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  current news   Press   selected story    
     
  17th September  
  RUNX3 attenuates β-catenin/TCFs in intestinal tumorigenesis
 
 




Authors
Kosei Ito11,2,4, Anthony Chee-Beng Lim1, Manuel Salto-Tellez2, Lena Motoda1, Motomi Osato1,2, Linda Shyue Huey Chuang1, Cecilia Wei Lin Lee1, Dominic Chih-Cheng Voon2, Jason Kin Wai Koo2, Huajing Wang2, Hiroshi Fukamachi3 and Yoshiaki Ito1, 2

1 Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
2 Oncology Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, 28 Medical Drive, Singapore 117456
3 Department of Molecular Oncology, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo, Japan 113-8519
4Present address; Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, Japan 852-8588

Running title; RUNX3 attenuates β-catenin/TCFs

Correspondence and requests for materials should be addressed to Y.I.
(itoy@imcb.a-star.edu.sg)

Abstract

SUMMARY Inactivation of APC, a key regulator of the Wnt pathway, in intestinal epithelial cells activates β-catenin to initiate tumorigenesis. However, other alterations for intestinal tumorigenesis are plausible. Here we found that RUNX3, a gastric tumor suppressor, forms a ternary complex with β-catenin/TCF4 and attenuates the Wnt signaling activity. A significant fraction of human sporadic colorectal adenomas and Runx3+/- mouse intestinal adenomas showed inactivation of RUNX3 without apparent β-catenin accumulation, indicating that RUNX3 inactivation independently induces intestinal adenomas. In human colon cancers, RUNX3 is frequently inactivated with concomitant β-catenin accumulation, suggesting that adenomas induced by inactivation of RUNX3 may progress to malignancy. Taken together, these data demonstrate that RUNX3 functions as a tumor suppressor by attenuating Wnt signaling. SIGNIFICANCE It is known that biallelic inactivation of APC induces colon adenomas. We found that biallelic inactivation of RUNX3 without nuclear/cytoplasmic accumulation of β-catenin also induces colon adenomas. The results suggest that APC and RUNX3 may independently function as gatekeepers in colon adenoma development. Wnt signaling is an oncogenic pathway whereas TGF-β is a tumor suppressor pathway. The nuclear effectors of these pathways, β-catenin/TCF4 and RUNX3, respectively, form a ternary complex with diminished DNA binding ability. This ternary complex appears to integrate growth promoting and cytostatic signals for homeostatic balance of growth and differentiation in intestinal epithelial cells

Significance

It is known that biallelic inactivation of APC induces colon adenomas. We found that biallelic inactivation of RUNX3 without nuclear/cytoplasmic accumulation of β-catenin also induces colon adenomas. The results suggest that APC and RUNX3 may independently function as gatekeepers in colon adenoma development. Wnt signaling is an oncogenic pathway whereas TGF- is a tumor suppressor pathway. The nuclear effectors of these pathways, -catenin/TCF4 and RUNX3, respectively, form a ternary complex with diminished DNA binding ability. This ternary complex appears to integrate growth promoting and cytostatic signals for homeostatic balance of growth and differentiation in intestinal epithelial cells.




Figure Legend

The most well-known tumor suppressor of colon cancer is APC gene. When APC is inactivated, adenomas are induced which are considered to be the first step of colon carcinogenesis. In such adenomas, β-catenin, which is normally associated with surface membrane, becomes stabilized and migrates into the cytoplasm and the nucleus. We found that less than half of sporadic colon adenomas that we examined show nuclear/cytoplasmic accumulation of β-catenin. Upper two panels show serial sections of this type of adenoma. Upper left panel shows nuclear/cytoplasmic accumulation of β-catenin, while upper right shows that RUNX3 is expressed normally in the nucleus. Earlier, we reported that RUNX3 is a tumor suppressor of gastric cancer. About 30% of colon adenomas showed inactivation of RUNX3 (lower right panel), while all of them show normal membranous β-catnin (lower left). By characterizing Runx3 knock-out mice and human samples, we found that inactivation of APC and RUNX3 independently induces colon adenomas. Our studies show that inactivation of both APC and RUNX3 provide greater chance to induce colon cancers.

Cancer Cell. 2008 Sep 9;14(3):226-37.

For more information on RUNXs lab, Please Click here.