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Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis
Ming Chen, … , Robin Plevin, Pier Paolo Pandolfi
Ming Chen, … , Robin Plevin, Pier Paolo Pandolfi
Published November 26, 2018
Citation Information: J Clin Invest. 2019;129(1):215-222. https://doi.org/10.1172/JCI99699.
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Concise Communication Genetics Oncology

Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis

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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.

Authors

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

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Figure 2

Histopathology of lung tumors in Dok2+/− and Dok2+/−Dusp4+/− mice.

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Histopathology of lung tumors in Dok2+/− and Dok2+/−Dusp4+/− mice.
(A) G...
(A) Gross view of the 5 lung lobes from a representative Dok2+/− and Dok2+/− Dusp4+/− mouse. Arrowheads indicate tumor nodules. Quantification of the size of tumors was carried out with ImageJ software (n = 5 mice per genotype). Scale bars: 2 mm. (B) IHC and quantification of Ki-67 staining in lung tumors from age-matched Dok2+/− and Dok2+/− Dusp4+/− mice (n = 3 mice per genotype). Scale bars: 50 μm. (C) IHC of phosphorylated Erk in lung tumors from age-matched Dok2+/− and Dok2+/− Dusp4+/− mice (n = 3 mice per genotype). Scale bars: 50 μm. (D) Western blot analysis of lung lysates from 9-month-old WT, Dusp4+/−, Dok2+/−, and Dok2+/− Dusp4+/− mice. Numbers indicate the ratios relative to controls for phospho-protein/total protein. (E) Serial sections of lung tissue stained with H&E and IHC for Dok2 and Dusp4 from an 18-month-old WT and Dok2+/− Dusp4+/− mouse. Scale bars: 50 μm. In A and B, data are shown as mean ± SEM. Student’s t test (2 tailed) was used to determine significance.

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