EGFR over-expression in non-small cell lung cancers harboring EGFR mutations is associated with marked down-regulation of CD82

Chi Hwa Yang, Hsiao Chin Chou, Yu Ning Fu, Chi Ling Yeh, Hui Wen Cheng, Il Chi Chang, Ko Jiunn Liu, Gee Chen Chang, Ting Fen Tsai, Shih Feng Tsai, Hui Ping Liu, Yi Cheng Wu, Ya Ting Chen, Shiu Feng Huang*, Yi Rong Chen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1540-1549
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1852
Issue number7
DOIs
StatePublished - 1 Jul 2015

Keywords

  • CD82
  • EGFR mutation
  • Exosome
  • Lung cancer

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