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Proof Only 3 178 PROOF ONLY C M Falch et al. Fast- and slow-growing 178:3 295–307 Clinical Study gonadotroph NFPAs Gene expression profiling of fast- and slow-growing non-functioning gonadotroph pituitary adenomas Camilla Maria Falch1,2,3,4, Arvind Y M Sundaram5, Kristin Astrid Øystese1,6, Kjersti Ringvoll Normann1,2,6, Tove Lekva2, Ivars Silamikelis7, Alexander Kirkeby Eieland1, Marianne Andersen3, Jens Bollerslev1,6 and Nicoleta Cristina Olarescu1,2 1Section of Specialized Endocrinology, Department of Endocrinology, 2Research Institute for Internal Medicine, Oslo University Hospital, Oslo, Norway, 3Department of Endocrinology and Metabolism, Odense University Hospital, Correspondence Odense, Denmark, 4University of Southern Denmark, Odense, Denmark, 5Department of Medical Genetics, Oslo should be addressed University Hospital, Oslo, Norway, 6Faculty of Medicine, University of Oslo, Oslo, Norway, and 7Latvian Biomedical to C M Falch Research and Study Centre (LV BMC), Riga, Latvia Email [email protected] Abstract Objective: Reliable biomarkers associated with aggressiveness of non-functioning gonadotroph adenomas (GAs) are lacking. As the growth of tumor remnants is highly variable, molecular markers for growth potential prediction are necessary. We hypothesized that fast- and slow-growing GAs present different gene expression profiles and reliable biomarkers for tumor growth potential could be identified, focusing on the specific role of epithelial-mesenchymal transition (EMT). Design and methods: Eight GAs selected for RNA sequencing were equally divided into fast- and slow-growing group by the tumor volume doubling time (TVDT) median (27.75 months). Data were analyzed by tophat2, cufflinks and cummeRbund pipeline. 40 genes were selected for RT-qPCR validation in 20 GAs based on significance, fold-change and pathway analyses. The effect of silencing MTDH (metadherin) and EMCN (endomucin) on in vitro migration of European Journal European of Endocrinology human adenoma cells was evaluated. Results: 350 genes were significantly differentially expressed (282 genes upregulated and 68 downregulated in the fast group, P-adjusted <0.05). Among 40 selected genes, 11 showed associations with TVDT (−0.669<R<−0.46, P < 0.05). These were PCDH18, UNC5D, EMCN, MYO1B, GPM6A and six EMT-related genes (SPAG9, SKIL, MTDH, HOOK1, CNOT6L and PRKACB). MTDH, but not EMCN, demonstrated involvement in cell migration and association with EMT markers. Conclusions: Fast- and slow-growing GAs present different gene expression profiles, and genes related to EMT have higher expression in fast-growing tumors. In addition to MTDH, identified as an important contributor to aggressiveness, the other genes might represent markers for tumor growth potential and possible targets for drug therapy. European Journal of Endocrinology (2018) 178, 295–307 Introduction The pathogenesis of sporadic non-functioning pituitary aggressiveness or recurrence, making the prediction of tumor adenomas (NFPAs) remains elusive. Regardless of intensive behavior a demanding challenge. Consequently, prolonged effort, specific genetic mutations are rarely found in NFPAs observation is necessary, constituting a significant burden (1). There are no reliable molecular markers associated with in terms of medical resources and societal costs. www.eje-online.org © 2018 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-17-0702 Printed in Great Britain Downloaded from Bioscientifica.com at 10/02/2021 12:15:28PM via free access 10.1530/EJE-17-0702 Clinical Study C M Falch et al. Fast- and slow-growing 178:3 296 gonadotroph NFPAs The silent gonadotroph NFPAs (GAs) are the most Subjects and methods common (75%) of all the immunohistochemical subgroups of NFPAs (2). Gene expression profiling Patients and samples analyses have shown to be of importance in identifying The patients included in this study (n = 20) were selected molecular markers, as well as to determine essential from a larger cohort of patients (n = 88) based on the signaling pathways for correct histological stratification possibility to assess growth modeling (only tumors with and thereby adequate treatment of a wide range of cancers regrowth and four or more consecutive magnetic resonance (3). Recent studies have investigated the differential gene imaging (MRI) examinations or five years of follow-up, expression according to tumor invasiveness or recurrence not interrupted by new interventions), the availability of characteristics (i.e. comparing invasive vs non-invasive stored tumor tissue and the positivity for gonadotroph (4, 5) and early recurrent vs non-recurrent pituitary hormones (follicle-stimulating hormone (FSH) and/or adenomas (6)). Tumor volume doubling time (TVDT) luteinizing hormone (LH)) and/or steroidogenic factor describes the growth velocity by measuring the time it (SF)-1 on immunohistochemistry (IHC). Tumor volume, takes for a tumor to double in volume. It is calculated early TVDT and growth models (logistic, exponential or presuming the tumor has an exponential growth curve, linear) were estimated for all samples (13). The patients enabling the clinician to estimate a safe interval between underwent surgery at Oslo University Hospital between follow-up investigations and is used to predict the clinical 2002 and 2009, and all samples were from the primary course of tumors in several cancer types. Information of operation. The tumor tissue was immediately placed on adenoma growth kinetics and TVDT, collaborated with ice and snap frozen in liquid nitrogen, and later stored at data about tumor biology, would substantially enhance the −80°C or embedded in Tissue-Tek. clinical knowledge of tumor behavior and help to adjust Written informed consent was obtained from all and individualize follow-up (7). Previous studies usually patients. The study was approved by the regional ethics describe the growth of NFPAs by an exponential, logistic committee (REK no: 2014/635 and REK no: 2014/1680) or linear growth model (7, 8, 9, 10, 11). The presence of and hospital authority. The genetic expression analyses tumor remnants following initial surgery indicates a high were exclusively connected to tumor biology. Thus, no risk of regrowth (12), and we have recently presented that information about the patient’s genotype was given, and the calculation of early TVDT as a prediction of ‘worst- the study did not influence treatment or patient follow-up. case’ scenario for future growth can be a tool to tailor safe follow-up intervals (13). European Journal European of Endocrinology RNA isolation and reverse transcription Epithelial-mesenchymal transition (EMT) is a well- studied regulatory programming process in various After homogenization of tumor tissue, total RNA was cancers, which also plays a role in the pathogenesis of extracted using TRIzol (Invitrogen) and later purified pituitary adenomas (14, 15, 16). Epithelial cells undergo with the QIAGEN miRNeasy Mini Kit (Qiagen) according changes to show mesenchymal cell characteristics to the manufacturer’s instructions, including the DNase with increased motility, invasiveness and even distant digestion step for removal of genomic DNA. RNA integrity metastasis (14, 15, 16). Loss of membranous E-cadherin was determined by Agilent 2100 Bioanalyzer (Agilent is a hallmark of EMT (14). Studies of growth hormone Technologies) and the concentrations were measured by and ACTH-producing adenomas have linked EMT to OD readings on a NanoDrop ND-1000 Spectrophotometer the progression of tumors. The reduction in E-cadherin (Nanodrop Technologies, Wilmington, DE, USA). All content in these tumors has been associated with tumor samples had RNA integrity numbers (RIN) >7, indicating size, invasiveness and poor response to medical treatment an adequate quality. A high-capacity cDNA Reverse (15, 17, 18, 19, 20). Transcription Kit (Applied Biosystems) was used to In this study, we hypothesized that GAs with different perform reverse transcription in a Labnet MultiGene initial growth velocities (high vs low) have different gene Gradient Thermal Cylinder (Labnet International, Edison, expression profiles. We aimed to identify target genes NJ, USA) using 1 μg RNA in reaction. After the reaction, in fast- and slow-growing tumors, estimated by early the cDNA was diluted 1:10 and all real-time quantitative postoperative TVDT, and to find reliable biomarkers reverse transcription polymerase chain reaction (RT-qPCR) predicting growth potential of the residual tumor tissue, measurements were performed with the same batch focusing on the specific role of EMT. of cDNA. www.eje-online.org Downloaded from Bioscientifica.com at 10/02/2021 12:15:28PM via free access Clinical Study C M Falch et al. Fast- and slow-growing 178:3 297 gonadotroph NFPAs RNA sequencing 7900 (Applied Biosystems) on the entire cohort (n = 20). Reaction mix (with Power SYBR Green PCR Master Mix, Library preparation and sequencing Applied Biosystems) and samples were dispensed in the The RNA sequencing (RNA-seq) was performed using 2 μg corresponding wells by an automated pipetting system RNA for each sample (n = 8) at the Norwegian Sequencing (epMotion5070 CB, Hamburg, Germany). RT-qPCR Centre, Oslo, Norway. Eight RNA-seq libraries with amplification was performed as previously described 26( ). unique indexes were prepared using TruSeq stranded We used the primer bank (https://pga.mgh.harvard. mRNA library prep kit (Illumina, San Diego, CA, USA) edu/primerbank/) or searched the literature to
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