figure posted on 2023-03-31, 02:27 authored by Rui Zhang, Fan Zhang, Zeguo Sun, Pengpeng Liu, Xiao Zhang, Yingnan Ye, Beiqi Cai, Martin J. Walsh, Xiubao Ren, Xishan Hao, Weijia Zhang, Jinpu Yu
The schematic diagram for the hypothesis of smoking-induced genome disturbance and tumor development and progression. The red oval indicates upregulation, and the green oval indicates downregulation.
National Natural Science Foundation of China
National Science and Technology support Program of China
The Net construction of human genetic resource Bio-bank in North China
Projects of Science and Technology of Tianjin
Key project of Tianjin Health and Family Planning Commission
Tianjin Medical University Cancer Institute and Hospital
ARTICLE ABSTRACTSomatic 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.
LINE-1-FGGY is a prognosis predictive biomarker and potential therapeutic target to overcome local immune evasion in lung squamous cell carcinoma.