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

Jun Won Park, Min Sik Kim, Dominic C. Voon, Su Jin Kim, Jingi Bae, Dong Gi Mun, Seung Ik Ko, Hark K. Kim, Sang Won Lee, Dae Yong Kim

    Research output: Contribution to journalArticlepeer-review

    22 Citations (Scopus)

    Abstract

    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-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.

    Original languageEnglish
    Pages (from-to)947-954
    Number of pages8
    JournalMolecular Carcinogenesis
    Volume57
    Issue number7
    DOIs
    Publication statusPublished - 2018 Jul

    Bibliographical note

    Publisher Copyright:
    © 2018 Wiley Periodicals, Inc.

    Keywords

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

    ASJC Scopus subject areas

    • Molecular Biology
    • Cancer Research

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