期刊
MOLECULAR CARCINOGENESIS
卷 57, 期 7, 页码 947-954出版社
WILEY
DOI: 10.1002/mc.22803
关键词
LC-MS; MS; osteopontin; thymosin 4; WNT signaling
资金
- Collaborative Genome Program for Fostering New Post-Genome Industry of National Research Foundation (NRF) - Korean Ministry of Science and ICT [NRF-2017M3C9A5031597]
- Brain Research Program through the NRF [NRF-2017M3C7A1027472]
- Basic Science Research Program through the NRF [NRF-20100020209]
- Korea Mouse Phenotyping Project through the NRF [NRF-2016M3A9D5A01952416]
- Research Institute of Veterinary Science, College of Veterinary Medicine, Seoul National University
The molecular mechanisms underlying the pathogenesis of diffuse-type gastric cancer (DGC) have not been adequately explored due to a scarcity of appropriate animal models. A recently developed tool well suited for this line of investigation is the Pdx-1-Cre;Cdh1(F/+);Trp53(F/F);Smad4(F/F) (pC(he)PS) mouse model that spontaneously develops metastatic DGC showing nearly complete E-cadherin loss. Here, we performed a proteogenomic analysis to uncover the molecular changes induced by the concurrent targeting of E-cadherin, p53, and Smad4 loss. The gene expression profiles of mouse DGCs and in vivo gastric phenotypes from various combinations of gene knockout demonstrated that these mutations collaborate to activate cancer-associated pathways to generate aggressive DGC. Of note, WNT-mediated epithelial-to-mesenchymal transition (EMT) and extracellular matrix (ECM)-cytokine receptor interactions were prominently featured. In particular, the WNT target gene osteopontin (OPN) that functions as an ECM cytokine is highly upregulated. In validation experiments, OPN contributed to DGC stemness by promoting cancer stem cell (CSC) survival and chemoresistance. It was further found that Bcl-xL acts as a targetable downstream effector of OPN in DGC CSC survival. In addition, Zeb2 and thymosin-4 (T4) were identified as prime candidates as suppressors of E-cadherin expression from the remaining Cdh1 allele during DGC development. Specifically, T4 suppressed E-cadherin expression and anoikis while promoting cancer cell growth and migration. Collectively, these proteogenomic analyses broaden and deepen our understanding of the contribution of key driver mutations in the stepwise carcinogenesis of DGC through novel effectors, namely OPN and T4.
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