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Restoration of Epithelial Cell Polarity in a Colorectal Cancer Cell Line by Suppression of ß-catenin/T-Cell Factor 4-mediated Gene Transactivation¹

Pathology Division, National Cancer Center Research Institute, Tokyo 104-0045 [Y. N., T. Y., A. S. T., R. H., F. H., S. H.], and the First Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8543 [Y. N., A. S. T., K. I.], Japan

ß-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 ß-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 ß-catenin/TCF4-mediated gene transactivation by dominant-negative TCF4B (N30) 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 ß-catenin (N89) induced the formation of similar piled-up foci in untransformed IEC6 intestinal epithelial cells. Sulindac, a nonsteroidal anti-inflammatory 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 ß-catenin/TCF4-mediated intestinal tumorigenesis.

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