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Tumor-specific usage of alternative transcription start sites in colorectal cancer identified by genome-wide exon array analysis.
Tumor-specific usage of alternative transcription start sites in colorectal cancer identified by genome-wide exon array analysis.
- Source :
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BMC genomics [BMC Genomics] 2011 Oct 14; Vol. 12, pp. 505. Date of Electronic Publication: 2011 Oct 14. - Publication Year :
- 2011
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Abstract
- Background: Approximately half of all human genes use alternative transcription start sites (TSSs) to control mRNA levels and broaden the transcriptional output in healthy tissues. Aberrant expression patterns promoting carcinogenesis, however, may arise from alternative promoter usage.<br />Results: By profiling 108 colorectal samples using exon arrays, we identified nine genes (TCF12, OSBPL1A, TRAK1, ANK3, CHEK1, UGP2, LMO7, ACSL5, and SCIN) showing tumor-specific alternative TSS usage in both adenoma and cancer samples relative to normal mucosa. Analysis of independent exon array data sets corroborated these findings. Additionally, we confirmed the observed patterns for selected mRNAs using quantitative real-time reverse-transcription PCR. Interestingly, for some of the genes, the tumor-specific TSS usage was not restricted to colorectal cancer. A comprehensive survey of the nine genes in lung, bladder, liver, prostate, gastric, and brain cancer revealed significantly altered mRNA isoform ratios for CHEK1, OSBPL1A, and TCF12 in a subset of these cancer types.To identify the mechanism responsible for the shift in alternative TSS usage, we antagonized the Wnt-signaling pathway in DLD1 and Ls174T colorectal cancer cell lines, which remarkably led to a shift in the preferred TSS for both OSBPL1A and TRAK1. This indicated a regulatory role of the Wnt pathway in selecting TSS, possibly also involving TP53 and SOX9, as their transcription binding sites were enriched in the promoters of the tumor preferred isoforms together with their mRNA levels being increased in tumor samples. Finally, to evaluate the prognostic impact of the altered TSS usage, immunohistochemistry was used to show deregulation of the total protein levels of both TCF12 and OSBPL1A, corresponding to the mRNA levels observed. Furthermore, the level of nuclear TCF12 had a significant correlation to progression free survival in a cohort of 248 stage II colorectal cancer samples.<br />Conclusions: Alternative TSS usage in colorectal adenoma and cancer samples has been shown for nine genes, and OSBPL1A and TRAK1 were found to be regulated in vitro by Wnt signaling. TCF12 protein expression was upregulated in cancer samples and correlated with progression free survival.
- Subjects :
- Adaptor Proteins, Vesicular Transport genetics
Adaptor Proteins, Vesicular Transport metabolism
Alternative Splicing
Basic Helix-Loop-Helix Transcription Factors genetics
Basic Helix-Loop-Helix Transcription Factors metabolism
Carrier Proteins genetics
Carrier Proteins metabolism
Checkpoint Kinase 1
Cohort Studies
Colorectal Neoplasms pathology
Humans
Oligonucleotide Array Sequence Analysis
Promoter Regions, Genetic
Protein Isoforms genetics
Protein Isoforms metabolism
Protein Kinases genetics
Protein Kinases metabolism
RNA, Messenger metabolism
Receptors, Steroid
Wnt Signaling Pathway
Oxysterol Binding Proteins
Colorectal Neoplasms genetics
Exons
Transcription Initiation Site
Subjects
Details
- Language :
- English
- ISSN :
- 1471-2164
- Volume :
- 12
- Database :
- MEDLINE
- Journal :
- BMC genomics
- Publication Type :
- Academic Journal
- Accession number :
- 21999571
- Full Text :
- https://doi.org/10.1186/1471-2164-12-505