Aim: To extensively explore microRNA expression profiles in lung carcinoids in correlation with clinical and pathological features. Methods: A PCR-based array was employed in the screening phase to analyze 752 microRNAs in a discovery set of 12 lung carcinoids, including 6 typical (3 with lymph node metastasis) and 6 atypical (3 with lymph node metastasis). The results were validated by means of real-time PCR in 37 carcinoids, including 22 typical (4 with lymph node metastasis) and 15 atypical (7 with lymph node metastasis), and 19 high-grade neuroendocrine carcinomas. Results: Unsupervised cluster analysis segregated the pilot cases into 3 distinct groups. Twenty-four microRNAs were differentially regulated in atypical versus typical carcinoids, and 29 in metastatic versus nonmetastatic cases. Eleven microRNAs were selected for validation. All but 1 were significantly different among lung neuroendocrine tumor histotypes. Moreover, 5 (miR-129-5p, miR-409-3p, miR-409-5p, miR-185 and miR-497) were significantly upregulated in typical compared to atypical carcinoids. MiR-409-3p, miR-409-5p and miR-431-5p were also significantly downregulated in carcinoids metastatic to the lymph nodes. Predictive in silico analysis of specific target genes showed that these 3 latter microRNAs linked to metastatic potential are implicated in several cellular functions and highlighted several novel genes which may be worth exploring. Conclusions: Our findings demonstrate that lung carcinoids have distinct microRNA expression profiles as compared to high-grade neuroendocrine carcinomas and that specific microRNAs might have potential implications as diagnostic tools or clinical biomarkers.

Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC: World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of the Lung, Pleura, Thymus and Heart. Lyon, IARC Press, 2004, pp 19-20.
Gustafsson BI, Kidd M, Chan A, Malfertheiner MV, Modlin IM: Bronchopulmonary neuroendocrine tumors. Cancer 2008;113:5-21.
Öberg K, Hellman P, Ferolla P, Papotti M: Neuroendocrine bronchial and thymic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012;23 Suppl 7:vii120-123.
Beasley MB, Thunnissen FB, Brambilla E, Hasleton P, Steele R, Hammar SP, Colby TV, Sheppard M, Shimosato Y, Koss MN, Falk R, Travis WD: Pulmonary atypical carcinoid: predictors of survival in 106 cases. Hum Pathol 2000;31:1255-1265.
Aydin E, Yazici U, Gulgosteren M, Agackiran Y, Kaya S, Gulhan E, Tastepe I, Karaoglanoglu N: Long-term outcomes and prognostic factors of patients with surgically treated pulmonary carcinoid: our institutional experience with 104 patients. Eur J Cardiothorac Surg 2011;39:549-554.
Naalsund A, Rostad H, Strøm EH, Lund MB, Strand TE: Carcinoid lung tumors - incidence, treatment and outcomes: a population-based study. Eur J Cardiothorac Surg 2011;39:565-569.
Rindi G, Klersy C, Inzani F, Fellegara G, Ampollini L, Ardizzoni A, Campanini N, Carbognani P, De Pas TM, Galetta D, Granone PL, Righi L, Rusca M, Spaggiari L, Tiseo M, Viale G, Volante M, Papotti M, Pelosi G: Grading the neuroendocrine tumors of the lung: an evidence-based proposal. Endocr Relat Cancer 2013;21:1-16.
Swarts DR, Ramaekers FC, Speel EJ: Molecular and cellular biology of neuroendocrine lung tumors: evidence for separate biological entities. Biochim Biophys Acta 2012;1826:255-271.
Di Leva G, Croce CM: miRNA profiling of cancer. Curr Opin Genet Dev 2013;23:3-11.
de Cubas AA, Leandro-García LJ, Schiavi F, Mancikova V, Comino-Méndez I, Inglada-Pérez L, Perez-Martinez M, Ibarz N, Ximénez-Embún P, López-Jiménez E, Maliszewska A, Letón R, Gómez Graña A, Bernal C, Alvarez-Escolá C, Rodríguez-Antona C, Opocher G, Muñoz J, Megias D, Cascón A, Robledo M: Integrative analysis of miRNA and mRNA expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways. Endocr Relat Cancer 2013;20:477-493.
Li SC, Essaghir A, Martijn C, Lloyd RV, Demoulin JB, Oberg K, Giandomenico V: Global microRNA profiling of well-differentiated small intestinal neuroendocrine tumors. Mod Pathol 2013;26:685-696.
Roldo C, Missiaglia E, Hagan JP, Falconi M, Capelli P, Bersani S, Calin GA, Volinia S, Liu CG, Scarpa A, Croce CM: MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. J Clin Oncol 2006;24:4677-4684.
Gilad S, Lithwick-Yanai G, Barshack I, Benjamin S, Krivitsky I, Edmonston TB, Bibbo M, Thurm C, Horowitz L, Huang Y, Feinmesser M, Hou JS, St Cyr B, Burnstein I, Gibori H, Dromi N, Sanden M, Kushnir M, Aharonov R: Classification of the four main types of lung cancer using a microRNA-based diagnostic assay. J Mol Diagn 2012;14:510-517.
Lee HW, Lee EH, Ha SY, Lee CH, Chang HK, Chang S, Kwon KY, Hwang IS, Roh MS, Seo JW: Altered expression of microRNA miR-21, miR-155, and let-7a and their roles in pulmonary neuroendocrine tumors. Pathol Int 2012;62:583-591.
Mairinger FD, Ting S, Werner R, Walter RF, Hager T, Vollbrecht C, Christoph D, Worm K, Mairinger T, Sheu-Grabellus SY, Theegarten D, Schmid KW, Wohlschlaeger J: Different micro-RNA expression profiles distinguish subtypes of neuroendocrine tumors of the lung: results of a profiling study. Mod Pathol 2014;27:1632-1640.
Suzuki R, Shimodaira H: Pvclust: an R package for assessing the uncertainty in hierarchical clustering. Bioinformatics 2006;22:1540-1542.
Weng C, Dong H, Chen G, Zhai Y, Bai R, Hu H, Lu L, Xu Z: miR-409-3p inhibits HT1080 cell proliferation, vascularization and metastasis by targeting angiogenin. Cancer Lett 2012;323:171-179.
Xu X, Chen H, Lin Y, Hu Z, Mao Y, Wu J, Xu X, Zhu Y, Li S, Zheng X, Xie L: MicroRNA-409-3p inhibits migration and invasion of bladder cancer cells via targeting c-Met. Mol Cells 2013;36:62-68.
Zheng B, Liang L, Huang S, Zha R, Liu L, Jia D, Tian Q, Wang Q, Wang C, Long Z, Zhou Y, Cao X, Du C, Shi Y, He X: MicroRNA-409 suppresses tumour cell invasion and metastasis by directly targeting radixin in gastric cancers. Oncogene 2012;31:4509-4516.
Swarts DR, Van Neste L, Henfling ME, Eijkenboom I, Eijk PP, van Velthuysen ML, Vink A, Volante M, Ylstra B, Van Criekinge W, van Engeland M, Ramaekers FC, Speel EJ: An exploration of pathways involved in lung carcinoid progression using gene expression profiling. Carcinogenesis 2013;34:2726-2737.
Swarts DR, Henfling ME, Van Neste L, van Suylen RJ, Dingemans AM, Dinjens WN, Haesevoets A, Rudelius M, Thunnissen E, Volante M, Van Criekinge W, van Engeland M, Ramaekers FC, Speel EJ: CD44 and OTP are strong prognostic markers for pulmonary carcinoids. Clin Cancer Res 2013;19:2197-2207.
Ozbudak IH, Shilo K, Tavora F, Rassaei N, Chu WS, Fukuoka J, Jen J, Travis WD, Franks TJ: Glucose transporter-1 in pulmonary neuroendocrine carcinomas: expression and survival analysis. Mod Pathol 2009;22:633-638.
Magnuson B, Ekim B, Fingar DC: Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. Biochem J 2012;441:1-21.
Righi L, Volante M, Rapa I, Tavaglione V, Inzani F, Pelosi G, Papotti M: Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung. Endocr Relat Cancer 2010;17:977-987.
Mergler S, Strauss O, Strowski M, Prada J, Drost A, Langrehr J, Neuhaus P, Wiedenmann B, Ploeckinger U: Insulin-like growth factor-1 increases intracellular calcium concentration in human primary neuroendocrine pancreatic tumor cells and a pancreatic neuroendocrine tumor cell line (BON-1) via R-type Ca2+ channels and regulates chromogranin a secretion in BON-1 cells. Neuroendocrinology 2005;82:87-102.
Ho AS, Kannan K, Roy DM, Morris LG, Ganly I, Katabi N, Ramaswami D, Walsh LA, Eng S, Huse JT, Zhang J, Dolgalev I, Huberman K, Heguy A, Viale A, Drobnjak M, Leversha MA, Rice CE, Singh B, Iyer NG, Leemans CR, Bloemena E, Ferris RL, Seethala RR, Gross BE, Liang Y, Sinha R, Peng L, Raphael BJ, Turcan S, Gong Y, Schultz N, Kim S, Chiosea S, Shah JP, Sander C, Lee W, Chan TA: The mutational landscape of adenoid cystic carcinoma. Nat Genet 2013;45:791-798.
Okosun J, Bödör C, Wang J, Araf S, Yang CY, Pan C, Boller S, Cittaro D, Bozek M, Iqbal S, Matthews J, Wrench D, Marzec J, Tawana K, Popov N, O'Riain C, O'Shea D, Carlotti E, Davies A, Lawrie CH, Matolcsy A, Calaminici M, Norton A, Byers RJ, Mein C, Stupka E, Lister TA, Lenz G, Montoto S, Gribben JG, Fan Y, Grosschedl R, Chelala C, Fitzgibbon J: Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet 2014;46:176-181.
Peifer M, Fernández-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, Plenker D, Leenders F, Sun R, Zander T, Menon R, Koker M, Dahmen I, Müller C, Di Cerbo V, Schildhaus HU, Altmüller J, Baessmann I, Becker C, de Wilde B, Vandesompele J, Böhm D, Ansén S, Gabler F, Wilkening I, Heynck S, Heuckmann JM, Lu X, Carter SL, Cibulskis K, Banerji S, Getz G, Park KS, Rauh D, Grütter C, Fischer M, Pasqualucci L, Wright G, Wainer Z, Russell P, Petersen I, Chen Y, Stoelben E, Ludwig C, Schnabel P, Hoffmann H, Muley T, Brockmann M, Engel-Riedel W, Muscarella LA, Fazio VM, Groen H, Timens W, Sietsma H, Thunnissen E, Smit E, Heideman DA, Snijders PJ, Cappuzzo F, Ligorio C, Damiani S, Field J, Solberg S, Brustugun OT, Lund-Iversen M, Sänger J, Clement JH, Soltermann A, Moch H, Weder W, Solomon B, Soria JC, Validire P, Besse B, Brambilla E, Brambilla C, Lantuejoul S, Lorimier P, Schneider PM, Hallek M, Pao W, Meyerson M, Sage J, Shendure J, Schneider R, Büttner R, Wolf J, Nürnberg P, Perner S, Heukamp LC, Brindle PK, Haas S, Thomas RK: Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 2012;44:1104-1110.
Park MH, Lee HS, Lee CS, You ST, Kim DJ, Park BH, Kang MJ, Heo WD, Shin EY, Schwartz MA, Kim EG: p21-Activated kinase 4 promotes prostate cancer progression through CREB. Oncogene 2013;32:2475-2482.
Senanayake U, Das S, Vesely P, Alzoughbi W, Fröhlich LF, Chowdhury P, Leuschner I, Hoefler G, Guertl B: miR-192, miR-194, miR-215, miR-200c and miR-141 are downregulated and their common target ACVR2B is strongly expressed in renal childhood neoplasms. Carcinogenesis 2012;33:1014-1021.
Kuzmanov A, Hopfer U, Marti P, Meyer-Schaller N, Yilmaz M, Christofori G: LIM-homeobox gene 2 promotes tumor growth and metastasis by inducing autocrine and paracrine PDGF-B signaling. Mol Oncol 2014;8:401-416.
Nakamura Y, Migita T, Hosoda F, Okada N, Gotoh M, Arai Y, Fukushima M, Ohki M, Miyata S, Takeuchi K, Imoto I, Katai H, Yamaguchi T, Inazawa J, Hirohashi S, Ishikawa Y, Shibata T: Krüppel-like factor 12 plays a significant role in poorly differentiated gastric cancer progression. Int J Cancer 2009;125:1859-1867.
Hong J, Sun J, Huang T: Increased expression of TRPS1 affects tumor progression and correlates with patients' prognosis of colon cancer. Biomed Res Int 2013;2013:454085.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.