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 journalArticle

4 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;Cdh1F/+;Trp53F/F;Smad4F/F (pChePS) 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
JournalMolecular Carcinogenesis
DOIs
Publication statusAccepted/In press - 2018 Jan 1

Fingerprint

Cadherins
Stomach Neoplasms
Stomach
Carcinogenesis
Osteopontin
Thymosin
Genes
Neoplastic Stem Cells
Cell Survival
Anoikis
Gene Knockout Techniques
Mutation
Cytokine Receptors
Epithelial-Mesenchymal Transition
Transcriptome
Cell Movement
Extracellular Matrix
Neoplasms
Animal Models
Alleles

Keywords

  • LC-MS/MS
  • Osteopontin
  • Thymosin β4
  • WNT signaling

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Multi-omics analysis identifies pathways and genes involved in diffuse-type gastric carcinogenesis induced by E-cadherin, p53, and Smad4 loss in mice. / Park, Jun Won; Kim, Min Sik; Voon, Dominic C.; Kim, Su Jin; Bae, Jingi; Mun, Dong Gi; Ko, Seung Ik; Kim, Hark K.; Lee, Sang-Won; Kim, Dae Yong.

In: Molecular Carcinogenesis, 01.01.2018.

Research output: Contribution to journalArticle

Park, Jun Won ; Kim, Min Sik ; Voon, Dominic C. ; Kim, Su Jin ; Bae, Jingi ; Mun, Dong Gi ; Ko, Seung Ik ; Kim, Hark K. ; Lee, Sang-Won ; Kim, Dae Yong. / Multi-omics analysis identifies pathways and genes involved in diffuse-type gastric carcinogenesis induced by E-cadherin, p53, and Smad4 loss in mice. In: Molecular Carcinogenesis. 2018.
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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;Cdh1F/+;Trp53F/F;Smad4F/F (pChePS) 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.",
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AU - Kim, Su Jin

AU - Bae, Jingi

AU - Mun, Dong Gi

AU - Ko, Seung Ik

AU - Kim, Hark K.

AU - Lee, Sang-Won

AU - Kim, Dae Yong

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