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. 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. 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. 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. 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.

中文翻译：

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LINE-1通过刺激非小细胞肺癌的代谢重编程促进致瘤性并加剧肿瘤进展

Long Interspersed Nuclear Element-1 (LINE-1, L1) 越来越被认为是肺癌的遗传风险。具有转录活性的 LINE-1 通过体细胞 L1 逆转录转座 (LRT) 或 L1 反义启动子 (L1-ASP) 激活形成 L1 基因嵌合转录物 (LCT)，在癌症进展中发挥致癌作用。在这里，我们开发了反转录转座子基因融合估计程序 (ReFuse)，以识别和量化来自 TCGA 肺癌队列 (n = 1146) 的 RNA 测序数据中的 LCT，然后在一个独立队列中进一步验证了这些 LCT。 n = 134)。我们接下来检查了癌症特异性 LCT (L1-FGGY) 在 LUSC 细胞系和小鼠的细胞增殖和肿瘤进展中的功能作用。LCT 事件与特定的代谢过程和线粒体功能相对应，并与基因组不稳定性、低甲基化、肿瘤分期和肿瘤免疫微环境 (TIME) 相关。对涉及 FGGY (L1-FGGY) 的肿瘤特异性和频繁 LCT 的功能分析表明，花生四烯酸 (AA) 代谢途径是通过 L1-FGGY 嵌合转录物丢失 FGGY 来激活的，从而促进肿瘤生长。联合使用抗 HIV 药物 (NVR) 和代谢抑制剂 (ML355)。最后，我们确定了一组转录组特征，以对预后不良风险较高的 LUSC 患者进行分层，这些患者可能受益于单独使用 NVR 或与抗代谢药物联合使用的治疗。这项研究首次描述了 L1 在肺癌代谢重编程中的作用，并为 L1 特异性预后和肺癌治疗策略的潜力提供了依据。移动元件L1-FGGY通过12-LOX/Wnt通路促进肺鳞癌增殖、侵袭和免疫逃逸的机制研究，Ek2020111。2020 年 3 月 27 日注册 - 追溯注册。