Abstract
The expression of specific mRNA isoforms may uniquely reflect the biological state of a cell because it reflects the integrated outcome of both transcriptional and posttranscriptional regulation. In this study, we constructed a splicing array to examine approximately 1,500 mRNA isoforms from a panel of genes previously implicated in prostate cancer and identified a large number of cell type-specific mRNA isoforms. We also developed a novel "two-dimensional" profiling strategy to simultaneously quantify changes in splicing and transcript abundance; the results revealed extensive covariation between transcription and splicing in prostate cancer cells. Taking advantage of the ability of our technology to analyze RNA from formalin-fixed, paraffin-embedded tissues, we derived a specific set of mRNA isoform biomarkers for prostate cancer using independent panels of tissue samples for feature selection and cross-analysis. A number of cancer-specific splicing switch events were further validated by laser capture microdissection. Quantitative changes in transcription/RNA stability and qualitative differences in splicing ratio may thus be combined to characterize tumorigenic programs and signature mRNA isoforms may serve as unique biomarkers for tumor diagnosis and prognosis.
Highlights
Prostate cancer is a leading cause of morbidity and mortality among men in the U.S [1]
A variety of approaches have been used to search for DNA, RNA, and protein-based biomarkers associated with specific tumor types www.aacrjournals.org and/or stages [49], our current effort represents the first systematic attempt to identify tumor-specific mRNA isoforms
Our analysis is based on the rationale that mRNA isoforms may better reflect the biological state of specific cell types or tissues, and may serve as more robust biomarkers for disease diagnosis and prognosis
Summary
Prostate cancer is a leading cause of morbidity and mortality among men in the U.S [1]. Classic approaches based on gene expression profiling have revealed many potential cancer biomarkers, several studies indicate that tumor-specific mRNA isoforms may further improve. Alternative splicing may serve as a mechanism to achieve temporal and spatial regulation of gene expression as increasing evidence suggests that alternative splicing may be tightly coupled with both upstream events in transcription and downstream steps in mRNA export, degradation, and translation [10,11,12,13]. Because distinct mRNA isoforms may be uniquely associated with a disease process, either as products of cellular transformation or as causative factors for a specific disease phenotype, characteristic mRNA isoforms may serve as biomarkers for disease diagnosis and prognosis as well as unique targets for disease intervention [14, 15]
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