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Microarray analysis identifies Autotaxin, a tumour cell motility and angiogenic factor with lysophospholipase D
Elizabeth J Black1, Timothy Clair, Jeffrey Delrow
1Beatson Institute for Cancer Research, Cancer Research Campaign Beatson Laboratories, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
Abstract:
We have used chicken cDNA microarrays to investigate gene-expression changes induced during transformation of chick embryo fibroblasts (CEF) by the viral Jun oncoprotein encoded by ASV17. This analysis reveals that v-Jun induces increases and decreases of varying magnitude in the expression of genes involved in diverse cellular functions, most of which have not been detected in previous screens for putative v-Jun targets. In all, 27 individual genes were identified, whose expression is increased threefold or more in v-Jun-transformed cells, including genes involved in energy generation, protein synthesis, and gene transcription. Interestingly, this group includes the hypoxia-inducible factor-1 alpha (Hif-1alpha) transcription factor and the glycolytic enzyme enolase, suggesting that adaptation to hypoxia could play a role in tumorigenesis by v-Jun. We also identified 32 genes whose expression is decreased threefold or more, including chaperones, components of the cytoskeleton, and, unexpectedly, DNA replication factors. The gene whose expression is upregulated most dramatically (approximately 100-fold) encodes Autotaxin (ATX), a secreted tumor motility-promoting factor with lysophospholipase D activity. Strikingly, v-Jun-transformed CEF secrete catalytically active ATX and chemotactic activity, which can be detected in conditioned medium. ATX is not detectably expressed in normal CEF or CEF transformed by the v-Src or v-Myc oncoproteins, indicating that induction of this putative autocrine/paracrine factor is a specific consequence of cell transformation by v-Jun. ATX has been implicated in both angiogenesis and invasion, and could therefore play an important role in tumorigenesis by v-Jun in vivo.
Insights
Viral Jun oncoprotein alters gene expression in chick cells, upregulating Autotaxin (ATX) and hypoxia-inducible factor-1 alpha (Hif-1alpha). This suggests ATX and hypoxia adaptation are key to v-Jun-driven tumorigenesis.
Area of Science:
- Oncology
- Molecular Biology
- Gene Expression Analysis
Background:
- Viral oncoproteins like v-Jun drive cellular transformation.
- Understanding gene expression changes is crucial for deciphering oncogenic mechanisms.
- Previous studies have identified some, but not all, v-Jun targets.
Purpose of the Study:
- To comprehensively investigate gene-expression alterations in chick embryo fibroblasts (CEF) induced by the ASV17 viral Jun oncoprotein.
- To identify novel genes regulated by v-Jun during cellular transformation.
- To explore the role of specific upregulated genes, such as Autotaxin (ATX) and Hypoxia-Inducible Factor-1 alpha (Hif-1alpha), in v-Jun-mediated tumorigenesis.
Main Methods:
- Utilized chicken cDNA microarrays for high-throughput gene expression profiling.
- Compared gene expression patterns between normal CEF and v-Jun-transformed CEF.
- Quantified gene expression changes, focusing on those altered threefold or more.
Main Results:
- Identified 27 genes with increased expression (≥3-fold) and 32 genes with decreased expression (≥3-fold) in v-Jun-transformed CEF.
- Notable upregulated genes include Hypoxia-Inducible Factor-1 alpha (Hif-1alpha) and enolase, suggesting a role for hypoxia adaptation.
- Autotaxin (ATX), a tumor motility factor, showed the most dramatic upregulation (~100-fold) and was secreted by transformed cells, unlike in normal or v-Src/v-Myc transformed cells.
Conclusions:
- v-Jun significantly alters the expression of a broad range of genes involved in diverse cellular functions.
- The specific induction of ATX and Hif-1alpha by v-Jun points to their critical roles in promoting tumorigenesis, potentially through enhanced motility, angiogenesis, invasion, and hypoxia adaptation.
- Secreted ATX from v-Jun-transformed cells may act in an autocrine or paracrine manner to facilitate tumor progression.
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