LINE-1 Retrotransposition Promotes the Development and Progression of Lung Squamous Cell Carcinoma by Disrupting the Tumor-Suppressor Gene FGGY
Authors: Jinpu Yu
Zeguo Sun
Yingnan Ye
Xiao Zhang
Xishan Hao
Weijia Zhang
Xiubao Ren
Rui Zhang
Martin J Walsh
Pengpeng Liu
Beiqi Cai
Fan Zhang
Journal: Cancer Research (2019)
Discipline: CLINICAL MEDICINE
Keywords: LINE-1 retrotransposition; lung squamous cell carcinoma; LUSC; transcriptomes; tumor samples
Affiliations: 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., Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York., Department of Imaging, Nanjing Bayi Hospital, Nanjing, China., Departments of Pharmacological Sciences, Genetics and Genomic Sciences and the Mount Sinai Center for RNA Biology and Medicine, Icahn School of Medicine at Mount Sinai, New York, New York., Department of Immunology, Biotherapy Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China., Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.  ., 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.  .

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. 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. 

Retracted: No

PubPeer comments:
 I noticed in this article, two images from different groups are the same. Figure 5G and Figure 6C, two images are the same one. ![file] , 
 Dear Roseum, We appreciate your comment on our article entitled  LINE-1 Retrotransposition Promotes the Development and Progression of Lung Squamous Cell Carcinoma by Disrupting the Tumor-Suppressor Gene FGGY in which you raised the question that 2 images from different groups were the same. Indeed the image of sh-FGGY in Figure 5G and the image of CTRL in Figure 6C are identical since they represented the same group in this study. Because all invasion experiments included in Figure 5G and 6C were conducted simultaneously in one batch, which included 6 groups in total: H520OV-NC, H520OV-L1-FGGY, H520sh-NC, H520sh-FGGY, EFV, and NVR. Among these groups, H520sh-FGGY cells were used as the experimental group in Figure 5G to demonstrate the high tumorigenesis capacity of FGGY knock-down NCI-H520 cells, which were also applied as the control group in Figure 6C to evaluate the therapeutic efficacy of LINE-1 inhibitors EFV and NVR on FGGY knock-down NCI-H520 cells and xenografts in vitro and vivo. Therefore, H520sh-FGGY cells were labeled as CTRL in Figure 6C which might cause misunderstanding of readers. During the experiment, we repeated the experiments in triplicate (invasive cell numbers in different groups: H520OV-NC: 101, 87, 92; H520OV-L1-FGGY: 176, 152, 138; H520sh-NC: 95, 74, 81; H520sh-FGGY: 120, 112, 140; NVR: 72, 59, 42; EFV: 80, 62, 70), and took the most representative pictures of each group to present in Figures. Although the experimental design was clearly grouped and repeatable, we apologized for the confusion caused by unclear cell labeling in the article. We will communicate with Cancer Research journal to clarify this control (sh-FGGY) referred in figure 6C. We will pay more attention on cell labeling and undergo more rigorous check in advance to avoid similar problems. ,