Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in mice

Xiaoling Xu, Steven G. Brodie, Xiao Yang, Young Hyuck Im, W. Tony Parks, Lin Chen, Yong Xing Zhou, Michael Weinstein, Seong Jin Kim, Chu Xia Deng*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

187 Scopus citations

Abstract

The tumor suppressor SMAD4, also known as DPC4, deleted in pancreatic cancer, is a central mediator of TGF-β signaling. It was previously shown that mice homozygous for a null mutation of Smad4 (Smad4(-/-)) died prior to gastrulation displaying impaired extraembryonic membrane formation and endoderm differentiation. Here we show that Smad4(+/-) mice began to develop polyposis in the fundus and antrum when they were over 6-12 months old, and in the duodenum and cecum in older animals at a lower frequency. With increasing age, polyps in the antrum show sequential changes from hyperplasia, to dysplasia, in-situ carcinoma, and finally invasion. These alterations are initiated by a dramatic expansion of the gastric epithelium where Smad4 is expressed. However, loss of the remaining Smad4 wild-type allele was detected only in later stages of tumor progression, suggesting that haploinsufficiency of Smad4 is sufficient for tumor initiation. Our data also showed that overexpression of TGF-β1 and Cyclin D1 was associated with increased proliferation of gastric polyps and tumors. These studies demonstrate that Smad4 functions as a tumor suppressor in the gastrointestinal tract and also provide a valuable model for screening factors that promote or prevent gastric tumorigenesis.

Original languageEnglish (US)
Pages (from-to)1868-1874
Number of pages7
JournalOncogene
Volume19
Issue number15
DOIs
StatePublished - Apr 6 2000

Keywords

  • Cyclin D1
  • Dpc4
  • Gastric cancer
  • Juvenile polyposis
  • Smad4
  • TGFβ1

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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