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

Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis.

Author information

1
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, Massachusetts, USA.
2
School of Biological Sciences, The University of Hong Kong, Hong Kong, China.
3
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
4
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
5
Department of Pathology, Champalimaud Center for the Unknown, Lisbon, Portugal.
6
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom.

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

PMID:
30475228
PMCID:
PMC6307955
[Available on 2019-04-02]
DOI:
10.1172/JCI99699
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