LINE-1 Retrotransposition Promotes the Development and Progression of Lung Squamous Cell Carcinoma by Disrupting the Tumor-Suppressor Gene FGGY
LINE-1 Retrotransposition Promotes the Development and Progression of Lung Squamous Cell Carcinoma by Disrupting the Tumor-Suppressor Gene FGGY
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LINE-1逆转录转座通过破坏抑癌基因FGGY促进肺鳞状细胞癌的发生和进展
DOI：
10.1158/0008-5472.can-19-0076
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发表时间：
2019-09-01
期刊：
影响因子：
11.2
通讯作者：
Yu, Jinpu
中科院分区：
文献类型：
--
作者：
Zhang, Rui;Zhang, Fan;Yu, Jinpu
体细胞长散布元件-1(LINE-1)逆转录转座是一个与基因破坏和肿瘤发生有关的基因组过程。然而，LINE-1逆转录转座在肺鳞状细胞癌(LUSC)中的表达和功能仍不清楚。我们分析了癌症基因组图谱中LUSC样本的转录，并观察到90%的肿瘤样本中有LINE-1逆转录转座。从一个独立的中国LUSC队列中鉴定并进一步验证了13个高发率的LINE-1逆转座。其中LINE-1-FGGY(L1-FGGY)是中国人群中最常见的LINE-1逆转录转位，与不良的临床结局显著相关。L1-FGGY的发生与吸烟诱导的LINE-1启动子的低甲基化有关，并有助于局部免疫逃避和代谢功能障碍的发展。L1-FGGY过表达或FGGY基因敲除在体外促进了细胞的增殖和侵袭，促进了体内肿瘤的发生，并使细胞能量代谢和细胞因子/趋化因子转录紊乱。重要的是，特定的逆转录抑制剂奈韦拉平和伊法韦仑显著逆转了L1-FGGY的丰度，抑制了肿瘤的生长，恢复了代谢功能障碍，并改善了局部免疫逃避。总之，低甲基化诱导的L1-FGGY表达是促进LUSC发生发展的一种常见的基因组事件，是LUSC中一个很有前景的预测生物标志物和治疗靶点。意义：Line-1-FGGY是一个预后预测生物标志物和克服肺鳞癌局部免疫逃避的潜在治疗靶点。
Somatic long interspersed element-1 (LINE-1) retrotransposition is a genomic process that relates to gene disruption and tumor occurrence. However, the expression and function of LINE-1 retrotransposition in lung squamous cell carcinoma (LUSC) remain unclear. We analyzed the transcriptomes of LUSC samples in The Cancer Genome Atlas and observed LINE-1 retrotransposition in 90% of tumor samples. Thirteen LINE-1 retrotranspositions of high occurrence were identified and further validated from an independent Chinese LUSC cohort. Among them, LINE-1-FGGY (L1-FGGY) was identified as the most frequent LINE-1 retrotransposition in the Chinese cohort and significantly correlated with poor clinical outcome. L1-FGGY occurred with smoke-induced hypomethylation of the LINE-1 promoter and contributed to the development of local immune evasion and dysfunctional metabolism. Overexpression of L1-FGGY or knockdown of FGGY promoted cell proliferation and invasion in vitro, facilitated tumorigenesis in vivo, and dysregulated cell energy metabolism and cytokine/chemotaxin transcription. Importantly, specific reverse transcription inhibitors, nevirapine and efavirenz, dramatically countered L1-FGGY abundance, inhibited tumor growth, recovered metabolism dysfunction, and improved the local immune evasion. In conclusion, hypomethylation-induced L1-FGGY expression is a frequent genomic event that promotes the development and progression of LUSC and represents a promising predictive biomarker and therapeutic target in LUSC.Significance: LINE-1-FGGY is a prognosis predictive biomarker and potential therapeutic target to overcome local immune evasion in lung squamous cell carcinoma.