Bioinformatic Interrogation of 5p-arm and 3p-arm Specific miRNA Expression Using TCGA Datasets.

Wei-Ting Kuo,Wen-Chang Lin,Ming-Wei Su,Chew-Wun Wu,Wen-Liang Fang,Kuo-Hung Huang,Chien-Hsiun Chen,Yungling Lee

doi:10.3390/jcm4091798

Abstract

MicroRNAs (miRNAs) play important roles in cellular functions and developmental processes. They are also implicated in oncogenesis mechanisms and could serve as potential cancer biomarkers. Using high-throughput miRNA sequencing information, expression of both the 5p-arm and 3p-arm mature miRNAs were demonstrated and generated from the single miRNA hairpin precursor. However, current miRNA annotations lack comprehensive 5p-arm/3p-arm feature annotations. Among known human mature miRNAs, only half of them are annotated with arm features. This generated ambiguous results in many miRNA-Sequencing (miRNA-Seq) studies. In this report, we have interrogated the TCGA (the Cancer Genome Atlas) miRNA expression datasets with an improved, fully annotated human 5p-arm and 3p-arm miRNA reference list. By utilizing this comprehensive miRNA arm-feature annotations, enhanced determinations and clear annotations were achieved for the miRNA isoforms (isomiRs) recognized from the sequencing reads. In the gastric cancer (STAD) dataset, as an example, 32 5p-arm/3p-arm specific miRNAs were found to be down-regulated and 24 5p-arm/3p-arm specific miRNAs were found to be up-regulated. We have further extended miRNA biomarker discoveries to additional TCGA miRNA-Seq datasets and provided extensive expression information on 5p-arm/3p-arm miRNAs across multiple cancer types. Our results identified several miRNAs that could be potential common biomarkers for human cancers.

Highlights

Cancer is one of the most devastating human diseases [1] and there are devoted efforts to improve cancer treatments
We have established a comprehensive arm feature annotation list on almost all known human miRNAs in order to better understand the intrinsic properties of 5p-arm and 3p-arm miRNAs [27]. We have utilized such an annotated 5p-arm and 3p-arm miRNA list to further analyze the TCGA miRNA-Seq dataset for the interrogation of miRNAs as useful cancer biomarkers
Due to the significance of miRNAs in cancer development and progression, there are many studies interrogating the roles of miRNAs in human cancers [4,5,12,31], including the TCGA project [28]

Summary

Introduction

Cancer is one of the most devastating human diseases [1] and there are devoted efforts to improve cancer treatments. MicroRNAs (miRNAs) have become the emerging potential cancer biomarkers in recent years [3,4,5,6] They are small RNA molecules, which are derived from endogenous non-protein-coding gene transcripts [7,8]. In the miRNA biogenesis processes, the primary miRNA transcripts are transcribed and cleaved by the Drosha enzyme before being exported to the cytoplasm They are further processed by the Dicer enzyme to generate the mature miRNA duplex [21,22,23]. We have utilized such an annotated 5p-arm and 3p-arm miRNA list to further analyze the TCGA (the Cancer Genome Atlas) miRNA-Seq dataset for the interrogation of miRNAs as useful cancer biomarkers. MiRNA NGS data, our results demonstrated that the arm-specific miRNA expression profile would be beneficial for thorough analysis of dys-regulated miRNAs in human cancers

Arm Feature Assignment of Human Mature miRNAs

Bioinformatic Analysis with Comprehensive Arm-Feature-Annotated miRNA

Results and Discussion

Arm Features and isomiR Quantifications

TCGA miRNA-Seq Analysis

Conclusions