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L. Packer, S. Pavey, A. Parker,
M. Stark, P. Johansson, B. Clarke,
P. Pollock, M. Ringnér, and
N. Hayward
Osteopontin is a downstream effector of the
PI3-kinase pathway in melanomas that is inversely
correlated with functional PTEN
Carcinogenesis 27, 1778-1786 (2006)
Abstract:
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
secretedglycophosphoprotein 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 ofOPN. These data indicate that OPN acts
downstream of PI3K in melanoma and provides insight into
how PTEN loss contributes to melanoma development.
LU TP 06-04
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