Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis

Ming Chen, Jiangwen Zhang, Alice H. Berger, Moussa S. Diolombi, Christopher Ng, Jacqueline Fung, Roderick T. Bronson, Mireia Castillo-Martin, Tin Htwe Thin, Carlos Cordon-Cardo, Robin Plevin, Pier Paolo Pandolfi

Research output: Contribution to journalArticle

3 Citations (Scopus)
10 Downloads (Pure)

Abstract

Recurrent broad-scale heterozygous deletions are frequently observed in human cancer. Here we tested the hypothesis that compound haploinsufficiency of neighboring genes at chromosome 8p promotes tumorigenesis. By targeting the mouse orthologs of human DOK2 and DUSP4 genes, which were co-deleted in approximately half of human lung adenocarcinomas, we found that compound-heterozygous deletion of Dok2 and Dusp4 in mice resulted in lung tumorigenesis with short latency and high incidence, and that their co-deletion synergistically activated MAPK signaling and promoted cell proliferation. Conversely, restoration of DOK2 and DUSP4 in lung cancer cells suppressed MAPK activation and cell proliferation. Importantly, in contrast to downregulation of DOK2 or DUSP4 alone, concomitant downregulation of DOK2 and DUSP4 was associated with poor survival in human lung adenocarcinoma. Therefore, our findings lend in vivo experimental support to the notion that compound haploinsufficiency, due to broad-scale chromosome deletions, constitutes a driving force in tumorigenesis.

Original languageEnglish
Pages (from-to)215-222
Number of pages8
JournalJournal of Clinical Investigation
Volume129
Issue number1
Early online date26 Nov 2018
DOIs
Publication statusE-pub ahead of print - 26 Nov 2018

Keywords

  • DUSP4
  • lung tumorigenesis
  • adenocarcinomas

Cite this