Genome-wide DNA Methylation Analysis Reveals <i>GABBR2</i> as a Novel Epigenetic Target for <i>EGFR</i> 19 Deletion Lung Adenocarcinoma with Induction Erlotinib Treatment
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- Xiaomin Niu
- 1Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, P.R. China.
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- Fatao Liu
- 2Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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- Yi Zhou
- 4Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, P.R. China.
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- Zhen Zhou
- 1Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, P.R. China.
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- Daizhan Zhou
- 5Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, P.R. China.
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- Ting Wang
- 2Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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- Ziming Li
- 1Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, P.R. China.
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- Xiangyun Ye
- 1Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, P.R. China.
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- Yongfeng Yu
- 1Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, P.R. China.
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- Xiaoling Weng
- 6Institutes of Biomedical Sciences, Fudan University, Shanghai, P.R. China.
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- Hong Zhang
- 6Institutes of Biomedical Sciences, Fudan University, Shanghai, P.R. China.
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- Junyi Ye
- 6Institutes of Biomedical Sciences, Fudan University, Shanghai, P.R. China.
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- Meilin Liao
- 1Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, P.R. China.
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- Yun Liu
- 6Institutes of Biomedical Sciences, Fudan University, Shanghai, P.R. China.
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- Zhiwei Chen
- 1Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, P.R. China.
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- Shun Lu
- 1Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, P.R. China.
説明
<jats:title>Abstract</jats:title> <jats:p>Purpose: The past decade has witnessed the rapid development of personalized targeted therapies in lung cancer. It is still unclear whether epigenetic changes are involved in the response to tyrosine kinase inhibitor (TKI) treatment in epidermal growth factor receptor (EGFR)-mutated lung cancer.</jats:p> <jats:p>Experimental Design: Methyl-sensitive cut counting sequencing (MSCC) was applied to investigate the methylation changes in paired tissues before and after erlotinib treatment for 42 days with partial response (PR) from stage IIIa (N2) lung adenocarcinoma patients (N = 2) with EGFR 19 deletion. The Sequenom EpiTYPER assay was used to validate the changed methylated candidate genes. Up- or downregulation of the candidate gene was performed to elucidate the potential mechanism in the regulation of erlotinib treatment response.</jats:p> <jats:p>Results: Sixty aberrant methylated genes were screened using MSCC sequencing. Two aberrant methylated genes, CBFA2T3 and GABBR2, were clearly validated. A same differential methylated region (DMR) between exon 2 and exon 3 of GABBR2 gene was confirmed consistently in both patients. GABBR2 was significantly downregulated in EGFR 19 deletion cells, HCC4006 and HCC827, but remained conserved in EGFR wild-type A549 cells after erlotinib treatment. Upregulation of GABBR2 expression significantly rescued erlotinib-induced apoptosis in HCC827 cells. GABBR2 was significantly downregulated, along with the reduction of S6, p-p70 S6, and p-ERK1/2, demonstrating that GABBR2 may play an important role in EGFR signaling through the ERK1/2 pathway.</jats:p> <jats:p>Conclusions: We demonstrated that GABBR2 gene might be a novel potential epigenetic treatment target with induction erlotinib treatment for stage IIIa (N2) EGFR 19 deletion lung adenocarcinoma. Clin Cancer Res; 23(17); 5003–14. ©2017 AACR.</jats:p>
収録刊行物
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- Clinical Cancer Research
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Clinical Cancer Research 23 (17), 5003-5014, 2017-08-31
American Association for Cancer Research (AACR)
