MicroRNAs as Biomarkers in Pituitary Tumors The use of extracellular microRNAs (miRNAs) as circulating biomarkers is currently leading to relevant advances in the diagnosis and assessment of prognosis of several diseases. Specific miRNAs have also been shown to play a role in the pathophysiology of many neoplastic and non-neoplastic diseases. A number of studies have demon- strated that miRNAs show differential expression in various tumors, such as in the prostate, ovary, lung, breast, brain, and pituitary. Recent findings have built connections between miRNAs that are deregulated within the tumor and their presence in peripheral blood. MiRNAs have been shown to be stable in the blood where they are present in either free and/or uncomplexed form, as well as packed in microvesicles, exosomes, and apoptotic bodies, or bound to different proteins. Because the pituitary is a highly vascularized organ that releases hormones into the circulation, miRNAs would be useful biomarkers for the diagnosis of pituitary tumors, as well as for predicting or detecting recurrence after surgery. Here we review the biological significance of miRNAs in pituitary tumors and the potential value of circulating miRNAs as biomarkers. KEY WORDS: Biomarker, miRNA, Pituitary adenoma, Pituitary gland, Pituitary tumor Neurosurgery 75:181–189, 2014 DOI: 10.1227/NEU.0000000000000369 www.neurosurgery-online.com M icroRNAs (miRNAs) are a class of non- coding RNAs that regulate posttran- scriptional gene expression. They are considered to be negative regulators that control cell proliferation, metabolism, apoptosis, and dif- ferentiation. They are involved in many physiolog- ical and pathophysiological conditions, such as cardiovascular diseases andcancer. 1-5 There is a wide range of potential clinical utility of miRNAs, as recently reviewed. 6 Although they are known to act as intracellular regulators of posttranscriptional gene expression, several studies demonstrated that miRNAs can be measured in different body fluids including urine and blood and might be useful as disease bio- markers in cardiovascular diseases, liver diseases, and several neoplasms. 7-13 Studies have documented that miRNAs show differential expression in various tumors, such as in prostate, ovary, lung, breast, brain, and pituitary tumors. 14,15 miRNAs as biomarkers in circulating blood have been implicated in the diagnosis, prognosis, and recurrence of pituitary tumors. 16,17 Recent findings demonstrated significant connec- tions between miRNAs that are deregulated in the tumor and those released into the peripheral blood. These findings raised the question of whether circulating miRNAs may also play a role as diagnostic or prognostic biomarkers and in detecting or even predicting recurrence in several tumors. 16,17 Here, we review the biological significance of miRNAs in pituitary tumors and the potential value of circulating miRNAs as biomarkers. miRNA BIOGENESIS AND FUNCTION miRNAs are 19 to 25 nucleotides (nt) long, noncoding RNA molecules that regulate posttran- scriptional gene expression via RNA interference by targeting multiple mRNAs at the 39,59 untrans- lated regions or within the coding sequence. 18-21 Genes encoding miRNAs can be located in the genome individually or in clusters, as a part of broader noncoding sequences, or in introns of protein-coding genes. 22 miRNAs are transcribed by RNA polymerase II, which generates a long primary precursor miRNA (pre-miRNA). The Antonio Di Ieva, MD, PhD*‡ Henriett Butz, MD, PhD*§ Marzia Niamah, Hon. HBSc‡ Fabio Rotondo, BSc§ Salvatore De Rosa, MD, PhD¶ Aydin Sav, MDk George M. Yousef, MD, PhD§ Kalman Kovacs, MD, PhD§ Michael D. Cusimano, MD, PhD‡ ‡Division of Neurosurgery, Department of Surgery, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; §Department of Laboratory Medicine, Division of Pathology, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Canada; ¶Division of Cardiology, Magna Graecia University, Catanzaro, Italy; kDepartment of Pathology, Acıbadem University, School of Medicine, Maltepe, Istanbul, Turkey *These authors contributed equally. Correspondence: Antonio Di Ieva, MD, PhD, Division of Neurosurgery, St. Michael’s Hospital, 30 Bond Street, M5B 1W8 Toronto, ON, Canada. E-mail: diieva@hotmail.com Received, January 5, 2014. Accepted, March 27, 2014. Published Online, April 15, 2014. Copyright © 2014 by the Congress of Neurological Surgeons. ABBREVIATIONS: ACTH, adrenocorticotropic hor- mone; AGO, argonaute; AKL, a-Klotho; GH, growth hormone; HCC, hepatocellular carcinoma; HDL, high-density lipoprotein; miRNA, microRNA; NFA, nonfunctioning adenoma; nt, nucleotide; pre- miRNA, precursor micro-ribonucleic acid; PRL, prolactin REVIEW REVIEW NEUROSURGERY VOLUME 75 | NUMBER 2 | AUGUST 2014 | 181 Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.