MicroRNAs as biomarkers in pituitary tumors.

REVIEW REVIEW

MicroRNAs as Biomarkers in Pituitary Tumors 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: [email protected] Received, January 5, 2014. Accepted, March 27, 2014. Published Online, April 15, 2014. Copyright © 2014 by the Congress of Neurological Surgeons.

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 demonstrated 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

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icroRNAs (miRNAs) are a class of noncoding RNAs that regulate posttranscriptional gene expression. They are considered to be negative regulators that control cell proliferation, metabolism, apoptosis, and differentiation. They are involved in many physiological and pathophysiological conditions, such as cardiovasculardiseasesandcancer.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 biomarkers 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

ABBREVIATIONS: ACTH, adrenocorticotropic hormone; AGO, argonaute; AKL, a-Klotho; GH, growth hormone; HCC, hepatocellular carcinoma; HDL, high-density lipoprotein; miRNA, microRNA; NFA, nonfunctioning adenoma; nt, nucleotide; premiRNA, precursor micro-ribonucleic acid; PRL, prolactin

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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 connections 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 posttranscriptional gene expression via RNA interference by targeting multiple mRNAs at the 39, 59 untranslated 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

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primary pre-miRNA is then cleaved by an RNase III (Drosha)– enzyme containing complex into an approximately 60- to 70-nt long pre-miRNA, which has a hairpin secondary structure.23 The pre-miRNA molecule is transported to the cytoplasm by Exportin5 and processed by another RNase III enzyme (Dicer)–cleaving pre-miRNA into an approximately 21-nt miRNA:miRNA* duplex.24 One strand of this RNA duplex (matured miRNA) is incorporated into miRNA-induced silencing complex, whereas the other strand (passenger strand or miRNA*) is usually degraded25

(Figure). Recent data, however, suggest that miRNA* also could be loaded into a miRNA-induced silencing complex.26,27 Approximately 30% to 50% of all protein-coding genes might be controlled by miRNAs.28,29 A single miRNA potentially affects the expression of several proteins, and 1 protein is influenced by numerous miRNAs. In addition, multiple miRNAs can modulate the expression of the same gene and interact with each other forming cotargeting networks.30 Because they can be actively exported or taken up by cells, miRNAs can cross cellular

FIGURE. The origin of extracellular microRNAs (miRNAs). miRNA biogenesis begins in the nucleus transcribing by RNA pol II or III. Then primary (pri-) miRNAs are cleaved by the Drosha/DGCR8 complex into the hairpin structured pre-miRNAs, transported to cytoplasm by Exportin 5, and then processed by another RNA enzyme Dicer to an miRNA duplex. One strand of the duplex is incorporated into RNA-induced silencing complex (RISC) and represses protein translation by inhibiting protein synthesis, mRNA cleavage by AGO2 protein or by mRNA degradation through deadenylation. The other strand is usually degraded or can be packaged to export. miRNAs can be incorporated into multivesicular endosomes or shedding microvesicles (1 and 2). Extracellular miRNAs can also be vesicle free complexed with RNA binding proteins (such as AGO proteins) or high-density lipoprotein (HDL). Apoptotic bodies are larger than vesicles and also contain miRNAs in addition to other cell organelles as well. (See text for details). AAAA, poly(A) tail of RNA; AGO, argonaute; TRBP, transactivating response RNA (TAR) binding protein.

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MicroRNAs IN PITUITARY TUMORS

borders and exert their function in other cells.31 Their role is considered to put gene expression to the optimal level, in other words, “fine tune.”32

miRNAs IN PITUITARY TUMORS Pituitary tumor miRNAs are become an emerging focus of pituitary tumor research.33 The differential expression of miRNAs has been extensively researched to show their role in tumorigenesis and tumor suppression. Bottoni et al1 identified 30 miRNAs that are differentially expressed between normal and adenomatous pituitary using microarray. They also described histotype-specific miRNAs.1 The overexpression of miR-23a, -23b, and -24-2 and underexpression of miR-26b were characteristic to growth hormone– (GH) and prolactin- (PRL) secreting tumors. The strong expression of miR-30a, b, and c were typical in adrenocorticotropic hormone (ACTH)–producing tumors. It was found that miR-26b can distinguish between GH- and PRL-secreting adenomas compared with nonfunctioning adenomas (NFAs) because the expression is higher in NFAs. Other signatures related to NFAs include the downregulation of miR-24-2, -127, -129, -134, and -203. Stilling et al34 reported that miR-122 and miR-493 were upregulated in pituitary carcinomas compared with adenomas. miRNAs have also been shown to correlate with clinical data. MiR-140 was described as differentially expressed in nonfunctioning micro- and macroadenomas, and the expression of miR-450b, miR-424, miR-503, miR-542-3p, miR-629, and miR-214 showed correlation with tumor size in NFAs.35 ACTH adenomas underexpressing miR-141 were found to have higher remission rates after surgical removal.2 Qian et al36 reported that adenomas having a higher grade and that are more invasive had lower expression of let-7 than the low-grade tumors. According to treatment response to dopamine agonist, treated vs nontreated NFAs, miR-134, miR148, miR-155, miR-29b, miR-29c, and miR-200a showed a significantly different expression.1 Other groups identified 13 miRNAs to be different in somatostatin analogue–treated and –nontreated GH-secreting tumors, and 7 miRNAs were linked to drug response.37 Regarding miRNAs’ function, some target genes have been validated in pituitary adenoma. Functional or experimental validation of miRNA-target interaction is labor intensive because it requires cloning of the transcript region of interest into a vector and performing site-directed mutagenesis to confirm exact binding sites of miRNAs on the transcript. Also, protein is required to verify the effect of miRNAs on protein level after miRNA transfection. Bottoni et al1 suggested that miR-16-1 is underexpressed in GH- and PRL-secreting tumors. There is an inverse correlation with their target arginyl-tRNA synthetase that is linked to tumor growth.1 It was previously shown that tumor suppressor Wee-1 kinase, which controls cell cycle, was regulated by 3 overexpressed miRNAs: miR-128a, miR-155, and miR-516a-3p.38 HMGA1 and 2 proteins were also described to be targeted by several miRNAs (let-7a, miR-15, miR-16, miR-26a, miR-196a2, miR-34b, miR-326, miR-432, miR-548c-3p, miR-570, and miR-603)

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in GH-/PRL-secreting adenomas.36,39,40 Members of the HMGA (high-mobility group A) family are nonhistone chromosomal proteins that are involved in cell growth, proliferation, differentiation, and death,41 and through them, numerous miRNAs influence pituitary adenoma development. Pleiomorphic adenoma gene 1 (PLAG1), which induces cell-cycle arrest and apoptosis, has also been suggested to be the target of miR-26a overexpression in NFAs.1 Transforming growth factor-b signaling influenced by miRNAs in NFAs as well as 5 miRs showed negative correlation with Smad3 expression,35 among which miR-140 was experimentally validated. In ACTH-secreting tumors, the role of miR-26 was verified as targeting protein kinase Cd (PRKCD), and through this, miRNA plays an important role in cell-cycle control of ACTH pituitary cells.42

EXTRACELLULAR miRNAs miRNAs can be found in various human biological fluids including blood, urine, saliva, breast milk, peritoneal fluid, tears, and cerebrospinal fluid.43 Extracellular miRNAs can be packed in membrane vesicles that protect them from circulating RNases or can be bound to transporter proteins, such as argonaute (AGO) proteins,44,45 or even within macromolecular complexes, such as high-density lipoprotein (HDL)46 (Figure). Microvesicles are well-known to be secreted by several cell types such as neural cells, stem cells, epithelial cells, dendritic cells, and lymphocytes.47-52 The term microvesicles is often used to describe various types of vesicles regardless of the size or origin. Both exosomes and other microvesicles contain various molecules specific for their cell origin including mRNA, miRNA, proteins, cytokines, and different surface receptors.53 Exosomes are a specific subtype of secreted membrane vesicles54 that are formed intracellularly in endosomal compartments (multivesicular endosomes). In the endosomes, extracellular molecules are stored, released, or degraded by fusing with lysosomes after endocytosis. They are small and homogeneous in size; vesicles are 30 to 100 nm in length. Exosomes can be released by fusion of the multivesicular endosomes with the plasma membrane.54 Cells can release other types of vesicles by directly budding off the plasma membrane. These vesicles are called microvesicles, shed vesicles, or ectosomes, and their size, 50 to 1000 nm, is more variable than that of the exosomes. Several miRNAs were found in 8- to 12-nm HDL particles; therefore, their extracellular uptake by the host cells is dependent on the presence of HDL receptors.55 Apoptotic bodies are approximately 1 to 4 mm in size and are remnants of programmed cell death. They are not considered circulating miRNAs because they are easily removed during the early phase of isolation methods.55 Interestingly, microvesicles can be actively exported or taken up by cells, thus providing a means by which miRNAs can cross cellular borders and exert their function in other cells.31 As with intracellular miRNAs, the extracellular miRNAs are often associated with AGO proteins, and their remarkable stability makes them resistant to RNases. Recently, AGO-miRNA



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complexes released by activated platelets have been shown to exert regulatory functions on endothelial cells.56 It has been suggested that miRNAs packed in microvesicles or in HDL are also associated with AGO proteins, which are supported by the presence of AGO2 proteins in exosomes.46,55 Extracellular miRNAs can also be a byproduct of cellular activity and cell death, and the amount of miRNAs correlates with cell death in vitro.55 Interestingly, not all mRNA molecules were found in exosomes. Data suggest that different RNA species can be specifically packaged by active sorting.47,57,58 miRNAs in membrane vesicles or complexed with RNA binding proteins are protected against RNases even if they are in exosomes, shedding vesicles, apoptotic bodies, or HDL.

EXTRACELLULAR miRNAs’ FUNCTION The function of exosomes is not yet clear; however, studies found that they play a significant role in cell-to-cell communication in immunology and tumor biology in a manner that resembles hormones. Zitvogel et al51 found that exosomes secreted by dendritic cells carry antigens and are able to induce immune response. It has been shown that in malignant tumors, cancer cells may influence their environment by exosome secretion as a paracrine effect to promote angiogenesis and metastasis as well as growth by inhibiting antitumor immune response.59-61 Microvesicles in glioblastomas have been shown to stimulate proliferation in a human glioma cell line, indicating a self-promoting effect,8 whereas glioblastoma cell–derived exosomes can modulate endothelial cells for activation and migration.8,60 It was demonstrated that cancer cells can eliminate tumor-suppressor miRNAs by exosome secretion to maintain their oncogenesis in metastatic gastric cancer and proapoptotic function of secreted exosomes on pancreatic tumor cells.62,63 Recently, cell-to-cell transfer of selected miRNAs through microvescicles has been described between different cell populations within vessel walls.31 Similarly, cell-to-cell miRNA transfer has also been described from platelets to endothelial cells in the form of AGO-miRNA complexes.56 The relevance of such findings is not limited to the cardiovascular system, but represents proof of concept that an intercellular communication pathway exists that is mediated by miRNAs. Despite increasing experimental evidence regarding the role of the extracellular miRNAs, further investigation is warranted to clarify their function.

EXTRACELLULAR miRNAs AS BIOMARKERS miRNAs are stable in extracellular fluids, and miRNA levels were demonstrated to be reproducible across individuals and resistant to enzymatic cleavage, thawing-freezing cycles, and pH changes.7,64,65 The fact that miRNAs are detectable in various body fluids makes them a potential marker for different pathophysiological conditions. The major contributors of extracellular miRNA in blood are hematocytes including platelets. However, other tissue-specific miRNAs (such as miR-122 from the liver, miR-124 from the brain, and miR-208b from the heart) are also detectable in the blood.66-68 To corroborate information found in the various


miRNA biomarker studies, proper controls are necessary to limit platelet contamination for circulating miRNA biomarker studies.69 Tissue-specific miRNAs can be released from tissues on injury and act as potential biomarkers in tissue injury. Release of selected miRNAs from myocardial tissue can be detected in the coronary circulation on myocardial injury and necrosis70 and in peripheral blood after myocardial infarction.68 There is also clinical evidence indicating the release of miR-122 into the circulatory system resulting from drug-induced liver injury.71 Cancer tumor–associated miRNAs were detected in the serum of patients having not only hematological diseases but in solid tumors as well. However, it is not clear whether they are derived from the tumor directly or from nonmalignant cells as a response to cancer.55 Several miRNAs used as cancer biomarkers were identified from different body fluids (Table). The serum levels of miR-141, an miRNA expressed in prostate cancer, could distinguish prostate cancer patients from healthy individuals.7 The ratio of miR-126 to miR-152 in urine samples was found to be a reliable marker for the detection of urothelial bladder cancer,92 whereas miR-31 in saliva was identified as a clinical biomarker of oral squamous cell carcinoma.82 Other miRNAs have been identified as potential prognostic biomarkers for breast cancer and diffuse large B-cell lymphoma.16,17 Correlations have been made between serum or plasma and the expression profile of miRNAs in different tumors and diseases.7,16,93 In lung cancer patients, expression of the miR-1792 cluster and miR-17- 5p was increased in both the serum and lung tumors.81 This phenomenon was also seen with miR-155, which showed higher levels of expression in tumor tissues as well as in the serum of breast cancer patients.94,95 However, in the liver, there was an inverse relationship between tumor tissue and peripheral expression, with increased miR-122 expression in the serum of hepatocellular carcinoma (HCC) but decreased in the tumor.79,96,97 This was seen in HCC cell cultures and culture medium as well; hence, cell culture medium relates to serum that contains higher levels of miR-122, and the cultured HCC cells behave as the tumor cells expressing lower levels of miR-122.98

SERUM BIOMARKERS IN PITUITARY TUMORS Recurring pituitary adenomas have been subdivided into various subtypes based on size, dural invasion, suprasellar extension, cavernous sinus invasion, remission, and outcome predictors after transsphenoidal resection.99 Roelfsema et al100 reported that the mean remission values and ranges were 68.8% (27%-100%) in prolactinoma, 47.3% (3%-92%) in nonfunctioning pituitary adenoma, 61.2% (37%-88%) in GH, and 71.3% (41%-98%) in ACTH- secreting tumors. The pituitary gland is highly vascularized,101 and pituitary tumors show characteristic microvascular networks, as demonstrated by computer-aided fractal-based analysis.102,103 The high amount of vascularization of the pituitary gland and tumors indicates the increasing likelihood of detecting molecules expressed in the peripheral blood of patients who have undergone




TABLE. Circulating miRNAs as Biomarkers in Cancer Patientsa References

Cancer Acute leukemia (AML and ALL)

miR-92a decreased, miR-92a/miR-638 ratio differentiates patients having cancer from healthy controls

Zhu et al73 Heneghan et al74 Ng et al75

Breast

miR-155 differentiates hormone-sensitive and -insensitive breast cancer miR-195 increased miR-92 differentiates patients having cancer from healthy controls, gastric cancer, IBD patients miR-29a, miR-92a differentiate patients having cancer from healthy controls and patients having advanced adenomas

Colorectal cancer

Huang et al76 Lawrie et al16

Diffuse large B-cell lymphoma

Tsujiura et al77

Gastric cancer

Yamamoto et al78 Ko¨berle et al79 Hu 201080 Chen et al81 Liu et al82,83

Hepatocellular carcinoma

Liu et al83

Oral squamous cell cancer

Lin et al84 Wong et al85 Resnick et al86 Mao et al87

a

Circulating miRNA as Biomarker Candidate

Tanaka et al72

Lung cancer Oral squamous cell cancer

Ovarian cancer

Chen et al88

Primary central nervous system lymphoma Prostate cancer

Mitchell et al7 Wang et al89

Pancreatic cancer

Ho et al90 Redova et al91

Renal cell carcinoma

miR-21, miR-155, miR-210 differentiate patients having cancer from healthy controls; miR-21 expression was associated with relapse-free survival miR-17-5p, miR-21, miR-106a, miR-106b increased, let-7a decreased; miR-106a/let-7a ratio differentiates patients having cancer from healthy controls miR-500 increased miR-1 miR-486, miR-30d, miR-1 and miR-499 associated with overall survival miR-17-5p, miR-17-92 increased miR-31 increased and differentiates patients having cancer from healthy controls miR-31 increased and differentiates patients having cancer from healthy controls miR-24 increased miR-184 increased miR-21, miR-92, miR-93, miR-126, miR-29a increased; miR-155, miR-127, miR-99b decreased miR-21 increased let-7e, let-7c, miR-30c decreased; miR-622, miR-1285 upregulated the combination of 5 miRNAs that differentiates patients having cancer from healthy controls miR-141 differentiates patients having cancer from healthy controls Combination of miR-21, miR-210, miR-155, and miR-196a differentiates patients having cancer from healthy controls miR-210 increased miR-378 increased, miR-451 decreased, combination of miR-378 and miR-451 differentiates patients having cancer from healthy controls

miRNAs, microRNAs; AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; IBD, inflammatory bowel disease.

surgical resection of a tumor. As the pituitary gland releases hormones into the circulation, secreted hormones are used as biomarkers for diagnosis or follow-up; however, deregulated miRNAs have been proposed as potential biomarkers of pituitary tumor recurrence.1,104,105 Identifying biomarkers would be important, especially in the case of clinical NFAs that are mostly of gonadotroph origin, because increased levels of circulating gonadotrope hormones usually do not cause clinical symptoms for patients, nor are they used as biological tumor markers. Greenman et al106 described a relationship between b-luteinizing hormone levels, tumor size, and surgical outcome, but this association is insufficient to allow for the routine use of either

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basal or thyrotropin-releasing hormone–induced b-luteinizing hormone responses in postsurgical follow-up of clinical NFAs. Recently, Hu et al107 identified 9 serum protein biomarkers for NFAs using surface-enhanced laser desorption/ionization time-offlight mass spectrometry technology, and 7 serum protein spots were characteristic of acromegaly and can serve as potential biomarkers to assess the effectiveness of surgical treatment in acromegalic individuals.108 Others developed a model based on serum proteome fingerprint to diagnose pituitary adenomas using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.109 More research is needed to ascertain how mass spectrometry-based results can be validated and applied to clinical practice.



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Findings in a 2013 publication by Neidert et al110 showed that in patients having GH-producing adenomas, high soluble a-Klotho (aKL) serum levels were specific to tumors and decreased rapidly after adenoma removal.110 The a-Klotho gene was discovered as a life span–influencing gene in mice after recognizing that its disruption caused accelerated aging.111 The Klotho protein family is expressed in the kidney and choroid plexus, and endocrine organs such as the pituitary, parathyroid, testis, ovary, placenta, and pancreas.111 Soluble aKL may attenuate insulin/insulin-like growth factor 1 signaling and regulate calcium homoeostasis.111 Immunohistochemistry demonstrated that in acromegaly, the increase in serum aKL is caused by systemic actions of GH rather than increased expression by the pituitary adenoma. Because these results were independent of age, sex, and kidney function, the authors suggested soluble aKL to be a novel, specific, and sensitive biomarker indicating disease activity in acromegaly.110 In pituitary tumorigenesis, TGF-b1 was found to be a useful serum marker for tumor invasiveness in PRL-secreting tumors and suggested that the simultaneous determination of TGF-b1 and PRL levels could improve the noninvasive assessment of prolactinoma behavior.112

miRNA BIOMARKERS IN PITUITARY TUMORS miRNAs have been proposed as ideal biomarkers for early tumor detection, prognosis, and diagnosis. Tumor biomarkers should be tumor specific; the level of deregulated expression found in the serum, plasma, urine, or other body fluids should correspond to the extent of tumor development.98 It is also suggested that circulating miRNAs can be linked to tissue miRNA expression, further supporting the hypothesis that circulating miRNAs can reflect the status of specific tumors. miRNAs are actively released by either normal or tumor cells and can serve as noninvasive biomarkers for the diagnosis of tumors. Currently, there are no studies profiling circulating miRNAs as biomarkers in pituitary tumors. However, Wang et al113 investigated the plasma levels of 3 miRNAs (miR21, miR-128, and miR-342-3p) in 10 pituitary adenomas used as controls for identifying biomarkers for gliomas. They concluded that the 3 miRNAs could only be localized in gliomas and were thus tumor specific. In a recent study, Kelly et al114 found that 4 miRNAs were differentially expressed in individuals using therapeutic replacement doses of recombinant human GH compared with individuals with naturally high levels of GH and normal controls.

CONCLUSION miRNAs are promising biomarkers because they are highly stable in extracellular fluids. Compared with protein markers, which can be affected by posttranslational modifications, miRNAs can be difficult to detect and can be easily degraded and easily quantified by polymerase chain reaction, and, in certain cases, are found to be sensitive and specific and able to predict prognosis. As


they are released from cells in an energy-dependent manner, miRNAs reflect intracellular processes and may have relevant information. In addition, their involvement in cell-to-cell communication makes their impact as circulating biomarkers even higher. To date, few reports are available regarding blood levels of circulating miRNAs in patients with pituitary tumors. A complete profiling would be of great interest and would allow identification of potential biomarkers to be exploited for diagnosis and follow-up as well as for early detection of recurrence after surgery. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

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Acknowledgment The authors are grateful to the Jarislowsky and Lloyd Carr-Harris Foundations for their generous support.

COMMENT

T

his paper addresses an important topic describing the significance of microRNAs in pituitary tumors and their role as biomarkers. A good marker should be characterized by a high sensitivity and specificity as well as a low intra- and interindividual variability. All these aspects should be extensively investigated and represent a challenge for the near future. Beforehand, to understand diagnostic and prognostic potential of miRNAs, it is crucial to explore the role of deregulated miRNAs in the




settings of pituitary adenomas. To date, the functional aftermath of miRNA dysregulation in pituitary adenomas has not fully elucidated. To this aim, the identification of the miRNA targets is especially challenging. The goal in using miRNAs as biomarkers is to improve the management of patients with pituitary adenomas. Therefore, the open-ended question is “would microRNAs significantly advance the currently diagnostic, prognostic, and therapeutic methods compared with already in-use standards?” This up-to-date review encourages future miRNA studies. Ettore degli Uberti Ferrara, Italy

m

iRNAs, non-coding RNA molecules that regulate post transcriptional gene expression, have been used as biomarkers in the diagnosis and prognosis of several diseases, mainly in cancer, including

NEUROSURGERY

pituitary tumors. Cancer tumor-associated miRNAs were previously detected in serum of patients having hematological diseases. More recently, data have suggested that miRNAs are deregulated not only within the solid tumors but also in peripheral blood of these patients. Therefore, circulating miRNAs could also have a potential value as biomarkers in the cancer diagnosis and prognosis. In this article, the authors have provided a clear and concise description of miRNAs biological significance in pituitary tumors. In addition, they reviewed the putative role of blood levels of circulating miRNAs in the diagnosis and prognosis of patients with pituitary tumors. Few reviews have addressed this in progress issue; although our knowledge on miRNAs remains mainly exploratory, it is an important new area, which makes the present review highly appropriate for any neurosurgeon interested in this field. Margaret de Castro São Paulo, Brazil



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