Chromosomal instability by beta-catenin/TCF transcription in APC or beta-catenin mutant cells.
ABSTRACT Adenomatous polyposis coli (APC/Apc) gene encodes a key tumor suppressor whose mutations activate beta-catenin/T-cell factor (TCF)-mediated transcription (canonical Wnt signaling). Here, we show that Wnt signaling can cause chromosomal instability (CIN). As an indicator of CIN, we scored anaphase bridge index (ABI) in mouse polyps and ES cells where Wnt signaling was activated by Apc or beta-catenin mutations. We found three to nine times higher ABI than in wild-type controls. Furthermore, karyotype analysis confirmed that the Wnt signal-activated ES cells produced new chromosomal aberrations at higher rates; hence CIN. Consistently, expression of dominant-negative TCFs in these cells reduced their ABI. We also found that Wnt signal activation increased phosphorylation of Cdc2 (Cdk1) that inhibited its activity, and suppressed apoptosis upon exposure of the cells to nocodazole or colcemid. The data suggest that Wnt signaling stimulates the cells to escape from mitotic arrest and apoptosis, resulting in CIN. In human gastric cancer tissues with nuclear beta-catenin, ABI was significantly higher than in those without. These results collectively indicate that beta-catenin/TCF-mediated transcription itself increases CIN through dysregulation of G2/M progression.
- SourceAvailable from: Toshikazu Ushijima
Article: Focus on gastric cancer.Cancer Cell 03/2004; 5(2):121-5. · 24.76 Impact Factor
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ABSTRACT: CDX2, a transcriptional factor expressed in the intestine, is implicated in the development and maintenance of the intestinal mucosa. Recent studies have demonstrated that CDX2 is expressed in the intestinal metaplasia of the stomach and intestinal-type gastric cancer, while it is not expressed in the normal gastric mucosa. To investigate the role of CDX2 in gastric cancer, we determined CDX2 expression and cell proliferation rate in various types of gastric cancer tissues by immunostaining. Surgically dissected gastric cancer tissues were collected from 40 patients. Consistent with previous reports, CDX2 was expressed in most gastric mucosa samples with intestinal metaplasia (89%, 16/18), although it was not found in the adjacent normal mucosa. CDX2 expression was also detected in 64% (18/28) of intestinal-type gastric cancer cases, whereas it was not observed in the diffuse-type gastric cancer (0/12). Moreover, the CDX2-positive gastric cancer samples showed significantly lower index for Ki-67 immunostaining, indicating reduced cell proliferation rates than in the CDX2-negative samples. Importantly, multivariate analysis for the overall survival rate revealed that the CDX2-positive gastric cancer patients survived significantly longer than the CDX2-negative patients. Even among the intestinal-type gastric cancer cases, the CDX2-positive group showed a lower Ki-67 index and longer postoperative survival than the CDX2-negative group. These results collectively indicate that CDX2 expression in gastric cancer tissues can be a novel prognostic marker for patient survival.International Journal of Oncology 11/2002; 21(4):769-74. · 2.66 Impact Factor
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ABSTRACT: The laboratory mouse (Mus musculus) has become one of the best model animal species in biomedical research today because of its abundant genetic/genomic information, and easy mutagenesis using transgenic and gene knockout technology. Genetically engineered mice have become essential tools in both mechanistic studies and drug development. In this article I will review recent topics in gastrointestinal cancer model mice, with emphasis on the results obtained in our laboratory. They include: (i) mouse models for familial adenomatous polyposis (Apc mutant mice; modifier genes of Apc intestinal polyposis; stabilizing beta-catenin mutant mice); (ii) mouse models for colon cancer (mouse models for hereditary non-polyposis colon cancer; additional mutations in Apc mutant mice; models with mutations in other genes; models for colon cancer associated with inflammatory bowel diseases); and (iii) mouse models for gastric cancer.Cancer Science 06/2006; 97(5):355-61. · 3.48 Impact Factor