L1 retrotransposons, cancer stem cells and oncogenesis

Abstract

Retrotransposons have played a central role in human genome evolution. The accumulation of heritable L1, Alu and SVA retrotransposon insertions continues to generate structural variation within and between populations, and can result in spontaneous genetic disease. Recent works have reported somatic L1 retrotransposition in tumours, which in some cases may contribute to oncogenesis. Intriguingly, L1 mobilization appears to occur almost exclusively in cancers of epithelial cell origin. In this review, we discuss how L1 retrotransposition could potentially trigger neoplastic transformation, based on the established correlation between L1 activity and cellular plasticity, and the proven capacity of L1-mediated insertional mutagenesis to decisively alter gene expression and functional output.

Keywords: Alu; EMT; L1; LINE-1; SVA; cancer genomics; oncogenesis; plasticity; retrotransposon; tumorigenesis.

Figure 1

L1 retrotransposition and silencing pathways. L1 mobilization requires the key steps of transcription, mRNA export to the cytoplasm, translation, ribonucleoprotein particle formation, entry into the nucleus and, finally, integration. The Piwi‐induced methylation silencing pathway involves a selective amplification cycle fuelled by Piwi‐mediated cleavage of L1 transcripts. The repeat‐associated small interfering RNA degradation pathway is regulated by the generation of siRNAs from dsRNAs by Dicer and the fragmentation of L1 RNAs by AGO family proteins. L1 integration is also inhibited by several host factors, including members of the APOBEC3 family. Proteins and RNAs implicated in L1‐silencing pathways are represented in blue. L1 RNAs and proteins are represented in pink.

Figure 2

Hypotheses for L1 involvement in tumorigenesis and cancer progression. (A) Environmental factors initially cause cells to change the methylation status of the L1 promoter, activating full‐length L1 transcription. (B) This is followed by de novo L1 retrotransposition into an oncogenic region, resulting in tumorigenesis. (C) Once the tumour is established, the canonical L1 promoter is increasingly hypomethylated, potentially activating the antisense promoter and nearby genes. Moreover, L1 promoter hypomethylation appears to be correlated with an epithelial to mesenchymal transition that could eventually lead to metastasis.

Figure 3

Schematic representation of tumorigenesis in epithelial cancers. A stem cell undergoes differentiation, giving rise to normal tissue. If mutation of an oncogenic region occurs, a normal stem cell can turn into a cancer stem cell. This cancer stem cell can also be generated from a differentiated cell via a mesenchymal to epithelial transition. Once established, cancer stem cells can differentiate into the various cell types that form a tumour.