RUNX3 attenuates beta-catenin/T cell factors in intestinal tumorigenesis

Cancer Cell. 2008 Sep 9;14(3):226-37. doi: 10.1016/j.ccr.2008.08.004.

Abstract

In intestinal epithelial cells, inactivation of APC, a key regulator of the Wnt pathway, activates beta-catenin to initiate tumorigenesis. However, other alterations may be involved in intestinal tumorigenesis. Here we found that RUNX3, a gastric tumor suppressor, forms a ternary complex with beta-catenin/TCF4 and attenuates Wnt signaling activity. A significant fraction of human sporadic colorectal adenomas and Runx3(+/-) mouse intestinal adenomas showed inactivation of RUNX3 without apparent beta-catenin accumulation, indicating that RUNX3 inactivation independently induces intestinal adenomas. In human colon cancers, RUNX3 is frequently inactivated with concomitant beta-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli Protein / genetics
  • Adenomatous Polyposis Coli Protein / metabolism
  • Adenomatous Polyps / genetics
  • Adenomatous Polyps / metabolism
  • Adenomatous Polyps / pathology
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Blotting, Western
  • Cell Line, Tumor
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Core Binding Factor Alpha 3 Subunit / genetics
  • Core Binding Factor Alpha 3 Subunit / metabolism
  • Core Binding Factor Alpha 3 Subunit / physiology*
  • Cyclin D
  • Cyclins / genetics
  • Cyclins / metabolism
  • HCT116 Cells
  • Humans
  • Hyperplasia
  • Intestinal Mucosa / metabolism
  • Intestinal Neoplasms / genetics
  • Intestinal Neoplasms / metabolism
  • Intestinal Neoplasms / pathology*
  • Intestines / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • TCF Transcription Factors / genetics
  • TCF Transcription Factors / metabolism*
  • Transcription Factor 4
  • Transcription Factor 7-Like 2 Protein
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • Adenomatous Polyposis Coli Protein
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Core Binding Factor Alpha 3 Subunit
  • Cyclin D
  • Cyclins
  • Nerve Tissue Proteins
  • TCF Transcription Factors
  • TCF7L2 protein, human
  • Tcf4 protein, mouse
  • Tcf7l2 protein, mouse
  • Transcription Factor 4
  • Transcription Factor 7-Like 2 Protein
  • beta Catenin