LINE-1 retrotransposons and let-7 miRNA: partners in the pathogenesis of cancer?

Stephen Ohms,Sung-Hun Lee,Danny Rangasamy

doi:10.3389/fgene.2014.00338

Abstract

Long interspersed nuclear element-1 (LINE-1 or L1) retrotransposons are insertional mutagens capable of altering the genomic landscape in many ways. Activation of the normally silent LINE-1 retrotransposon is associated with a high level of cancer-associated DNA damage and genomic instability. Studies of LINE-1 have so far focused mainly on changes in gene expression, and our knowledge of its impact on functional non-coding RNAs is in its infancy. However, current evidence suggests that a significant number of human miRNAs originate from retrotransposon sequences. Furthermore, LINE-1 is generally not expressed in normal tissues while its expression is widespread in epithelial cancers. Based on our recent studies, we demonstrate a functional link between aberrant LINE-1 expression and deregulation of let-7 miRNA expression. Since the expression of let-7 is modulated by LINE-1 activity, we discuss possible mechanisms for this effect and how the silencing of LINE-1 activation could provide new therapeutic options for cancer treatment. Based on the deep sequencing of small RNAs in parallel with gene expression profiling in breast cancer cells, we have identified potential pathways linking L1 activity to let-7 processing and maturation and ultimately to the control of stemness in human cancer cells.

Highlights

Retrotransposons, a family of mobile genetic element, are the most common repetitive elements in the human genome
The activation of L1 retrotransposons and ensuing L1 retrotransposition is associated with a high frequency of DNA breaks and genomic instability (Symer et al, 2002) and several studies have shown that there is a direct association between the severity of cancer-associated DNA damage and the activation of L1 expression (Belgnaoui et al, 2006; Wallace et al, 2010)
How might L1 influence the expression of the let-7a miRNA? One possible mechanism is that retrotransposon sequences located in the promoter regions of let-7 miRNAs might act as functional domains for their regulation

Summary

Introduction

Retrotransposons, a family of mobile genetic element, are the most common repetitive elements in the human genome. The function of Alu elements is linked to the expression of many disease-related lncRNAs. As a key regulatory element, Alu mediates the expression of an lncRNA, referred to as ANRIL (antisense non-coding RNA in the INK4 locus), which binds to polycomb group proteins and interacts with multiple target gene promoters during the process of atherosclerosis (Holdt et al, 2013).

Results

Conclusion