28 Jiang X, Ning Q, Wang J. Angiotensin II induced differentially expressed microRNAs in adult rat cardiac fibroblasts. J Physiol Sci 2013; 63: 31-38
• 29 Yaël Nossent A, Hansen JL, Rosendaal FR. et al. SNPs in microRNA binding sites in 3′-UTRs of RAAS genes influence arterial blood pressure and risk of myocardial infarction. Am J Hypertens 2011; 24: 999-1006
• 30 Butterworth MB, Alvarez de la Rosa D. Regulation of Aldosterone Signaling by microRNAs. Vitam Horm 2019; 109: 69-103
• 31 Syed M, Ball JP, Mathis KW. et al. MicroRNA-21 ablation exacerbates aldosterone-mediated cardiac injury, remodeling, and dysfunction. Am J Physiol Metab 2018; 315: E1154-E1167
• 32 Ball JP, Syed M, Marañon RO. et al. Role and regulation of microRNAs in aldosterone-mediated cardiac injury and dysfunction in male rats. Endocrinology 2017; 158: 1859-1874
• 33 Edinger RS, Coronnello C, Bodnar AJ. et al. Aldosterone regulates microRNAs in the cortical collecting duct to alter sodium transport. J Am Soc Nephrol 2014; 25: 2445-2457
• 34 Fallo F, Pezzi V, Barzon L. et al. Quantitative assessment of CYP11B1 and CYP11B2 expression in aldosterone-producing adenomas. Eur J Endocrinol 2002; 147: 795-802
• 35 Nakamura Y, Yamazaki Y, Tezuka Y. et al. Expression of CYP11B2 in aldosterone-producing adrenocortical adenoma: Regulatory mechanisms and clinical significance. Tohoku J Exp Med 2016; 240: 183-190
• 36 Nakano Y, Yoshimoto T, Watanabe R. et al. MiRNA-299 involvement in CYP11B2 expression in aldosterone-producing adenoma. Eur J Endocrinol 2019; 181: 69-78
• 37 Zhang G, Zou X, Liu Q. et al. MiR-193a-3p functions as a tumour suppressor in human aldosterone-producing adrenocortical adenoma by down-regulating CYP11B2. Int J Exp Pathol 2018; 99: 77-86
• 38 Williams TA, Monticone S, Schack VR. et al. Somatic ATP1A1, ATP2B3 and KCNJ5 mutations in aldosterone-producing adenomas. Hypertension 2014; 63: 188-195
• 39 Lenzini L, Rossitto G, Maiolino G. et al. A meta-analysis of somatic KCNJ5 K(+) channel mutations in 1636 patients with an aldosterone-producing adenoma. J Clin Endocrinol Metab 2015; 100: E1089-E1095
• 40 Nanba K, Omata K, Gomez-Sanchez CE. et al. Genetic characteristics of aldosterone-producing adenomas in blacks. Hypertension 2019; 73: 885-892
• 41 Omata K, Satoh F, Morimoto R. Cellular and genetic causes of idiopathic hyperaldosteronism. Hypertension 2018; 72: 874-880
• 42 Nishimoto K, Tomlins SA, Kuick R. et al. Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands. Proc Natl Acad Sci USA 2015; 112: E4591-E4599
• 43 Omata K, Anand SK, Hovelson DH. et al. Aldosterone-producing cell clusters frequently harbor somatic mutations and accumulate with age in normal adrenals. J Endocr Soc 2017; 1: 787-799
• 44 Yamazaki Y, Nakamura Y, Omata K. et al. Histopathological classification of cross-sectional image-negative hyperaldosteronism. J Clin Endocrinol Metab 2017; 102: 1182-1192
• 45 Zennaro M-C, Fernandes-Rosa F, Boulkroun S. et al. Bilateral idiopathic adrenal hyperplasia: Genetics and beyond. Horm Metab Res 2015; 47: 947-952
• 46 Robertson S, Diver LA, Alvarez-Madrazo S. et al. Regulation of corticosteroidogenic genes by microRNAs. Int J Endocrinol 2017; 1-11
• 47 Wang T, Satoh F, Morimoto R. et al. Gene expression profiles in aldosterone-producing adenomas and adjacent adrenal glands. Eur J Endocrinol 2011; 164: 613-619
• 48 Nusrin S, Tong SKH, Chaturvedi G. et al. Regulation of CYP11B1 and CYP11B2 steroidogenic genes by hypoxia-inducible miR-10b in H295R cells. Mar Pollut Bull 2014; 85: 344-351
• 49 He J, Cao Y, Su T. et al. Downregulation of miR-375 in aldosterone-producing adenomas promotes tumour cell growth via MTDH. Clin Endocrinol 2015; 83: 581-589
• 50 Lewis BP, Burge CB, Bartel DP. Conserved Seed Pairing, Often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005; 120: 15-20
• 51 Nakano H, Yamada Y, Miyazawa T. et al. Gain-of-function microRNA screensidentify miR-193a regulating proliferation and apoptosis in epithelial ovariancancer cells. Int J Oncol 2013; 42: 1875-1882
• 52 Wang J, Yang B, Han L. et al. Demethylation of miR-9-3 and miR-193a genes suppresses proliferation and promotes apoptosis in non-small cell lung cancer cell lines. Cell Physiol Biochem 2013; 32: 1707-1719
• 53 Liang H, Liu M, Yan X. et al. MiR-193a-3p functions as a tumor suppressor in lung cancer by down-regulating ERBB4. J Biol Chem 2015; 290: 926-940
• 54 Khoo CP, Roubelakis MG, Schrader JB. et al. MiR-193a-3p interaction with HMGB1 downregulates human endothelial cell proliferation and migration. Sci Rep 2017; 7: 44137
• 55 Hong GL, Chen XZ, Liu Y. et al. Genetic variations in MOV10 and CACNB2 are associated with hypertension in a Chinese Han population. Genet Mol Res 2013; 12: 6220-6227
• 56 Zennaro M-C, Jeunemaitre X, Boulkroun S. Integrating genetics and genomics in primary aldosteronism. Hypertens 2012; 60: 580-588
• 57 Czirják G, Enyedi P. TASK-3 Dominates the background potassium conductance in rat adrenal glomerulosa cells. Mol Endocrinol 2002; 16: 621-629
• 58 Lenzini L, Caroccia B, Campos AG. et al. Lower expression of the TWIK-related acid-sensitive K⁺ Channel 2 (TASK-2) gene is a hallmark of aldosterone-producing adenoma causing human primary aldosteronism. J Clin Endocrinol Metab 2014; 99: E674-E682
• 59 Lenzini L, Rossi GP. The molecular basis of primary aldosteronism: From chimeric gene to channelopathy. Curr Opin Pharmacol 2015; 21: 35-42
• 60 Bandulik S, Tauber P, Penton D. et al. Severe hyperaldosteronism in neonatal Task3 potassium channel knockout mice is associated with activation of the intraadrenal renin-angiotensin system. Endocrinology 2013; 154: 2712-2722
• 61 Davies LA, Hu C, Guagliardo NA. et al. TASK channel deletion in mice causes primary hyperaldosteronism. Proc Natl Acad Sci 2008; 105: 2203-2208
• 62 Peng K-Y, Chang H-M, Lin Y-F. et al. MiRNA-203 modulates aldosterone levels and cell proliferation by targeting Wnt5a in aldosterone-producing adenomas. J Clin Endocrinol Metab 2018; 103: 3737-3747
• 63 Heikkilä M, Peltoketo H, Leppäluoto J. et al. Wnt-4 deficiency alters mouse adrenal cortex function, reducing aldosterone production. Endocrinology 2002; 143: 4358-4365
• 64 Libè R, Fratticci A, Bertherat J. Adrenocortical cancer: Pathophysiology and clinical management. Endocr Relat Cancer 2007; 14: 13-28
• 65 Berthon A, Martinez A, Bertherat J. et al. Wnt/β-catenin signalling in adrenal physiology and tumour development. Mol Cell Endocrinol 2012; 351: 87-95
• 66 Berthon A, Drelon C, Ragazzon B. et al. WNT/β-catenin signalling is activated in aldosterone-producing adenomas and controls aldosterone production. Hum Mol Genet 2014; 23: 889-905
• 67 Taube JH, Malouf GG, Lu E. et al. Epigenetic silencing of microRNA-203 is required for EMT and cancer stem cell properties. Sci Rep 2013; 3: 2687
• 68 Poy MN, Eliasson L, Krutzfeldt J. et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature 2004; 432: 226-230
• 69 Zhang N, Lin J, Chen J. et al. MicroRNA-375 mediates the signaling pathway of corticotropin-releasing factor (CRF) regulating pro-opiomelanocortin (POMC) expression by targeting mitogen-activated protein kinase 8. J Biol Chem 2013; 288: 10361-10373
• 70 Tsukamoto Y, Nakada C, Noguchi T. et al. MicroRNA-375 is downregulated in gastric carcinomas and regulates cell survival by targeting PDK1 and 14-3-3. Cancer Res 2010; 70: 2339-2349
• 71 Shi X, Wang X. The role of MTDH/AEG-1 in the progression of cancer. Int J Clin Exp Med 2015; 8: 4795-4807
• 72 Yao Y, Gu X, Liu H. et al. Metadherin regulates proliferation and metastasis via actin cytoskeletal remodelling in non-small cell lung cancer. Br J Cancer 2014; 111: 355-364
• 73 He X-X, Chang Y, Meng F-Y. et al. MicroRNA-375 targets AEG-1 in hepatocellular carcinoma and suppresses liver cancer cell growth in vitro and in vivo. Oncogene 2012; 31: 3357-3369
• 74 Hu B, Emdad L, Bacolod MD. et al. Astrocyte elevated gene-1 interacts with Akt isoform 2 to control glioma growth, survival, and pathogenesis. Cancer Res 2014; 74: 7321-7332
• 75 Su H, Gu Y, Li F. et al. The PI3K/AKT/mTOR signaling pathway is overactivated in primary aldosteronism. PLoS One 2013; 8: e62399
• 76 Zha X, Wang F, Wang Y. et al. Lactate dehydrogenase B is critical for hyperactive mTOR-mediated tumorigenesis. Cancer Res 2011; 71: 13-18
• 77 Rosenbluh J, Nijhawan D, Cox AG. et al. β-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell 2012; 151: 1457-1473
• 78 Lim PO, Young WF, MacDonald TM. A review of the medical treatment of primary aldosteronism. J Hypertens 2001; 19: 353-361
• 79 Parthasarathy HK, Ménard J, White WB. et al. A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism. J Hypertens 2011; 29: 980-990
• 80 Young WF, Stanson AW, Thompson GB. et al. Role for adrenal venous sampling in primary aldosteronism. Surgery 2004; 136: 1227-1235
• 81 Decmann A, Nyírö G, Darvasi O. et al. Circulating miRNA expression profiling in primary aldosteronism. Front Endocrinol (Lausanne) 2019; 10: 739