Carcinogenesis Advance Access published online on March 29, 2006
Carcinogenesis, doi:10.1093/carcin/bgl016
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1 Human Genetics Laboratory, Queensland Institute of Medical Research, Herston 4006, QLD, Australia
* To whom correspondence should be addressed. The tumor suppressor PTEN antagonizes phosphatidylinositol 3-kinase (PI3K) which contributes to tumorigenesis in many cancer types. While PTEN mutations occur in some melanomas, their precise mechanistic consequences have yet to be elucidated. We sought to identify novel downstream effectors of PI3K using a combination of genomic and functional tests. Microarray analysis of 53 melanoma cell lines identified 610 genes differentially expressed (p<0.05) between wild-type lines and those with PTEN aberrations. Many of these genes are known to be involved in the PI3K pathway and other signaling pathways influenced by PTEN. Validation of differential gene expression by qRT-PCR was performed in the original 53 cell lines and an independent set of 18 melanoma lines with known PTEN status. Osteopontin (OPN), a secreted glycophosphoprotein which contributes to tumor progression, was more abundant at both the mRNA and protein level in PTEN mutants. The inverse correlation between OPN and PTEN expression was validated (p<0.02) by immunohistochemistry using melanoma tissue microarrays. Finally, treatment of cell lines with the PI3K inhibitor LY294002 caused a reduction in expression of OPN. These data indicate that OPN acts downstream of PI3K in melanoma and provides insight into how PTEN loss contributes to melanoma development.
Received January 27, 2006
Revised March 13, 2006
Accepted March 15, 2006
CANCER BIOLOGY
Osteopontin is a downstream effector of the PI3-kinase pathway in melanomas that is inversely correlated with functional PTEN
Leisl Packer 1 *,
Sandra Pavey 1,
Andrew Parker 2,
Mitchell Stark 1,
Peter Johansson 3,
Belinda Clarke 4,
Pamela Pollock 5,
Markus Ringner 3,
and
Nicholas Hayward 1
2 Department of Cellular Pathology, John Radcliffe Hospital, Oxford OX3 9DU, UK
3 Department of Theoretical Physics, Lund University, Lund SE-223 62, Sweden
4 Queensland Health Pathology Services, Prince Charles Hospital, Brisbane 4032, Australia
5 Melanoma Genetics Research Unit, Translational Genomics Research Institute, Phoenix 85004, USA
Leisl Packer, E-mail: Leisl.Packer{at}qimr.edu.au
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