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
N1 - Publisher Copyright:
© 2019 American Society for Clinical Investigation. All rights reserved.
PY - 2019/1/2
Y1 - 2019/1/2
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.
UR - http://www.scopus.com/inward/record.url?scp=85059405721&partnerID=8YFLogxK
U2 - 10.1172/JCI99699
DO - 10.1172/JCI99699
M3 - Article
C2 - 30475228
AN - SCOPUS:85059405721
SN - 0021-9738
VL - 129
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
M1 - CI99699
ER -