New Understanding of the Relevant Role of LINE-1 Retrotransposition in Human Disease and Immune Modulation

Abstract

Long interspersed nuclear element-1 (LINE-1) retrotransposition is a major hallmark of cancer accompanied by global chromosomal instability, genomic instability, and genetic heterogeneity and has become one indicator for the occurrence, development, and poor prognosis of many diseases. LINE-1 also modulates the immune system and affects the immune microenvironment in a variety of ways. Aberrant expression of LINE-1 retrotransposon can provide strong stimuli for an innate immune response, activate the immune system, and induce autoimmunity and inflammation. Therefore, inhibition the activity of LINE-1 has become a potential treatment strategy for various diseases. In this review, we discussed the components and regulatory mechanisms involved with LINE-1, its correlations with disease and immunity, and multiple inhibitors of LINE-1, providing a new understanding of LINE-1.

Understanding the immuno-biology of oesophageal adenocarcinoma: Towards improved therapeutic approaches

“…The immune-low group contained mainly OCs with enrichment in TP53 mutations, increased L1 expression and insertion frequency, and higher CNA numbers, further supporting the findings of Davoli et al [25,32]. L1 hypomethylation results in its activation and has been associated with poor survival in a range of cancers, including OAC [31,33]. DNA methyltransferase (DNMT) is an important enzyme involved in catalysing DNA methylation, and the use of DNMTinhibitors (DNMTis) can effectively inhibit L1 expression [31].…”

“…L1 overexpression can contribute to genomic instability and tumour progression through mutagenic insertions, and in OAC L1 was found to induce CCND1 oncogene amplification through inducing BFBs [29]. L1 activity is normally contained by the restrictive action of p53 [30,31]. However, TP53 is the most common mutated gene in OAC [11], and in a recent analysis, gastrointestinal cancers with TP53 mutations were found to have frequent L1 insertions [32].…”

“…L1 hypomethylation results in its activation and has been associated with poor survival in a range of cancers, including OAC [31,33]. DNA methyltransferase (DNMT) is an important enzyme involved in catalysing DNA methylation, and the use of DNMTinhibitors (DNMTis) can effectively inhibit L1 expression [31]. DNMTis have been shown to improve tumour immunogenicity and promote CD8 + T-cell and NK-cell function by inducing a type I interferon response [31,34].…”

“…DNA methyltransferase (DNMT) is an important enzyme involved in catalysing DNA methylation, and the use of DNMTinhibitors (DNMTis) can effectively inhibit L1 expression [31]. DNMTis have been shown to improve tumour immunogenicity and promote CD8 + T-cell and NK-cell function by inducing a type I interferon response [31,34]. Targeting L1 through DNMTis and potentially also in combination with immunotherapeutic approaches is an attractive area of research in OAC [34].…”

Reconsidering LINE-1’s role in cancer: does LINE-1 function as a reporter detecting early cancer-associated epigenetic signatures?

“…As such, L1 is widely considered an injurious endogenous agent with carcinogenic potential [ 5–7 ]. The current understanding of L1 as predominantly antagonistic to human health would appear consistent with the fact that active L1 is detected in almost half of human cancers [ 8 , 9 ]. L1 is the only autonomously active TE in humans and so it stands in stark contrast to all other transposons which have lost this ability [ 10 ].…”