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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

LanguageEnglish
Number of pages8
JournalJournal of Clinical Investigation
Early online date26 Nov 2018
DOIs
Publication statusE-pub ahead of print - 26 Nov 2018

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Haploinsufficiency
Carcinogenesis
Lung
Down-Regulation
Cell Proliferation
Chromosome Deletion
Genes
Lung Neoplasms
Chromosomes
Survival
Incidence
Neoplasms
Adenocarcinoma of lung

Keywords

  • DUSP4
  • lung tumorigenesis
  • adenocarcinomas

Cite this

Chen, M., Zhang, J., Berger, A. H., Diolombi, M. S., Ng, C., Fung, J., ... Pandolfi, P. P. (2018). Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis. Journal of Clinical Investigation . https://doi.org/10.1172/JCI99699
Chen, Ming ; Zhang, Jiangwen ; Berger, Alice H ; Diolombi, Moussa S ; Ng, Christopher ; Fung, Jacqueline ; Bronson, Roderick T ; Castillo-Martin, Mireia ; Thin, Tin Htwe ; Cordon-Cardo, Carlos ; Plevin, Robin ; Pandolfi, Pier Paolo. / Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis. In: Journal of Clinical Investigation . 2018.
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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.",
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Chen, M, Zhang, J, Berger, AH, Diolombi, MS, Ng, C, Fung, J, Bronson, RT, Castillo-Martin, M, Thin, TH, Cordon-Cardo, C, Plevin, R & Pandolfi, PP 2018, 'Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis' Journal of Clinical Investigation . https://doi.org/10.1172/JCI99699

Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis. / Chen, Ming; Zhang, Jiangwen; Berger, Alice H; Diolombi, Moussa S; Ng, Christopher; Fung, Jacqueline; Bronson, Roderick T; Castillo-Martin, Mireia; Thin, Tin Htwe; Cordon-Cardo, Carlos; Plevin, Robin; Pandolfi, Pier Paolo.

In: Journal of Clinical Investigation , 26.11.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis

AU - Chen, Ming

AU - Zhang, Jiangwen

AU - Berger, Alice H

AU - Diolombi, Moussa S

AU - Ng, Christopher

AU - Fung, Jacqueline

AU - Bronson, Roderick T

AU - Castillo-Martin, Mireia

AU - Thin, Tin Htwe

AU - Cordon-Cardo, Carlos

AU - Plevin, Robin

AU - Pandolfi, Pier Paolo

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N2 - 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.

AB - 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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