Tumor-specific usage of alternative transcription start sites in colorectal cancer identified by genome-wide exon array analysisReport as inadecuate




Tumor-specific usage of alternative transcription start sites in colorectal cancer identified by genome-wide exon array analysis - Download this document for free, or read online. Document in PDF available to download.

BMC Genomics

, 12:505

Human and rodent genomics

Abstract

BackgroundApproximately 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.

ResultsBy 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.

ConclusionsAlternative 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.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2164-12-505 contains supplementary material, which is available to authorized users.

Download fulltext PDF



Author: Kasper Thorsen - Troels Schepeler - Bodil Øster - Mads H Rasmussen - Søren Vang - Kai Wang - Kristian Q Hansen - Philip

Source: https://link.springer.com/article/10.1186/1471-2164-12-505







Related documents