RRC ID 39937
Author Naishiro Y, Yamada T, Takaoka AS, Hayashi R, Hasegawa F, Imai K, Hirohashi S.
Title Restoration of epithelial cell polarity in a colorectal cancer cell line by suppression of beta-catenin/T-cell factor 4-mediated gene transactivation.
Journal Cancer Res
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.
Volume 61(6)
Pages 2751-8
Published 2001-3-15
PMID 11289158
MeSH Adenocarcinoma / genetics Adenocarcinoma / metabolism Adenocarcinoma / pathology* Amino Acid Sequence Animals Anti-Inflammatory Agents, Non-Steroidal / pharmacology Cell Division / drug effects Cell Division / physiology Cell Membrane / metabolism Cell Polarity / physiology* Colorectal Neoplasms / genetics Colorectal Neoplasms / metabolism Colorectal Neoplasms / pathology* Cytoskeletal Proteins / biosynthesis Cytoskeletal Proteins / genetics Cytoskeletal Proteins / physiology* Doxycycline / pharmacology Epithelial Cells / cytology Epithelial Cells / metabolism Genes, MDR Humans Intestinal Mucosa / cytology Intestinal Mucosa / 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 Transcription Factors / genetics Transcription Factors / physiology* Transcriptional Activation / physiology* Tumor Cells, Cultured Zonula Occludens-1 Protein beta Catenin
IF 9.727
Times Cited 69
Human and Animal Cells 293(RCB1637) IEC 6(RCB0993)