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Genome-wide profiling reveals cancer-related genes with switched alternative polyadenylation sites in colorectal cancer.

ABSTRACT: Background:Alternative polyadenylation (APA) is an important post-transcriptional regulation in eukaryotic cells. It plays considerable roles in many biological processes and diseases, such as cell differentiation, proliferation and cancer. Colorectal cancer (CRC) is one of the most common malignancies worldwide, which is among the top five in incidence and mortality of all cancers in China. Although there have been some studies on the APA of CRC, the normal and carcinoma samples used for genome-wide profiling were not matched. The purpose of this study was to obtain genes with switched 3'-untranslated region (UTR) that may be associated with intracellular regulation of CRC by analyzing APA patterns of strict control groups from clinical patients. Materials and methods:CRC and matched normal tissues were acquired from surgical specimens from three CRC patients. Their libraries of 3'-terminal fragments of mRNA with poly(A) tails were constructed by 3T-seq technology and sequenced by Illumina Hiseq X Ten. APA patterns of cancer and matched normal tissues were analyzed by bioinformatics analysis, and a representative gene, GPI, was verified by quantitative reverse transcription PCR. Results:Overall, we identified 35,076 poly(A) sites in total. Compared to the matched normal tissues, we detected 350, 405 and 375 genes with significantly APA-mediated 3'-UTR alteration in cancer tissues of three patients, respectively. Forty-seven genes with switched 3'-UTR were shared in all three patients. In addition, most of these genes have shortened 3'-UTRs, some of which were associated with cancers, such as GPI. Conclusion:Our studies found several genes with switched 3'-UTR in CRC patients, which may provide some important clues for more in-depth study of the cellular regulation in CRC from the perspective of post-transcriptional regulation. It may also help in the search for new biomarkers of CRC.

SUBMITTER: Yang X

PROVIDER: S-EPMC6126484 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Genome-wide profiling reveals cancer-related genes with switched alternative polyadenylation sites in colorectal cancer.

Yang Xiaochen X Wu Jun J Xu Wei W Tan Sheng S Chen Changyu C Wang Xiaoyan X Sun Jielin J Kang Yani Y

OncoTargets and therapy 20180831

<h4>Background</h4>Alternative polyadenylation (APA) is an important post-transcriptional regulation in eukaryotic cells. It plays considerable roles in many biological processes and diseases, such as cell differentiation, proliferation and cancer. Colorectal cancer (CRC) is one of the most common malignancies worldwide, which is among the top five in incidence and mortality of all cancers in China. Although there have been some studies on the APA of CRC, the normal and carcinoma samples used fo ...[more]

PMID: 30214241

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Project description:BackgroundColorectal cancer (CRC) is one of the leading causes of cancer death worldwide. microRNAs (miRNAs) repress gene expression by binding to complementary sequences in the 3' untranslated region (3'UTR) of target mRNAs. Alternative polyadenylation (APA) are relevant to the variability of the 3'UTR of mRNA. However, the posttranscriptional dysregulation of miRNAs and APA in CRC are poorly understood.MethodIn this study, we conducted small RNA sequencing to identify differentially expressed miRNAs (DERs) and their target genes. Function analysis on DER-target genes can explain the regulation roles of miRNAs in CRC. The mutual regulation of miRNAs and APA was analyzed by combining miRNA data to 3'UTR alteration using 3' termini of polyadenylated RNAs sequencing (3T-seq) technique, and this was validated using TCGA gene expression data.ResultsOur results showed 64 significant differentially expressed miRNAs (DERs) in CRC patients. Their target genes were related to cell adhesion and transcription regulation and were prevailingly involved in the CRC-related pathway. Integrative analysis of the miRNA and APA profile revealed 16 DERs were correlated with 12 polyadenylation factors, and six of them were significantly differently expressed in CRC. We also found four DERs that lost binding sites due to APA and showed a positive correlation between the miRNA and gene expression.ConclusionOur study found that miRNAs regulated APA by modulating key polyadenylation factors, and several miRNAs lost their suppression on mRNA due to APA. Associating this with gene expression may provide some important clues for a deeper study of posttranscriptional cellular regulation and biomarker research in CRC. Our data provided the first evidence that the interaction between miRNAs and APA associated with gene expression could serve as biomarkers for CRC, suggesting that hsa-miR-133a-3p and MLEC, hsa-miR-145-5p and SET, hsa-miR-1-3p and PPIA, and hsa-miR-378d and YY1 might be novel and potential biomarkers in improving the diagnosis of CRC.

Dataset Information

Genome-wide profiling reveals cancer-related genes with switched alternative polyadenylation sites in colorectal cancer.

Publications

Genome-wide profiling reveals cancer-related genes with switched alternative polyadenylation sites in colorectal cancer.

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