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Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis
Ming Chen1, Jiangwen Zhang2, Alice H Berger1
1Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, Massachusetts, USA.
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.
Insights
Compound haploinsufficiency of neighboring genes DOK2 and DUSP4 on chromosome 8p drives lung cancer by activating MAPK signaling. Restoring these genes suppresses tumor growth, highlighting their role in tumorigenesis.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Recurrent heterozygous deletions are common in human cancers.
- Chromosome 8p deletions, including DOK2 and DUSP4, are frequent in lung adenocarcinoma.
- Compound haploinsufficiency is a potential driver of tumorigenesis.
Purpose of the Study:
- To investigate the role of compound haploinsufficiency of DOK2 and DUSP4 in lung tumorigenesis.
- To determine the impact of co-deleted genes on MAPK signaling and cell proliferation.
- To assess the prognostic significance of DOK2 and DUSP4 downregulation in human lung adenocarcinoma.
Main Methods:
- Targeted deletion of mouse orthologs of DOK2 and DUSP4.
- Analysis of MAPK signaling activation and cell proliferation in mouse models.
- Restoration of DOK2 and DUSP4 expression in human lung cancer cells.
- Correlation analysis of gene expression with patient survival data.
Main Results:
- Compound-heterozygous deletion of Dok2 and Dusp4 in mice led to rapid and frequent lung tumorigenesis.
- Co-deletion synergistically activated MAPK signaling and promoted cell proliferation.
- Restoration of DOK2 and DUSP4 suppressed MAPK activation and proliferation in cancer cells.
- Concomitant downregulation of DOK2 and DUSP4 correlated with poor survival in lung adenocarcinoma patients.
Conclusions:
- Compound haploinsufficiency of DOK2 and DUSP4 is a driving force in lung tumorigenesis.
- MAPK signaling pathway activation is a key mechanism in this process.
- DOK2 and DUSP4 are potential tumor suppressors and prognostic markers in lung adenocarcinoma.
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