Post-Transcriptional Dysregulation of microRNA and Alternative Polyadenylation in Colorectal Cancer

Zhanrui Mao; Hui Zhao; Yulan Qin; Jianming Wei; Jielin Sun; Weiwei Zhang; Yani Kang

doi:10.3389/fgene.2020.00064

Post-Transcriptional Dysregulation of microRNA and Alternative Polyadenylation in Colorectal Cancer

Front Genet. 2020 Feb 21:11:64. doi: 10.3389/fgene.2020.00064. eCollection 2020.

Authors

Zhanrui Mao¹, Hui Zhao¹, Yulan Qin¹, Jianming Wei², Jielin Sun³, Weiwei Zhang⁴, Yani Kang¹

Affiliations

¹ School of Biomedical Engineering, Bio-ID Center, Shanghai Jiao Tong University, Shanghai, China.
² Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.
³ Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
⁴ State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China.

Abstract

Background: Colorectal 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.

Method: In 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.

Results: Our 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.

Conclusion: Our 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.

Keywords: 3'UTR; alternative polyadenylation; colorectal cancer; microRNAs; posttranscriptional regulation.