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Mol Carcinog. 2018 Jul;57(7):947-954. doi: 10.1002/mc.22803. Epub 2018 Mar 30.

Multi-omics analysis identifies pathways and genes involved in diffuse-type gastric carcinogenesis induced by E-cadherin, p53, and Smad4 loss in mice.

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Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
National Cancer Center, Goyang, Gyeonggi, Republic of Korea.
Department of Applied Chemistry, College of Applied Science, Kyung Hee University, Yongin-si, Gyeonggi-do, Republic of Korea.
Department of Biomedical Science and Technology, Kyung Hee Medical Science Research Institute, Kyung Hee University, Yongin-si, Gyeonggi-do, Republic of Korea.
Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Department of Chemistry, Research Institute for Natural Sciences, Korea University, Seoul, Republic of Korea.
Department of Chemistry, Center for Proteogenome Research, Korea University, Seoul, Republic of Korea.


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;Cdh1F/+ ;Trp53F/F ;Smad4F/F (pChe 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-β4 (Tβ4) were identified as prime candidates as suppressors of E-cadherin expression from the remaining Cdh1 allele during DGC development. Specifically, Tβ4 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 Tβ4.


LC-MS/MS; WNT signaling; osteopontin; thymosin β4

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