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

20 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

Funding Information:
Collaborative Genome Program for Fostering New Post-Genome Industry of National Research Foundation (NRF) funded by the Korean Ministry of Science and ICT, Grant number: NRF-2017M3C9A5031597; Brain Research Program through the NRF, Grant number: NRF-2017M3C7A1027472; Basic Science Research Program through the NRF, Grant number: NRF-20100020209; Korea Mouse Phenotyping Project through the NRF, Grant number: NRF-2016M3A9D5A01952416; Research Institute of Veterinary Science, College of Veterinary Medicine, Seoul National University

Funding Information:
Foundation(NRF)fundedbytheMinistryofScienceandICT(Grantnumber: NRF-2017M3C7A1027472), and by Basic Science Research Program through the NRF (Grant number: NRF-20100020209).

Funding Information:
This study was supported by the Research Institute of Veterinary Science, College of Veterinary Medicine, Seoul National University and by the Korea Mouse Phenotyping Project (NRF-2016M3A9D5A01952416) of a Na-tionalResearchFoundationgrantfundedbytheKoreangovernment(MSIP). This work was also supported by the Collaborative Genome Program for Fostering New Post-Genome Industry (NRF-2017M3C9A5031597) of National Research Foundation funded by the Korean Ministry of Science and ICT, by the Brain Research Program through the National Research

Publisher Copyright:
© 2018 Wiley Periodicals, Inc.

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Multi-omics analysis identifies pathways and genes involved in diffuse-type gastric carcinogenesis induced by E-cadherin, p53, and Smad4 loss in mice'. Together they form a unique fingerprint.

Cite this