This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Onken, M. D. Articles by Harbour, J. W. Search for Related Content PubMed PubMed Citation Articles by Onken, M. D. Articles by Harbour, J. W.

Functional Gene Expression Analysis Uncovers Phenotypic Switch in Aggressive Uveal Melanomas

Departments of ¹ Ophthalmology and Visual Sciences and ² Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri and ³ Department of Biochemistry, Fukui Medical University, Fukui, Japan

Requests for reprints: J. William Harbour, Washington University School of Medicine, Box 8069, 660 South Euclid Avenue, St. Louis, MO 63110. Phone: 314-362-3315; Fax: 314-747-5073; E-mail: harbour{at}vision.wustl.edu.

Microarray gene expression profiling is a powerful tool for generating molecular cancer classifications. However, elucidating biological insights from these large data sets has been challenging. Previously, we identified a gene expression-based classification of primary uveal melanomas that accurately predicts metastatic death. Class 1 tumors have a low risk and class 2 tumors a high risk for metastatic death. Here, we used genes that discriminate these tumor classes to identify biological correlates of the aggressive class 2 signature. A search for Gene Ontology categories enriched in our class-discriminating gene list revealed a global down-regulation of neural crest and melanocyte-specific genes and an up-regulation of epithelial genes in class 2 tumors. Correspondingly, class 2 tumors exhibited epithelial features, such as polygonal cell morphology, up-regulation of the epithelial adhesion molecule E-cadherin, colocalization of E-cadherin and ß-catenin to the plasma membrane, and formation of cell-cell adhesions and acinar structures. One of our top class-discriminating genes was the helix-loop-helix inhibitor ID2, which was strongly down-regulated in class 2 tumors. The class 2 phenotype could be recapitulated by eliminating Id2 in cultured class 1 human uveal melanoma cells and in a mouse ocular melanoma model. Id2 seemed to suppress the epithelial-like class 2 phenotype by inhibiting an activator of the E-cadherin promoter. Consequently, Id2 loss triggered up-regulation of E-cadherin, which in turn promoted anchorage-independent cell growth, a likely antecedent to metastasis. These findings reveal new roles for Id2 and E-cadherin in uveal melanoma progression, and they identify potential targets for therapeutic intervention. (Cancer Res 2006; 66(9): 4602-9)

This article has been cited by other articles:

				Z. Tian, T. Hwang, and R. Kuang A hypergraph-based learning algorithm for classifying gene expression and arrayCGH data with prior knowledge Bioinformatics, November 1, 2009; 25(21): 2831 - 2838. [Abstract] [Full Text] [PDF]

				B. E. G. Rothberg, M. B. Bracken, and D. L. Rimm Tissue Biomarkers for Prognosis in Cutaneous Melanoma: A Systematic Review and Meta-analysis J Natl Cancer Inst, April 1, 2009; 101(7): 452 - 474. [Abstract] [Full Text] [PDF]

				M. Murakami, H. Kawachi, K. Ogawa, Y. Nishino, and M. Funaba Receptor expression modulates the specificity of transforming growth factor-beta signaling pathways. Genes Cells, April 1, 2009; 14(4): 469 - 482. [Abstract] [Full Text] [PDF]

				M. D. Onken, L. A. Worley, M. D. Long, S. Duan, M. L. Council, A. M. Bowcock, and J. W. Harbour Oncogenic Mutations in GNAQ Occur Early in Uveal Melanoma Invest. Ophthalmol. Vis. Sci., December 1, 2008; 49(12): 5230 - 5234. [Abstract] [Full Text] [PDF]

				W. Yan, G. Liu, A. Scoumanne, and X. Chen Suppression of Inhibitor of Differentiation 2, a Target of Mutant p53, Is Required for Gain-of-Function Mutations Cancer Res., August 15, 2008; 68(16): 6789 - 6796. [Abstract] [Full Text] [PDF]

				A. Sekulic, P. Haluska Jr, A. J. Miller, J. G. De Lamo, S. Ejadi, J. S. Pulido, D. R. Salomao, E. C. Thorland, R. G. Vile, D. L. Swanson, et al. Malignant Melanoma in the 21st Century: The Emerging Molecular Landscape Mayo Clin. Proc., July 1, 2008; 83(7): 825 - 846. [Abstract] [Full Text] [PDF]

				M. D. Onken, L. A. Worley, and J. W. Harbour A Metastasis Modifier Locus on Human Chromosome 8p in Uveal Melanoma Identified by Integrative Genomic Analysis Clin. Cancer Res., June 15, 2008; 14(12): 3737 - 3745. [Abstract] [Full Text] [PDF]

				G. M. Kreizenbeck, A. J. Berger, A. Subtil, D. L. Rimm, and B. E. Gould Rothberg Prognostic Significance of Cadherin-Based Adhesion Molecules in Cutaneous Malignant Melanoma Cancer Epidemiol. Biomarkers Prev., April 1, 2008; 17(4): 949 - 958. [Abstract] [Full Text] [PDF]

				S. Bakalian, J.-C. Marshall, P. Logan, D. Faingold, S. Maloney, S. Di Cesare, C. Martins, B. F. Fernandes, and M. N. Burnier Jr. Molecular Pathways Mediating Liver Metastasis in Patients with Uveal Melanoma Clin. Cancer Res., February 15, 2008; 14(4): 951 - 956. [Abstract] [Full Text] [PDF]

				M. Ye, D. Hu, L. Tu, X. Zhou, F. Lu, B. Wen, W. Wu, Y. Lin, Z. Zhou, and J. Qu Involvement of PI3K/Akt Signaling Pathway in Hepatocyte Growth Factor-Induced Migration of Uveal Melanoma Cells Invest. Ophthalmol. Vis. Sci., February 1, 2008; 49(2): 497 - 504. [Abstract] [Full Text] [PDF]

				K. V. Sharma, J. E. Gould, J. W. Harbour, G. P. Linette, T. K. Pilgram, P. N. Dayani, and D. B. Brown Hepatic Arterial Chemoembolization for Management of Metastatic Melanoma Am. J. Roentgenol., January 1, 2008; 190(1): 99 - 104. [Abstract] [Full Text] [PDF]

				T. Meir, R. Dror, X. Yu, J. Qian, I. Simon, J. Pe'er, and I. Chowers Molecular Characteristics of Liver Metastases from Uveal Melanoma Invest. Ophthalmol. Vis. Sci., November 1, 2007; 48(11): 4890 - 4896. [Abstract] [Full Text] [PDF]

				J. R. Latendresse, L. Muskhelishvili, A. Warbritton, and W. H. Tolleson Two Cases of Uveal Amelanotic Melanoma in Transgenic Tyr-HRAS+ Ink4a/Arf Heterozygous Mice Toxicol Pathol, October 1, 2007; 35(6): 825 - 830. [Abstract] [Full Text] [PDF]

				A. D Singh, K. Sisley, Y. Xu, J. Li, P. Faber, S. J Plummer, H. S Mudhar, I. G Rennie, P. M Kessler, G. Casey, et al. Reduced expression of autotaxin predicts survival in uveal melanoma Br J Ophthalmol, October 1, 2007; 91(10): 1385 - 1392. [Abstract] [Full Text] [PDF]

				T. Meir, M. Zeschnigk, L. Masshofer, J. Pe'er, and I. Chowers The Spatial Distribution of Monosomy 3 and Network Vasculogenic Mimicry Patterns in Uveal Melanoma Invest. Ophthalmol. Vis. Sci., May 1, 2007; 48(5): 1918 - 1922. [Abstract] [Full Text] [PDF]

				S. N. Markovic, L. A. Erickson, R. D. Rao, R. H. Weenig, B. A. Pockaj, A. Bardia, C. M. Vachon, S. E. Schild, R. R. McWilliams, J. L. Hand, et al. Malignant Melanoma in the 21st Century, Part 2: Staging, Prognosis, and Treatment Mayo Clin. Proc., April 1, 2007; 82(4): 490 - 513. [Abstract] [Full Text] [PDF]

				L. A. Worley, M. D. Onken, E. Person, D. Robirds, J. Branson, D. H. Char, A. Perry, and J. W. Harbour Transcriptomic versus Chromosomal Prognostic Markers and Clinical Outcome in Uveal Melanoma Clin. Cancer Res., March 1, 2007; 13(5): 1466 - 1471. [Abstract] [Full Text] [PDF]

				M. D. Onken, L. A. Worley, R. M. Davila, D. H. Char, and J. W. Harbour Prognostic Testing in Uveal Melanoma by Transcriptomic Profiling of Fine Needle Biopsy Specimens J. Mol. Diagn., November 1, 2006; 8(5): 567 - 573. [Abstract] [Full Text] [PDF]