LINE-1 promotes tumorigenicity and exacerbates tumor progression via stimulating metabolism reprogramming in non-small cell lung cancer

Abstract

Background Long Interspersed Nuclear Element-1 (LINE-1, L1) is increasingly regarded as a genetic risk for lung cancer. Transcriptionally active LINE-1 forms a L1-gene chimeric transcript (LCTs), through somatic L1 retrotransposition (LRT) or L1 antisense promoter (L1-ASP) activation, to play an oncogenic role in cancer progression. Methods Here, we developed Retrotransposon-gene fusion estimation program (ReFuse), to identify and quantify LCTs in RNA sequencing data from TCGA lung cancer cohort (n = 1146) and a single cell RNA sequencing dataset then further validated those LCTs in an independent cohort (n = 134). We next examined the functional roles of a cancer specific LCT (L1-FGGY) in cell proliferation and tumor progression in LUSC cell lines and mice. Results The LCT events correspond with specific metabolic processes and mitochondrial functions and was associated with genomic instability, hypomethylation, tumor stage and tumor immune microenvironment (TIME). Functional analysis of a tumor specific and frequent LCT involving FGGY (L1-FGGY) reveal that the arachidonic acid (AA) metabolic pathway was activated by the loss of FGGY through the L1-FGGY chimeric transcript to promote tumor growth, which was effectively targeted by a combined use of an anti-HIV drug (NVR) and a metabolic inhibitor (ML355). Lastly, we identified a set of transcriptomic signatures to stratify the LUSC patients with a higher risk for poor outcomes who may benefit from treatments using NVR alone or combined with an anti-metabolism drug. Conclusions This study is the first to characterize the role of L1 in metabolic reprogramming of lung cancer and provide rationale for L1-specifc prognosis and potential for a therapeutic strategy for treating lung cancer. Trial registration Study on the mechanisms of the mobile element L1-FGGY promoting the proliferation, invasion and immune escape of lung squamous cell carcinoma through the 12-LOX/Wnt pathway, Ek2020111. Registered 27 March 2020 ‐ Retrospectively registered.

p53 and RB Cooperate to Suppress Transposable Elements

“…Taken together, de-repression of repetitive elements may not be a barrier to transformation particularly when p53 and RB are co-deleted. Consistent with this notion is the observation in human cancers that the tumor suppressors p53 and RB are frequently co-mutated (31)(32)(33)(34)(35) and that these tumors often express high levels of repetitive elements, (25,(36)(37)(38). Furthermore, because retrotransposition of LINE-1 in human cancers can lead to large chromosomal deletions, translocations, and gene amplification (1) it is conceivable that suppression of repetitive elements by p53 and RB may be an important mechanism for tumor suppression.…”

Recent progress in targeted therapy for non-small cell lung cancer

“…NTRK contains NTRK1, NTRK2, and NTRK3, which respectively encode TRKA, TRKB, and TRKC (Koga et al, 2022;Manea et al, 2022). First-generation TRK inhibitors larotrectinib and entrectinib are currently the drugs of choice for patients with NTRK-fusion tumors (Liu et al, 2022;Manea et al, 2022). Solvent front mutations, such as G595R, G623R, and G667C, are the causes of the most common type of resistance.…”

“…PTEN (phosphatase and tensin homolog), which was recently identified as a tumor suppressor gene with bispecific phosphatase activity, is also a gene that is second only to the P53 gene in its close relationship to carcinogenesis and plays an important role in cell proliferation, apoptosis, adhesion, migration, and infiltration (Liu et al, 2022;Fang et al, 2022). PTEN is frequently inactivated in various malignancies, such as brain, prostate, endometrial, gastric cancers and NSCLC, and clinical data have suggested that PTEN loss of function occurs in 10%-25% of NSCLC cases (Liu et al, 2022). To date, studies have indicated that PTEN loss of function mainly affects the PI3K/AKT pathway, thereby affecting cell proliferation, migration and other processes (Figure 2) (Cho et al, 2022).…”

“…Then, phosphatidylinositol 4,5-bisphosphate (PIP2) was phosphorylated by PI3K, turning it to phosphatidylinositol-3,4,5-triphosphate (PIP3), a critical factor in activating downstream AKT, thereby mediating succeeding signals including cell survival, proliferation, and migration. Dephosphorylating PIP3 to produce PIP2 then antagonizing PI3K and stopping the activation of AKT are all effects of PTEN-lipid-phosphatase activity (Liu et al, 2022). PTEN loss of function results in overactivation of the PI3K signaling pathway, which has been linked to the cancer pathogenesis.…”

“…In the human genome, Long interspersed nuclear element-1 (LINE-1) is the most abounding (number of bases) known retrotransposon (approximately 500,000 copies), accounting for approximately 17% of the human genome sequence (Sun et al, 2022). LINE-1 is also the only known transposon in the human genome that can undergo spontaneous transposition.…”