Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.
Tianjin's Clinical Research Center for Cancer, Tianjin, China.
Cancer Res. 2019 Sep 1;79(17):4453-4465. doi: 10.1158/0008-5472.CAN-19-0076. Epub 2019 Jul 9.
Somatic long interspersed element-1 () retrotransposition is a genomic process that relates to gene disruption and tumor occurrence. However, the expression and function of retrotransposition in lung squamous cell carcinoma (LUSC) remain unclear. We analyzed the transcriptomes of LUSC samples in The Cancer Genome Atlas and observed retrotransposition in 90% of tumor samples. Thirteen retrotranspositions of high occurrence were identified and further validated from an independent Chinese LUSC cohort. Among them, ( was identified as the most frequent retrotransposition in the Chinese cohort and significantly correlated with poor clinical outcome. occurred with smoke-induced hypomethylation of the promoter and contributed to the development of local immune evasion and dysfunctional metabolism. Overexpression of or knockdown of promoted cell proliferation and invasion , facilitated tumorigenesis , and dysregulated cell energy metabolism and cytokine/chemotaxin transcription. Importantly, specific reverse transcription inhibitors, nevirapine and efavirenz, dramatically countered abundance, inhibited tumor growth, recovered metabolism dysfunction, and improved the local immune evasion. In conclusion, hypomethylation-induced 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: is a prognosis predictive biomarker and potential therapeutic target to overcome local immune evasion in lung squamous cell carcinoma.
体细胞长散布元件-1()逆转录转座是一种与基因中断和肿瘤发生相关的基因组过程。然而，在肺鳞状细胞癌（LUSC）中，逆转录转座的表达和功能仍不清楚。我们分析了癌症基因组图谱中 LUSC 样本的转录组，观察到 90%的肿瘤样本中存在逆转录转座。从一个独立的中国 LUSC 队列中，我们进一步鉴定和验证了 13 个高发生率的逆转录转座。其中，（被鉴定为中国队列中最常见的逆转录转座，与不良临床结局显著相关。发生在吸烟诱导的启动子低甲基化，导致局部免疫逃逸和功能障碍代谢。过表达 或敲低 促进细胞增殖和侵袭，促进肿瘤发生，并调节细胞能量代谢和细胞因子/趋化因子转录。重要的是，特异性逆转录抑制剂奈韦拉平（nevirapine）和依法韦仑（efavirenz）显著降低 丰度，抑制肿瘤生长，恢复代谢功能障碍，并改善局部免疫逃逸。总之，低甲基化诱导的表达是促进 LUSC 发生和发展的常见基因组事件，它是 LUSC 中一个有前途的预测生物标志物和治疗靶点。意义：是预测肺鳞状细胞癌局部免疫逃逸的预后生物标志物和潜在治疗靶点。
