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Comparative microarray analysis of microRNA expression profiles in primary cutaneous malignant melanoma, cutaneous malignant melanoma metastases, and benign melanocytic nevi

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Abstract

Perturbations in microRNA (miRNA) expression profiles have been reported for cutaneous malignant melanoma (CMM) predominantly when examined in cell lines. Despite the rapidly growing number of newly discovered human miRNA sequences, the availability of up-to-date miRNA expression profiles for clinical samples of primary cutaneous malignant melanoma (PCMM), cutaneous malignant melanoma metastases (CMMM), and benign melanocytic nevi (BMN) is limited. Specimens excised from the center of tumors (lesional) from patients with PCMM (n=9), CMMM (n=4), or BMN (n=8) were obtained during surgery. An exploratory microarray analysis was performed by miRNA expression profiling based on Agilent platform screening for 1205 human miRNAs. The results from the microarray analysis were validated by TaqMan quantitative real-time polymerase chain reaction. In addition to several miRNAs previously known to be associated with CMM, 19 unidentified miRNA candidates were found to be dysregulated in CMM patient samples. Among the 19 novel miRNA candidates, the genes hsa-miR-22, hsa-miR-130b, hsa-miR-146b-5p, hsa-miR-223, hsa-miR-301a, hsa-miR-484, hsa-miR-663, hsa-miR-720, hsa-miR-1260, hsa-miR-1274a, hsa-miR-1274b, hsa-miR-3663-3p, hsa-miR-4281, and hsa-miR-4286 were upregulated, and the genes hsa-miR-24-1*, hsa-miR-26a, hsa-miR-4291, hsa-miR-4317, and hsa-miR-4324 were downregulated. The results of this study partially confirm previous CMM miRNA profiling studies identifying miRNAs that are dysregulated in CMM. However, we report several novel miRNA candidates in CMM tumors; these miRNA sequences require further validation and functional analysis to evaluate whether they play a role in the pathogenesis of CMM.

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References

  • Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355

    Article  PubMed  CAS  Google Scholar 

  • Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S, Allgayer H (2008) MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene 27:2128–2136

    Article  PubMed  CAS  Google Scholar 

  • Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    Article  PubMed  CAS  Google Scholar 

  • Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B 57:289–300

    Google Scholar 

  • Bonazzi VF, Irwin D, Hayward NK (2009) Identification of candidate tumor suppressor genes inactivated by promoter methylation in melanoma. Genes Chromosomes Cancer 48:10–21

    Article  PubMed  CAS  Google Scholar 

  • Bonazzi VF, Stark MS, Hayward NK (2012) MicroRNA regulation of melanoma progression. Melanoma Res 22:101–113

    Article  PubMed  CAS  Google Scholar 

  • Boone B, Jacobs K, Ferdinande L, Taildeman J, Lambert J, Peeters M, Bracke M, Pauwels P, Brochez L (2011) EGFR in melanoma: clinical significance and potential therapeutic target. J Cutan Pathol 38:492–502

    Article  PubMed  Google Scholar 

  • Busse A, Keilholz U (2011) Role of TGF-beta in melanoma. Curr Pharm Biotechnol 12:2165–2175

    Article  PubMed  CAS  Google Scholar 

  • Caramuta S, Egyhazi S, Rodolfo M, Witten D, Hansson J, Larsson C, Lui WO (2010) MicroRNA expression profiles associated with mutational status and survival in malignant melanoma. J Invest Dermatol 130:2062–2070

    Article  PubMed  CAS  Google Scholar 

  • Chan E, Patel R, Nallur S, Ratner E, Bacchiocchi A, Hoyt K, Szpakowski S, Godshalk S, Ariyan S, Sznol M, Halaban R, Krauthammer M, Tuck D, Slack FJ, Weidhaas JB (2011) MicroRNA signatures differentiate melanoma subtypes. Cell Cycle 10:1845–1852

    Article  PubMed  CAS  Google Scholar 

  • Edgar R, Domrachev M, Lash AE (2002) Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res 30:207–210

    Article  PubMed  CAS  Google Scholar 

  • Elson-Schwab I, Lorentzen A, Marshall CJ (2010) MicroRNA-200 family members differentially regulate morphological plasticity and mode of melanoma cell invasion. PLoS One 5:pii:e13176

    Article  Google Scholar 

  • Fan T, Jiang S, Chung N, Alikhan A, Ni C, Lee CC, Hornyak TJ (2011) EZH2-dependent suppression of a cellular senescence phenotype in melanoma cells by inhibition of p21/CDKN1A expression. Mol Cancer Res 9:418–429

    Article  PubMed  CAS  Google Scholar 

  • Faraoni I, Antonetti FR, Cardone J, Bonmassar E (2009) miR-155 gene: a typical multifunctional microRNA. Biochim Biophys Acta 1792:497–505

    Article  PubMed  CAS  Google Scholar 

  • Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH (2008) Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem 283:1026–1033

    Article  PubMed  CAS  Google Scholar 

  • Friedman RC, Farh KK, Burge CB, Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105

    Article  PubMed  CAS  Google Scholar 

  • Gaur A, Jewell DA, Liang Y, Ridzon D, Moore JH, Chen C, Ambros VR, Israel MA (2007) Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. Cancer Res 67:2456–2468

    Article  PubMed  CAS  Google Scholar 

  • Geraldo MV, Yamashita AS, Kimura ET (2012) MicroRNA miR-146b-5p regulates signal transduction of TGF-beta by repressing SMAD4 in thyroid cancer. Oncogene 31:1910–1922

    Article  PubMed  CAS  Google Scholar 

  • Glud M, Rossing M, Hother C, Holst L, Hastrup N, Nielsen FC, Gniadecki R, Drzewiecki KT (2010) Downregulation of miR-125b in metastatic cutaneous malignant melanoma. Melanoma Res 20:479–484

    Article  PubMed  CAS  Google Scholar 

  • Grignol V, Fairchild ET, Zimmerer JM, Lesinski GB, Walker MJ, Magro CM, Kacher JE, Karpa VI, Clark J, Nuovo G, Lehman A, Volinia S, Agnese DM, Croce CM, Carson WE 3rd (2011) miR-21 and miR-155 are associated with mitotic activity and lesion depth of borderline melanocytic lesions. Br J Cancer 105:1023–1029

    Article  PubMed  CAS  Google Scholar 

  • Howell PM Jr, Li X, Riker AI, Xi Y (2010) MicroRNA in melanoma. Ochsner J 10:83–92

    PubMed  Google Scholar 

  • Igoucheva O, Alexeev V (2009) MicroRNA-dependent regulation of cKit in cutaneous melanoma. Biochem Biophys Res Commun 379:790–794

    Article  PubMed  CAS  Google Scholar 

  • Jiang L, Lv X, Li J, Li X, Li W, Li Y (2012) The status of microRNA-21 expression and its clinical significance in human cutaneous malignant melanoma. Acta Histochem 114:582–588

    Article  PubMed  CAS  Google Scholar 

  • Jiang Q, Wang Y, Hao Y, Juan L, Teng M, Zhang X, Li M, Wang G, Liu Y (2009) miR2Disease: a manually curated database for microRNA deregulation in human disease. Nucleic Acids Res 37:D98–D104

    Article  PubMed  CAS  Google Scholar 

  • Jukic DM, Rao UN, Kelly L, Skaf JS, Drogowski LM, Kirkwood JM, Panelli MC (2010) MicroRNA profiling analysis of differences between the melanoma of young adults and older adults. J Transl Med 8:27

    Article  PubMed  Google Scholar 

  • Karube Y, Tanaka H, Osada H, Tomida S, Tatematsu Y, Yanagisawa K, Yatabe Y, Takamizawa J, Miyoshi S, Mitsudomi T, Takahashi T (2005) Reduced expression of Dicer associated with poor prognosis in lung cancer patients. Cancer Sci 96:111–115

    Article  PubMed  CAS  Google Scholar 

  • Katakowski M, Zheng X, Jiang F, Rogers T, Szalad A, Chopp M (2010) MiR-146b-5p suppresses EGFR expression and reduces in vitro migration and invasion of glioma. Cancer Invest 28:1024–1030

    Article  PubMed  CAS  Google Scholar 

  • Katoh Y, Katoh M (2008) Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA (review). Int J Mol Med 22:271–275

    PubMed  CAS  Google Scholar 

  • Lee YS, Kim HK, Chung S, Kim KS, Dutta A (2005) Depletion of human micro-RNA miR-125b reveals that it is critical for the proliferation of differentiated cells but not for the down-regulation of putative targets during differentiation. J Biol Chem 280:16635–16641

    Article  PubMed  CAS  Google Scholar 

  • Leidinger P, Keller A, Borries A, Reichrath J, Rass K, Jager SU, Lenhof HP, Meese E (2010) High-throughput miRNA profiling of human melanoma blood samples. BMC Cancer 10:262

    Article  PubMed  Google Scholar 

  • Lesinski GB, Raig ET, Zimmerer JM, Karpa V, Nuovo G, Lehman A, Peters S, Kacher JE, Magro CM, Croce CM, Carson WE (2008) Micro-RNA-21 and micro-RNA-155 as predictors of a malignant phenotype in melanocytic lesions. J Clin Oncol 26:9001

    Google Scholar 

  • Levati L, Alvino E, Pagani E, Arcelli D, Caporaso P, Bondanza S, Di Leva G, Ferracin M, Volinia S, Bonmassar E, Croce CM, D'Atri S (2009) Altered expression of selected microRNAs in melanoma: antiproliferative and proapoptotic activity of miRNA-155. Int J Oncol 35:393–400

    PubMed  CAS  Google Scholar 

  • Lewis BP, Burge CB, Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120:15–20

    Article  PubMed  CAS  Google Scholar 

  • Lu Z, Li Y, Takwi A, Li B, Zhang J, Conklin DJ, Young KH, Martin R (2011) miR-301a as an NF-kappaB activator in pancreatic cancer cells. EMBO J 30:57–67

    Article  PubMed  CAS  Google Scholar 

  • McHugh JB, Fullen DR, Ma L, Kleer CG, Su LD (2007) Expression of polycomb group protein EZH2 in nevi and melanoma. J Cutan Pathol 34:597–600

    Article  PubMed  Google Scholar 

  • Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T (2007) MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133:647–658

    Article  PubMed  CAS  Google Scholar 

  • miRBase (2012) http://www.mirbase.org/

  • Molnar V, Tamasi V, Bakos B, Wiener Z, Falus A (2008) Changes in miRNA expression in solid tumors: an miRNA profiling in melanomas. Semin Cancer Biol 18:111–122

    Article  PubMed  CAS  Google Scholar 

  • Müller DW, Bosserhoff AK (2008) Integrin beta 3 expression is regulated by let-7a miRNA in malignant melanoma. Oncogene 27:6698–6706

    Article  PubMed  Google Scholar 

  • Mueller DW, Bosserhoff AK (2009) Role of miRNAs in the progression of malignant melanoma. Br J Cancer 101:551–556

    Article  PubMed  CAS  Google Scholar 

  • Mueller DW, Bosserhoff AK (2011) miRNAs in malignant melanoma. In: Bosserhoff AK (ed) Melanoma development: molecular biology genetics and clinical application. Springer, New York, pp 105–136

    Google Scholar 

  • Mueller DW, Rehli M, Bosserhoff AK (2009) miRNA expression profiling in melanocytes and melanoma cell lines reveals miRNAs associated with formation and progression of malignant melanoma. J Invest Dermatol 129:1740–1751

    Article  PubMed  CAS  Google Scholar 

  • Nguyen T, Kuo C, Nicholl MB, Sim MS, Turner RR, Morton DL, Hoon DS (2011) Downregulation of microRNA-29c is associated with hypermethylation of tumor-related genes and disease outcome in cutaneous melanoma. Epigenetics 6:388–394

    Article  PubMed  CAS  Google Scholar 

  • Philippidou D, Schmitt M, Moser D, Margue C, Nazarov PV, Muller A, Vallar L, Nashan D, Behrmann I, Kreis S (2010) Signatures of microRNAs and selected microRNA target genes in human melanoma. Cancer Res 70:4163–4173

    Article  PubMed  CAS  Google Scholar 

  • Quackenbush J (2001) Computational analysis of microarray data. Nat Rev Genet 2:418–427

    Article  PubMed  CAS  Google Scholar 

  • Sand M, Gambichler T, Sand D, Skrygan M, Altmeyer P, Bechara FG (2009) MicroRNAs and the skin: tiny players in the body's largest organ. J Dermatol Sci 53:169–175

    Article  PubMed  CAS  Google Scholar 

  • Sand M, Gambichler T, Sand D, Altmeyer P, Stuecker M, Bechara FG (2011) Immunohistochemical expression patterns of the microRNA-processing enzyme Dicer in cutaneous malignant melanomas, benign melanocytic nevi and dysplastic melanocytic nevi. Eur J Dermatol 21:18–21

    PubMed  Google Scholar 

  • Sand M, Skrygan M, Georgas D, Sand D, Gambichler T, Altmeyer P, Bechara FG (2012) The miRNA machinery in primary cutaneous malignant melanoma, cutaneous malignant melanoma metastases and benign melanocytic nevi. Cell Tissue Res 350(1):119–26

    Google Scholar 

  • Sander S, Bullinger L, Klapproth K, Fiedler K, Kestler HA, Barth TF, Moller P, Stilgenbauer S, Pollack JR, Wirth T (2008) MYC stimulates EZH2 expression by repression of its negative regulator miR-26a. Blood 112:4202–4212

    Article  PubMed  CAS  Google Scholar 

  • Satzger I, Mattern A, Kuettler U, Weinspach D, Voelker B, Kapp A, Gutzmer R (2010) MicroRNA-15b represents an independent prognostic parameter and is correlated with tumor cell proliferation and apoptosis in malignant melanoma. Int J Cancer 126:2553–2562

    PubMed  CAS  Google Scholar 

  • Schultz J, Lorenz P, Gross G, Ibrahim S, Kunz M (2008) MicroRNA let-7b targets important cell cycle molecules in malignant melanoma cells and interferes with anchorage-independent growth. Cell Res 18:549–557

    Article  PubMed  CAS  Google Scholar 

  • Segura MF, Belitskaya-Levy I, Rose AE, Zakrzewski J, Gaziel A, Hanniford D, Darvishian F, Berman RS, Shapiro RL, Pavlick AC, Osman I, Hernando E (2010) Melanoma microRNA signature predicts post-recurrence survival. Clin Cancer Res 16:1577–1586

    Article  PubMed  CAS  Google Scholar 

  • Sheng Y, Engstrom PG, Lenhard B (2007) Mammalian microRNA prediction through a support vector machine model of sequence and structure. PLoS One 2:e946

    Article  PubMed  Google Scholar 

  • Sigalotti L, Covre A, Fratta E, Parisi G, Colizzi F, Rizzo A, Danielli R, Nicolay HJ, Coral S, Maio M (2010) Epigenetics of human cutaneous melanoma: setting the stage for new therapeutic strategies. J Transl Med 8:56

    Article  PubMed  Google Scholar 

  • Sokal R, Michener C (1958) A statistical method for evaluating systematic relationships. Univ Kans Sci Bull 38:1409–1438

    Google Scholar 

  • Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T, Takahashi T (2004) Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 64:3753–3756

    Article  PubMed  CAS  Google Scholar 

  • Thompson KL, Pine PS, Rosenzweig BA, Turpaz Y, Retief J (2007) Characterization of the effect of sample quality on high density oligonucleotide microarray data using progressively degraded rat liver RNA. BMC Biotechnol 7:57

    Article  PubMed  Google Scholar 

  • Ueda Y, Richmond A (2006) NF-kappaB activation in melanoma. Pigment Cell Res 19:112–124

    Article  PubMed  CAS  Google Scholar 

  • Wit PE de, Moretti S, Koenders PG, Weterman MA, Muijen GN van, Gianotti B, Ruiter DJ (1992) Increasing epidermal growth factor receptor expression in human melanocytic tumor progression. J Invest Dermatol 99:168–173

    Google Scholar 

  • Xu Y, Brenn T, Brown ER, Doherty V, Melton DW (2012) Differential expression of microRNAs during melanoma progression: miR-200c, miR-205 and miR-211 are downregulated in melanoma and act as tumour suppressors. Br J Cancer 106:553–561

    Article  PubMed  CAS  Google Scholar 

  • Yang C, Wei W (2011) The miRNA expression profile of the uveal melanoma. Sci China Life Sci 54:351–358

    Article  PubMed  CAS  Google Scholar 

  • Yang CH, Yue J, Pfeffer SR, Handorf CR, Pfeffer LM (2011) MicroRNA miR-21 regulates the metastatic behavior of B16 melanoma cells. J Biol Chem 286:39172–39178

    Article  PubMed  CAS  Google Scholar 

  • Yeung ML, Yasunaga J, Bennasser Y, Dusetti N, Harris D, Ahmad N, Matsuoka M, Jeang KT (2008) Roles for microRNAs, miR-93 and miR-130b, and tumor protein 53-induced nuclear protein 1 tumor suppressor in cell growth dysregulation by human T-cell lymphotrophic virus 1. Cancer Res 68:8976–8985

    Article  PubMed  CAS  Google Scholar 

  • Zhang L, Huang J, Yang N, Greshock J, Megraw MS, Giannakakis A, Liang S, Naylor TL, Barchetti A, Ward MR, Yao G, Medina A, O'Brien-Jenkins A, Katsaros D, Hatzigeorgiou A, Gimotty PA, Weber BL, Coukos G (2006) microRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci USA 103:9136–9141

    Article  PubMed  CAS  Google Scholar 

  • Zhang JD, Biczok R, Ruschhaupt M (2011) The ddCt algorithm for the analysis of quantitative real-time PCR (qRT-PCR). Bioconductor 2.11 http://bioconductor.org/packages/release/bioc/html/ddCt.html

  • Zhang Z, Sun H, Dai H, Walsh RM, Imakura M, Schelter J, Burchard J, Dai X, Chang AN, Diaz RL, Marszalek JR, Bartz SR, Carleton M, Cleary MA, Linsley PS, Grandori C (2009) MicroRNA miR-210 modulates cellular response to hypoxia through the MYC antagonist MNT. Cell Cycle 8:2756–2768

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors are grateful to Dr. Cornelia Graf and Stefan Kotschote, MS, for technical advice.

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Authors and Affiliations

  1. Department of Dermatology, Venereology and Allergology, Ruhr University Bochum, 44791, Bochum, Germany

    Michael Sand, Marina Skrygan, Dimitrios Georgas, Thilo Gambichler, Peter Altmeyer & Falk G. Bechara

  2. Department of Medicine, Olive View UCLA Medical Center, University of California, Los Angeles (UCLA), Los Angeles, CA 91342, USA

    Daniel Sand

  3. Department of Internal Medicine, Knappschaftskrankenhaus University of Bochum, Zentrum für Klinische Forschung, Labor für Molekulare Gastroenterologische Onkologie, 44780, Bochum, Germany

    Stephan A. Hahn

  4. Dermatologic Surgery Unit, Department of Dermatology, Venereology and Allergology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, 44791, Bochum, Germany

    Michael Sand

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  1. Michael Sand
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  2. Marina Skrygan
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  3. Daniel Sand
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Correspondence to Michael Sand.

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This work was generously supported in part by the Fleur Hiege Stiftung gegen Hautkrebs, Hamburg, Germany.

The financial sponsors had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors alone are responsible for the content and writing of this manuscript.

The authors hereby disclose no commercial associations or any other associations that may pose or create a conflict of interest with the information presented in this manuscript.

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Sand, M., Skrygan, M., Sand, D. et al. Comparative microarray analysis of microRNA expression profiles in primary cutaneous malignant melanoma, cutaneous malignant melanoma metastases, and benign melanocytic nevi. Cell Tissue Res 351, 85–98 (2013). https://doi.org/10.1007/s00441-012-1514-5

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