MEN1 and microRNAs: The link between sporadic pituitary, parathyroid and adrenocortical tumors? Z. Nagy a , P.M. Szabó b , V.K. Grolmusz a,c , P. Perge a , I. Igaz d , A. Patócs c,e , P. Igaz a,⇑ a 2nd Department of Medicine, Faculty of Medicine, Semmelweis University, Szentkirályi str. 46, H-1088 Budapest, Hungary b National Institutes of Health/NCI/DCTD/BRP, 9609 Medical Center Dr Bethesda MD, USA c ‘‘Lendület-2013” Research Group, Hungarian Academy of Sciences and Semmelweis University, Szentkirályi str. 46, H-1088 Budapest, Hungary d Department of Gastroenterology, Szt Imre Teaching Hospital Budapest, Budapest, Hungary e Department of Laboratory Medicine, Faculty of Medicine, Semmelweis University, Szentkirályi str. 46, H-1088 Budapest, Hungary article info Article history: Received 16 July 2016 Accepted 17 December 2016 Keywords: Pituitary Parathyroid Adrenal cortex Tumor MEN1 MicroRNA abstract Sporadic tumors of the pituitary, parathyroids and adrenal cortex are unique, as their benign forms are very common, but malignant forms are exceptionally rare. Hereditary forms of these tumors occur in multiple endocrine neoplasia syndrome type 1 (MEN1). We hypothesize that the pathogenic link among the sporadic tumors of these organs of different germ layers might be represented by common molecular pathways involving the MEN1 gene and microRNAs (miR). miR-24 might be a microRNA linking the three tumor entities, but other candidates such as miR-142-3p and microRNAs forming the DLK1-MEG3 miRNA cluster might also be of importance. Ó 2016 Elsevier Ltd. All rights reserved. Introduction From an oncological point of view, tumors of the pituitary, parathyroids and the adrenal cortex can be regarded as unique, as their benign forms are very common, but malignant forms are exceptionally rare. Pituitary adenomas are the most common intracranial neoplasms with an incidence of 77.6-94/100000/year [1–3]. In contrast, pituitary cancer is extremely rare, representing only 0,2–1% of all pituitary tumors [4–6]. Similarly, despite the high incidence of parathyroid adenomas, parathyroid cancer is exceptional, only less than 1% of all primary hyperparathyroidism cases [7,8]. Moreover, the prevalence of adrenocortical adenomas reaches 4.4–6% [9] in elderly people contrasting the very low inci- dence of 0.5–2/million/year related to adrenocortical cancer [10]. It is unclear what differentiates these three organs from other organs where there is no such great discrepancy in the frequency of benign and malignant tumors (e.g. both benign and malignant tumors are common in the breast, liver and colon). These three organs derive from different germ layers (pituitary – ectoderm, adrenal cortex – mesoderm, parathyroid – endoderm) that make a potential molecular link between these three organs even more intriguing. Multiple endocrine neoplasia type 1 syndrome (MEN1) is a rare hereditary tumor syndrome (prevalence: 1:30.000) caused by mutations of the MEN1 gene. Its major clinical manifestations include primary hyperparathyroidism, duodenopancreatic neu- roendocrine tumors (gastrinoma, insulinoma, hormonally inactive tumors etc.) and pituitary adenomas. Moreover, adrenocortical tumors are also observed in 9–40% of MEN1 cases [11–13]. Whereas MEN1-related neuroendocrine tumors can be malignant, parathyroid lesions are always benign (hyperplasia) and pituitary lesions are also predominantly benign, however, their aggressive growth is common. MEN1-linked adrenocortical tumors are almost always benign, as well [14]. MicroRNAs are major regulators of gene expression at the post- transcriptional level that target the 3 0 untranslated region of mes- senger RNAs and induce their degradation or translational inhibi- tion. Altered expression of microRNAs is considered to be a major event in tumor formation and there are already plenty of data in many different organs and tumors showing their patho- genic relevance [15]. Differential expressions of microRNAs have been described between normal tissues, benign and malignant tumors of the pituitary [16–18], parathyroid [19,20] and adrenal cortex [21–24], as well. http://dx.doi.org/10.1016/j.mehy.2016.12.007 0306-9877/Ó 2016 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. E-mail address: igaz.peter@med.semmelweis-univ.hu (P. Igaz). Medical Hypotheses 99 (2017) 40–44 Contents lists available at ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy