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
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenomatous Polyposis Coli Protein / genetics
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Adenomatous Polyposis Coli Protein / metabolism
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Adenomatous Polyps / genetics
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Adenomatous Polyps / metabolism
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Adenomatous Polyps / pathology
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Animals
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Blotting, Western
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Cell Line, Tumor
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology
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Core Binding Factor Alpha 3 Subunit / genetics
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Core Binding Factor Alpha 3 Subunit / metabolism
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Core Binding Factor Alpha 3 Subunit / physiology*
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Cyclin D
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Cyclins / genetics
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Cyclins / metabolism
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HCT116 Cells
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Humans
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Hyperplasia
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Intestinal Mucosa / metabolism
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Intestinal Neoplasms / genetics
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Intestinal Neoplasms / metabolism
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Intestinal Neoplasms / pathology*
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Intestines / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Promoter Regions, Genetic / genetics
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Protein Binding
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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TCF Transcription Factors / genetics
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TCF Transcription Factors / metabolism*
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Transcription Factor 4
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Transcription Factor 7-Like 2 Protein
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beta Catenin / genetics
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beta Catenin / metabolism*
Substances
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Adenomatous Polyposis Coli Protein
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Core Binding Factor Alpha 3 Subunit
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Cyclin D
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Cyclins
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Nerve Tissue Proteins
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TCF Transcription Factors
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TCF7L2 protein, human
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Tcf4 protein, mouse
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Tcf7l2 protein, mouse
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Transcription Factor 4
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Transcription Factor 7-Like 2 Protein
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beta Catenin