Candidate pathways and genes for prostate cancer: a meta-analysis of gene expression data
Open Access
- 4 August 2009
- journal article
- review article
- Published by Springer Science and Business Media LLC in BMC Medical Genomics
- Vol. 2 (1), 48
- https://doi.org/10.1186/1755-8794-2-48
Abstract
The genetic mechanisms of prostate tumorigenesis remain poorly understood, but with the advent of gene expression array capabilities, we can now produce a large amount of data that can be used to explore the molecular and genetic mechanisms of prostate tumorigenesis. We conducted a meta-analysis of gene expression data from 18 gene array datasets targeting transition from normal to localized prostate cancer and from localized to metastatic prostate cancer. We functionally annotated the top 500 differentially expressed genes and identified several candidate pathways associated with prostate tumorigeneses. We found the top differentially expressed genes to be clustered in pathways involving integrin-based cell adhesion: integrin signaling, the actin cytoskeleton, cell death, and cell motility pathways. We also found integrins themselves to be downregulated in the transition from normal prostate tissue to primary localized prostate cancer. Based on the results of this study, we developed a collagen hypothesis of prostate tumorigenesis. According to this hypothesis, the initiating event in prostate tumorigenesis is the age-related decrease in the expression of collagen genes and other genes encoding integrin ligands. This concomitant depletion of integrin ligands leads to the accumulation of ligandless integrin and activation of integrin-associated cell death. To escape integrin-associated death, cells suppress the expression of integrins, which in turn alters the actin cytoskeleton, elevates cell motility and proliferation, and disorganizes prostate histology, contributing to the histologic progression of prostate cancer and its increased metastasizing potential. The results of this study suggest that prostate tumor progression is associated with the suppression of integrin-based cell adhesion. Suppression of integrin expression driven by integrin-mediated cell death leads to increased cell proliferation and motility and increased tumor malignancy.Keywords
This publication has 72 references indexed in Scilit:
- OKCAM: an ontology-based, human-centered knowledgebase for cell adhesion moleculesNucleic Acids Research, 2008
- Bayesian models and meta analysis for multiple tissue gene expression data following corticosteroid administrationBMC Bioinformatics, 2008
- Targeting the androgen receptor pathway in prostate cancerCurrent Opinion in Pharmacology, 2008
- Survival prediction of stage I lung adenocarcinomas by expression of 10 genesJCI Insight, 2007
- A Bayesian mixture model for metaanalysis of microarray studiesFunctional & Integrative Genomics, 2007
- Inhibition of Integrin-mediated Crosstalk with Epidermal Growth Factor Receptor/Erk or Src Signaling Pathways in Autophagic Prostate Epithelial Cells Induces Caspase-independent DeathMolecular Biology of the Cell, 2007
- Statistical issues and methods for meta-analysis of microarray data: a case study in prostate cancerFunctional & Integrative Genomics, 2003
- Gene expression analysis of prostate cancersMolecular Carcinogenesis, 2002
- Delineation of prognostic biomarkers in prostate cancerNature, 2001
- The file drawer problem and tolerance for null results.Psychological Bulletin, 1979