LINE-1 Retrotransposition Promotes the Development and Progression of Lung Squamous Cell Carcinoma by Disrupting the Tumor-Suppressor Gene FGGY

Abstract

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. Over-expression 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.

New Understanding of the Relevant Role of LINE-1 Retrotransposition in Human Disease and Immune Modulation

“…In colon cancer, Miki et al reported that LINE-1 insertion disrupts the tumor suppressor gene APC, which can lead to gene inactivation (Miki et al, 1992). In lung squamous cell carcinoma, we found that LINE-1 insertion into tumor suppressor gene FGGY promotes cell proliferation and invasion in vitro, and facilitates tumorigenesis in vivo (Zhang et al, 2019).…”

“…It was reported that LINE-1 insertions in the FGGY gene can upregulate cytochrome P450, arachidonic acid metabolism, and glycerolipid metabolism. These metabolic disorders can lead to the occurrence of a variety of diseases and poor prognosis (Zhang et al, 2019).…”

“…LINE-1 retrotransposons suppress FGGY, leading to lipid metabolism disturbance and diet-induced obesity in mice (Taylor et al, 2018). Lung squamous cell carcinoma patients with L1-FGGY + tissue have a poor prognosis, have low levels of CD3 + T cells, and have high levels of CD68 + macrophages and CD33 + myeloid-derived cells (Zhang et al, 2019). L1-FGGY + also regulates the abnormal transcription of cytokines related to the immunosuppressive micromilieu.…”

“…In vivo assays using murine models inoculated with various human cancer cell lines revealed that daily treatment of animals with EFV significantly delayed the progression of tumors (Oricchio et al, 2007). NVR and EFV dramatically countered L1-FGGY abundance, inhibited tumor growth, attenuated metabolism dysfunction, and improved the local immune evasion in lung squamous cell carcinomas (Zhang et al, 2019). EFV has recently undergone a phase II clinical trial in patients with metastatic prostate cancer (Houédé et al, 2014).…”

Modeling and analysis of site-specific mutations in cancer identifies known plus putative novel hotspots and bias due to contextual sequences

“…The Table 3 shows the hotpots for the rest of cancer types and the complete list is shown in Supplementary Table 1. This is interesting because it highlights genes not well studied such as NBPF12 in BRCA, LPAR6 or ASXL2 in BLCA, and FGGY in LUSC, which is being studied recently [41].…”