title: Expression of Neuroendocrine Factor VGF in Lung Cancer Cells Confers Resistance to EGFR Kinase Inhibitors and Triggers Epithelial-to-Mesenchymal Transition.
abstract: Mutations in EGFR drive tumor growth but render tumor cells sensitive to treatment with EGFR tyrosine kinase inhibitors (TKI). Phenotypic alteration in epithelial-to-mesenchymal transition (EMT) has been linked to the TKI resistance in lung adenocarcinoma. However, the mechanism underlying this resistance remains unclear. Here we report that high expression of a neuroendocrine factor termed VGF induces the transcription factor TWIST1 to facilitate TKI resistance, EMT, and cancer dissemination in a subset of lung adenocarcinoma cells. VGF silencing resensitized EGFR-mutated lung adenocarcinoma cells to TKI. Conversely, overexpression of VGF in sensitive cells conferred resistance to TKIs and induced EMT, increasing migratory and invasive behaviors. Correlation analysis revealed a significant association of VGF expression with advanced tumor grade and poor survival in patients with lung adenocarcinoma. In a mouse xenograft model of lung adenocarcinoma, suppressing VGF expression was sufficient to attenuate tumor growth. Overall, our findings show how VGF can confer TKI resistance and trigger EMT, suggesting its potential utility as a biomarker and therapeutic target in lung adenocarcinoma.Cancer Res; 77(11); 3013-26. ©2017 AACR.
authors.affiliation: Institute of Biotechnology, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Wen
authors.initials: W
authors.lastname: Hwang
authors.affiliation: Institute of Biotechnology, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Yu-Fan
authors.initials: YF
authors.lastname: Chiu
authors.affiliation: Institute of Biotechnology, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Ming-Han
authors.initials: MH
authors.lastname: Kuo
authors.affiliation: Institute of Biotechnology, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Kuan-Lin
authors.initials: KL
authors.lastname: Lee
authors.affiliation: Institute of Biotechnology, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: An-Chun
authors.initials: AC
authors.lastname: Lee
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chia-Cherng
authors.initials: CC
authors.lastname: Yu
authors.affiliation: Department of Pathology and Laboratory Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan.|Department of Biomedical Engineering, Ming Chuan University, Taoyuan, Taiwan.
authors.forename: Junn-Liang
authors.initials: JL
authors.lastname: Chang
authors.affiliation: Department of Thoracic Surgery, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Wen-Chien
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Shih-Hsin
authors.initials: SH
authors.lastname: Hsiao
authors.affiliation: Department of Pathology, Taipei Medical University Hospital, Taipei, Taiwan.|Department of Pathology, Taipei Municipal Wan Fang Hospital, Taipei, Taiwan.
authors.forename: Sey-En
authors.initials: SE
authors.lastname: Lin
authors.affiliation: Institute of Biotechnology, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan. ytchou@life.nthu.edu.tw.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Chou
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors