Comparative Analysis of microRNA Binding Site Distribution and microRNA-Mediated Gene Expression Repression of Oncogenes and Tumor Suppressor Genes.

Shuangmei Tian,Jing Wang,Degeng Wang,Fangyuan Zhang

doi:10.3390/genes13030481

Shuangmei Tian, Jing Wang + Show 2 more

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https://doi.org/10.3390/genes13030481

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Abstract

MicroRNAs (miRNAs) are a family of short, noncoding RNAs that can regulate gene expression levels of over half of the human genome. Previous studies on the role of miRNAs in cancer showed overall widespread downregulation of miRNAs as a hallmark of human cancer, though individual miRNAs can be both tumor suppressive and oncogenic, and cancer genes are speculated to be more targeted by miRNA. However, the extents to which oncogenes and tumor suppressor genes (TSG) are controlled by miRNA have not been compared. To achieve this goal, we constructed lists of oncogenes and TSGs and compared them with each other, and with the whole protein-coding gene population, in terms of miRNA binding sites distribution and expression level changes upon genetic disruption of miRNA production. As expected, the results show that cancer gene mRNAs anchor more miRNA binding sites, and are under a higher degree of miRNA-mediated repression at both mRNA abundance and translation efficiency levels than the whole protein-coding gene population. Importantly, on average, TSG mRNAs are more highly targeted and regulated by miRNA than oncogene mRNAs. To the best of our knowledge, this is the first comparison of miRNA regulation of oncogenes and TSGs.

Highlights

Published: 9 March 2022MicroRNAs are small (17–25 nucleotide (NT); on average 22 NT), endogenously-initiated, single-stranded noncoding RNAs that exist ubiquitously in animals, plants, and unicellular eukaryotes as key post-transcriptional regulators of gene expression [1–4]
These results demonstrate that cancer genes have more miRNA target sites than general protein-coding genes, and tumor suppressor genes (TSG) harbor more miRNA target sites than oncothan general protein-coding genes, and TSGs harbor more miRNA target sites than oncogenes
TSGs was significantly higher than that of oncogenes (p-value = 0.0094, Figure 5B), their expressions were both increased in Dicer KO mouse embryonic stem cells (mESCs). These results suggest that the mRNA levels of cancer genes are under stronger control by miRNA than the gen8 of 13 eral protein-coding genes, and among all cancer genes, miRNA down-regulates TSGs more than oncogenes

Summary

Introduction

MicroRNAs (miRNAs) are small (17–25 nucleotide (NT); on average 22 NT), endogenously-initiated, single-stranded noncoding RNAs that exist ubiquitously in animals, plants, and unicellular eukaryotes as key post-transcriptional regulators of gene expression [1–4]. In the canonical pathway of miRNA biogenesis in animals, miRNA genes are transcribed by RNA polymerase II (Pol II) as long primary transcripts (pri-miRNAs), processed to hairpin-structured precursor miRNAs (pre-miRNAs) by the nuclear Microprocessor complex (comprising Drosha and DGCR8), and exported by exportin 5 from the nucleus into the cytoplasm [4]. Pre-miRNAs are cleaved by Dicer to double-stranded RNA duplexes, and subsequently loaded into Argonaute (AGO) proteins to form the RNA-induced silencing complex (RISC). The passenger strand of the miRNA duplex will be cleaved quickly, and the mature RISC is generated, comprising the one-stranded mature miRNA and AGO proteins. The AGO proteins regulate translational repression and/or mRNA degradation by recruiting other effector proteins [5,6]

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