Functional gene expression analysis uncovers phenotypic switch in aggressive uveal melanomas

Michael D. Onken, Justis P. Ehlers, Lori A. Worley, Jun Makita, Yoshifumi Yokota, J. William Harbour

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

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 β-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.

Original languageEnglish
Pages (from-to)4602-4609
Number of pages8
JournalCancer Research
Volume66
Issue number9
DOIs
StatePublished - May 1 2006
Externally publishedYes

Fingerprint

Cadherins
Gene Expression
Neoplasms
Up-Regulation
Genes
Phenotype
Catenins
Gene Ontology
Neural Crest
Melanocytes
Gene Expression Profiling
Uveal melanoma
Cell Adhesion
Melanoma
Down-Regulation
Cell Membrane
Neoplasm Metastasis
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Functional gene expression analysis uncovers phenotypic switch in aggressive uveal melanomas. / Onken, Michael D.; Ehlers, Justis P.; Worley, Lori A.; Makita, Jun; Yokota, Yoshifumi; William Harbour, J.

In: Cancer Research, Vol. 66, No. 9, 01.05.2006, p. 4602-4609.

Research output: Contribution to journalArticle

Onken, Michael D. ; Ehlers, Justis P. ; Worley, Lori A. ; Makita, Jun ; Yokota, Yoshifumi ; William Harbour, J. / Functional gene expression analysis uncovers phenotypic switch in aggressive uveal melanomas. In: Cancer Research. 2006 ; Vol. 66, No. 9. pp. 4602-4609.
@article{a1260db5aef8471ab575a5fff1ec4d50,
title = "Functional gene expression analysis uncovers phenotypic switch in aggressive uveal melanomas",
abstract = "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 β-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.",
author = "Onken, {Michael D.} and Ehlers, {Justis P.} and Worley, {Lori A.} and Jun Makita and Yoshifumi Yokota and {William Harbour}, J.",
year = "2006",
month = "5",
day = "1",
doi = "10.1158/0008-5472.CAN-05-4196",
language = "English",
volume = "66",
pages = "4602--4609",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

TY - JOUR

T1 - Functional gene expression analysis uncovers phenotypic switch in aggressive uveal melanomas

AU - Onken, Michael D.

AU - Ehlers, Justis P.

AU - Worley, Lori A.

AU - Makita, Jun

AU - Yokota, Yoshifumi

AU - William Harbour, J.

PY - 2006/5/1

Y1 - 2006/5/1

N2 - 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 β-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.

AB - 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 β-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.

UR - http://www.scopus.com/inward/record.url?scp=33646405726&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33646405726&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-05-4196

DO - 10.1158/0008-5472.CAN-05-4196

M3 - Article

VL - 66

SP - 4602

EP - 4609

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 9

ER -