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Vol. 18, Issue 11, 4245-4260, November 2007

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Parallels between Global Transcriptional Programs of Polarizing Caco-2 Intestinal Epithelial Cells In Vitro and Gene Expression Programs in Normal Colon and Colon Cancer

Annika M. Sääf^*,, Jennifer M. Halbleib^,, Xin Chen, Siu Tsan Yuen^||, Suet Yi Leung^||, W. James Nelson^,¶, and Patrick O. Brown^*,#

Departments of *Biochemistry, Molecular and Cellular Physiology, and ^¶Biological Sciences and ^#Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305; University of California San Francisco, San Francisco, CA 94143; and ^||Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong

Submitted April 5, 2007; Revised July 26, 2007; Accepted August 8, 2007
Monitoring Editor: Sandra Schmid

Posttranslational mechanisms are implicated in the development of epithelial cell polarity, but little is known about the patterns of gene expression and transcriptional regulation during this process. We characterized temporal patterns of gene expression during cell–cell adhesion-initiated polarization of cultured human Caco-2 cells, which develop structural and functional polarity resembling enterocytes in vivo. A distinctive switch in gene expression patterns occurred upon formation of cell–cell contacts. Comparison to gene expression patterns in normal human colon and colon tumors revealed that the pattern in proliferating, nonpolarized Caco-2 cells paralleled patterns seen in human colon cancer in vivo, including expression of genes involved in cell proliferation. The pattern switched in polarized Caco-2 cells to one more closely resembling that in normal colon tissue, indicating that regulation of transcription underlying Caco-2 cell polarization is similar to that during enterocyte differentiation in vivo. Surprisingly, the temporal program of gene expression in polarizing Caco-2 cells involved changes in signaling pathways (e.g., Wnt, Hh, BMP, FGF) in patterns similar to those during migration and differentiation of intestinal epithelial cells in vivo, despite the absence of morphogen gradients and interactions with stromal cells characteristic of enterocyte differentiation in situ. The full data set is available at http://microarray-pubs.stanford.edu/CACO2.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

These authors contributed equally to this work.

Address correspondence to: Patrick O. Brown (pbrown{at}cmgm.stanford.edu) or W. James Nelson (wjnelson{at}stanford.edu).

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