Activation of LINE-1 Retrotransposon Increases the Risk of Epithelial-Mesenchymal Transition and Metastasis in Epithelial Cancer

Abstract

Epithelial cancers comprise 80-90% of human cancers. During the process of cancer progression, cells lose their epithelial characteristics and acquire stem-like mesenchymal features that are resistant to chemotherapy. This process, termed the epithelial-mesenchymal transition (EMT), plays a critical role in the development of metastases. Because of the unique migratory and invasive properties of cells undergoing the EMT, therapeutic control of the EMT offers great hope and new opportunities for treating cancer. In recent years, a plethora of genes and noncoding RNAs, including miRNAs, have been linked to the EMT and the acquisition of stem cell-like properties. Despite these advances, questions remain unanswered about the molecular processes underlying such a cellular transition. In this article, we discuss how expression of the normally repressed LINE-1 (or L1) retrotransposons activates the process of EMT and the development of metastases. L1 is rarely expressed in differentiated stem cells or adult somatic tissues. However, its expression is widespread in almost all epithelial cancers and in stem cells in their undifferentiated state, suggesting a link between L1 activity and the proliferative and metastatic behaviour of cancer cells. We present an overview of L1 activity in cancer cells including how genes involved in proliferation, invasive and metastasis are modulated by L1 expression. The role of L1 in the differential expression of the let-7 family of miRNAs (that regulate genes involved in the EMT and metastasis) is also discussed. We also summarize recent novel insights into the role of the L1-encoded reverse transcriptase enzyme in epithelial cell plasticity that suggest it might be a potential therapeutic target that could reverse the EMT and the metastasis-associated stem cell-like properties of cancer cells.

A role of LINE-1 in telomere regulation

“…We further suggest that the induction of c-myc and hTERT by LINE-1 could be the link to LINE-1-induced EMT activation in tumour cells as has been observed by Rangasamy and co-workers (16). On the one hand c-myc has been shown to play a role in TGF-beta mediated SNAIL expression and EMT (39), on the other hand hTERT was associated with the activation and induction of EMT markers (40).…”

“…Growth reduction can hardly be explained by a lack of active retro-transposition but may, for example, result from reduced expression of c-myc, a factor relevant for tumour growth (15). Moreover, Rangasamy and colleagues found that silencing of LINE-1 expression in tumour cell-lines reduces parameters relevant for epithelial mesenchymal transition (EMT) (16). EMT is an essential step in tumour progression where cancer cells gain migratory functions to metastasize.…”

APOBEC3B Activity Is Prevalent in Urothelial Carcinoma Cells and Only Slightly Affected by LINE-1 Expression

“…Also in hepatocellular carcinoma, L1 ORF1p was suggested to promote cell proliferation and resistance to chemotherapy ( Feng et al, 2013 ). Indeed, L1 expression is linked to the activation of epithelial-mesenchymal transition (EMT) and was shown to affect the expression of miRNA genes (let-7 miRNA family) specifically regulating tumor suppressor expression ( Rangasamy et al, 2015 ). Consistently, our study found cell growth impairment as a consequence of L1 silencing in UCCs, which requires further studies to identify any specific factor(s) or pathway that is involved in this regulation.…”

Crossing the LINE Toward Genomic Instability: LINE-1 Retrotransposition in Cancer

“…However, the overall results showed discordant rates of retrotransposition, suggesting that while increased L1 retrotransposition may not be a direct cause of metastatic PDAC, it may contribute to gene disregulation leading to metastasis (Rodic et al, 2015 ). Furthermore, activation of L1 increases the risk of epithelial-mesenchymal transition and metastasis in epithelial cancer (reviewed in Rangasamy et al, 2015 ) and promotes proliferation and invasion of LoVo colorectal cancer cells (Li et al, 2014 ) and MDA-MB-231 breast cancer cells (Yang et al, 2013 ). ORF1p and ORF2p levels are upregulated in breast cancers compared to normal tissues.…”