EGFR over-expression in non-small cell lung cancers harboring EGFR mutations is associated with marked down-regulation of CD82.
Epidermal growth factor receptor (EGFR) gene mutations are strongly associated with lung adenocarcinoma and favorable response to EGFR tyrosine kinase inhibitor. The mutated EGFR proteins (EGFRs) are hyper-phosphorylated and refractory to receptor down-regulation. To address the discrepancy between hyper-phosphorylation and lack of down-regulation of mutant EGFRs, we have examined the expression of EGFR negative regulators in non-small cell lung cancer (NSCLC) cell lines. We found that NSCLC cell lines expressing mutant EGFRs often had low expression of various negative regulators for EGFR. Among them, tumor suppressor CD82 was up-regulated by wild type (WT) EGFR but down-regulated by mutant EGFRs. Reconstitution of CD82 exerted stronger suppressive effects on mutant EGFRs than on WT EGFR. Active exportation of CD82 through the exosome was one of the mechanisms involved in achieving the overall CD82 down-regulation in mutant EGFR-expressing lung cancer cell lines. Over-expression of mutant EGFR protein frequently occurred in the lung cancer tissues of mutant EGFR-transgenic mice and also associated with CD82 down-regulation. Immunoblot analyses on the tumor tissues from 23 lung adenocarcinoma patients (12 with WT EGFR, and 11 with mutant EGFRs) also identified significantly stronger down-regulation of CD82 in tumors with mutant EGFRs than WT. Our data indicate that CD82 down-regulation could be a critical step involved in the EGFR over-expression and the stronger tumorigenic activity triggered by EGFR mutations. Up-regulation of the CD82 level may become a promising new treatment strategy for lung adenocarcinoma.
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
Chi-Hwa
CH
Yang
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
Hsiao-Chin
HC
Chou
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
Yu-Ning
YN
Fu
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
Chi-Ling
CL
Yeh
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
Hui-Wen
HW
Cheng
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
Il-Chi
IC
Chang
National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan.
Ko-Jiunn
KJ
Liu
Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
Gee-Chen
GC
Chang
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan; Institute of Genetics and Genome Research Center, National Yang-Ming University, Taipei, Taiwan.
Ting-Fen
TF
Tsai
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan; Institute of Genetics and Genome Research Center, National Yang-Ming University, Taipei, Taiwan.
Shih-Feng
SF
Tsai
Department of Cardiovascular and Thoracic Surgery, Chang Gung Memorial Hospital at Linko, Chang Gung University College of Medicine, Taoyuan, Taiwan.
Hui-Ping
HP
Liu
Department of Cardiovascular and Thoracic Surgery, Chang Gung Memorial Hospital at Linko, Chang Gung University College of Medicine, Taoyuan, Taiwan.
Yi-Cheng
YC
Wu
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan.
Ya-Ting
YT
Chen
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan; Department of Pathology, Chang Gung Memorial Hospital, Taoyuan, Taiwan. Electronic address: sfhuang@nhri.org.tw.
Shiu-Feng
SF
Huang
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan. Electronic address: yrchen@nhri.org.tw.
Yi-Rong
YR
Chen
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051861:Kangai-1 Protein / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation
D051861:Kangai-1 Protein; D066246:ErbB Receptors
CD82; EGFR mutation; Exosome; Lung cancer