Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis

J Clin Invest. 2019 Jan 2;129(1):215-222. doi: 10.1172/JCI99699. Epub 2018 Nov 26.

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.

Keywords: Cancer; Genetics; Molecular genetics; Mouse models; Oncology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing* / biosynthesis
  • Adaptor Proteins, Signal Transducing* / genetics
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic* / genetics
  • Cell Transformation, Neoplastic* / metabolism
  • Cell Transformation, Neoplastic* / pathology
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Neoplastic
  • Haploinsufficiency*
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • MAP Kinase Signaling System / genetics
  • Male
  • Mice
  • Mice, Knockout
  • Neoplasm Proteins* / biosynthesis
  • Neoplasm Proteins* / genetics
  • Phosphoproteins* / biosynthesis
  • Phosphoproteins* / genetics
  • Protein Tyrosine Phosphatases* / biosynthesis
  • Protein Tyrosine Phosphatases* / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Dok2 protein, mouse
  • Neoplasm Proteins
  • Phosphoproteins
  • MKP2 protein, mouse
  • Protein Tyrosine Phosphatases