LINE-1 promotes tumorigenicity and exacerbates tumor progression via stimulating metabolism reprogramming in non-small cell lung cancer.
LINE-1 promotes tumorigenicity and exacerbates tumor progression via stimulating metabolism reprogramming in non-small cell lung cancer.
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在非小细胞肺癌中，LINE-1通过刺激代谢重编程促进肿瘤的致瘤性和加速肿瘤的进展。
DOI：
10.1186/s12943-022-01618-5
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发表时间：
2022-07-16
期刊：
影响因子：
37.3
通讯作者：
Zhang, Weijia
中科院分区：
文献类型：
--
作者：
Sun, Zeguo;Zhang, Rui;Zhang, Xiao;Sun, Yifei;Liu, Pengpeng;Francoeur, Nancy;Han, Lei;Lam, Wan Yee;Yi, Zhengzi;Sebra, Robert;Walsh, Martin;Yu, Jinpu;Zhang, Weijia
长散布核元件-1（LINE-1，L1）越来越被认为是肺癌的遗传风险。转录活性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，我们开发了逆转录转座子-基因融合估计程序（Reynolds），以识别和定量来自TCGA肺癌队列（n = 1146）和单细胞RNA测序数据集的RNA测序数据中的LCT，然后在独立队列（n = 134）中进一步验证这些LCT。我们接下来检查了癌症特异性LCT（L1-FGGY）在LUSC细胞系和小鼠中的细胞增殖和肿瘤进展中的功能作用。LCT事件对应于特定的代谢过程和线粒体功能，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的功能分析揭示，花生四烯酸（AA）代谢途径通过L1-FGGY嵌合转录物的FGGY损失而被激活以促进肿瘤生长，其通过抗HIV药物（NVR）和代谢抑制剂（ML 355）的组合使用而被有效靶向。最后，我们确定了一组转录组学特征，以将具有较高不良结局风险的LUSC患者分层，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。本研究首次描述了L1在肺癌代谢重编程中的作用，并为L1特异性预后和治疗肺癌的治疗策略提供了理论基础。移动的元件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，Ek 2020111. 2020年3月27日注册-追溯注册。在线版本包含补充材料，可通过10.1186/s12943-022-01618-5获得。
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. The online version contains supplementary material available at 10.1186/s12943-022-01618-5.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
24.5
作者：
Hur K;Cejas P;Feliu J;Moreno-Rubio J;Burgos E;Boland CR;Goel A
通讯作者：
Goel A
DOI：
10.1093/bioinformatics/bts565
发表时间：
2012-12-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Fu L;Niu B;Zhu Z;Wu S;Li W
通讯作者：
Li W
DOI：
10.1186/s40880-018-0301-4
发表时间：
2018-05-21
期刊：
Cancer communications (London, England)
影响因子：
--
作者：
Cheng C;Geng F;Cheng X;Guo D
通讯作者：
Guo D
影响因子：
11.5
作者：
Ha, SA;Shin, SM;Kim, JW
通讯作者：
Kim, JW