Restoration of epithelial cell polarity in a colorectal cancer cell line by suppression of beta-catenin/T-cell factor 4-mediated gene transactivation.

Abstract	Beta-catenin acts as a transcriptional coactivator by forming a complex with T-cell factor/lymphoid enhancer factor (TCF/LEF) DNA-binding proteins. Aberrant transactivation of a certain set of target genes by beta-catenin and TCF4 complexes has been implicated in familial and sporadic colorectal tumorigenesis. A colorectal cancer cell line, DLD-1, becomes irregularly multilayered, when maintained confluent for 2-3 weeks, and forms numerous dome-like polypoid foci piled-up over the surface of cell sheets. By the use of a strict tetracycline-regulation system, we found that the continuous suppression of beta-catenin/TCF4-mediated gene transactivation by dominant-negative TCF4B (deltaN30) reduced these piled-up foci and restored a simple monolayer of polarized columnar cells resembling normal intestinal epithelium. The restoration of epithelial cell polarity was evident in two ways: (a) the formation of microvilli over the apical surface; and (b) the distribution of a tight junction protein, ZO-1, to the lateral plasma membrane. Retroviral expression of stabilized beta-catenin (deltaN89) induced the formation of similar piled-up foci in untransformed IEC6 intestinal epithelial cells. Sulindac, a nonsteroidal antiinflammatory drug effective against colorectal tumorigenesis in familial adenomatous polyposis syndrome, suppressed the formation of foci. The loss of epithelial cell polarity may be a critical cellular event driving beta-catenin/TCF4-mediated intestinal tumorigenesis.
Authors	Y Naishiro, T Yamada, A S Takaoka, R Hayashi, F Hasegawa, K Imai, S Hirohashi
Journal	Cancer research (Cancer Res) Vol. 61 Issue 6 Pg. 2751-8 (Mar 15 2001) ISSN: 0008-5472 [Print] United States
PMID	11289158 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Anti-Inflammatory Agents, Non-Steroidal CTNNB1 protein, human Ctnnb1 protein, rat Cytoskeletal Proteins Membrane Proteins Phosphoproteins TCF Transcription Factors TCF7L2 protein, human TJP1 protein, human Tcf7l2 protein, rat Tjp1 protein, rat Trans-Activators Transcription Factor 7-Like 2 Protein Transcription Factors Zonula Occludens-1 Protein beta Catenin Sulindac Doxycycline
Topics	Adenocarcinoma (genetics, metabolism, pathology) Amino Acid Sequence Animals Anti-Inflammatory Agents, Non-Steroidal (pharmacology) Cell Division (drug effects, physiology) Cell Membrane (metabolism) Cell Polarity (physiology) Colorectal Neoplasms (genetics, metabolism, pathology) Cytoskeletal Proteins (biosynthesis, genetics, physiology) Doxycycline (pharmacology) Epithelial Cells (cytology, metabolism) Genes, MDR Humans Intestinal Mucosa (cytology, metabolism) Membrane Proteins (metabolism) Molecular Sequence Data Phosphoproteins (metabolism) Rats Retroviridae (genetics) Sulindac (pharmacology) TCF Transcription Factors Trans-Activators Transcription Factor 7-Like 2 Protein Transcription Factors (biosynthesis, genetics, physiology) Transcriptional Activation (physiology) Tumor Cells, Cultured Zonula Occludens-1 Protein beta Catenin

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