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
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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Concise Communication Genetics Oncology

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.

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 4

Compound loss of DOK2 and DUSP4 expression and its clinical implication in human lung adenocarcinomas.

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Compound loss of DOK2 and DUSP4 expression and its clinical implication ...
(A and B) Percentage of tumors with deletion of DOK2 or DUSP4 (A) and co-deletion of DOK2 and DUSP4 (B) in the TCGA dataset. (C) DUSP4 protein expression in a TMA of normal lung tissue or lung cancer samples. P values were determined by 2-tailed t tests. Data are shown as mean ± SD. (D) Representative imagines of IHC staining for DOK2 and DUSP4 protein from normal lung tissue or 2 pairs of tumor samples with moderate or low expression of DOK2 and DUSP4 protein. Arrows indicate positive staining of DOK2 or DUSP4 protein in lung epithelial cells. Scale bars: 50 μm. (E) Kaplan-Meier survival curve of lung adenocarcinoma patients stratified by DOK2 and DUSP4 expression. P values were determined by log-rank test. (F) Models of compound haploinsufficiency of DUSP4 and DOK2 promoting lung tumorigenesis. DSUP4-heterozygous cells: The activation of RTK signaling is tightly controlled by a negative feedback loop involving the recruitment of DOK2 and RASA1. The remaining WT DUSP4 allele is sufficient to suppress the low level of ERK activity transduced by RTK signaling. DUSP4 and DOK2 compound-heterozygous cells: Loss of DOK2 results in decreased recruitment of RASA1, allowing enhanced RTK and downstream ERK activation. The remaining WT DUSP4 allele is insufficient to suppress the high level of ERK activity and leads to increased lung tumorigenesis. White rectangles indicate genomic deletions; gray text indicates low expression of proteins of interest.