Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis.
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.
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https://hdl.handle.net/10161/18169Published Version (Please cite this version)
10.1172/jci99699Publication Info
Chen, Ming; Zhang, Jiangwen; Berger, Alice H; Diolombi, Moussa S; Ng, Christopher;
Fung, Jacqueline; ... Pandolfi, Pier Paolo (2019). Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis. The Journal of clinical investigation, 129(1). pp. 215-222. 10.1172/jci99699. Retrieved from https://hdl.handle.net/10161/18169.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Ming Chen
Assistant Professor in Pathology
Our laboratory is interested in understanding the molecular and genetic events underlying
cancer progression and metastasis. The focus of our work is a series of genetically
engineered mouse models that faithfully recapitulate human disease. Using a combination
of mouse genetics, omics technologies, cross-species analyses and in vitro approaches,
we aim to identify cancer cell–intrinsic and –extrinsic mechanisms driving
metastatic cancer progression, with a long

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