TY - JOUR
T1 - KLF4 regulation in intestinal epithelial cell maturation
AU - Flandez, M.
AU - Guilmeau, S.
AU - Blache, P.
AU - Augenlicht, L. H.
N1 - Funding Information:
We are grateful to Drs. Lidija Klampfer, Anna Velcich, John Mariadason and Barbara Heerdt for their suggestions and critical reading of the manuscript. This work was supported by grants RO1 CA114265, U54 CA100926, PO 13330, and a postdoctoral fellowship to Marta Flandez from the Spanish Ministerio de Educacion y Ciencia.
PY - 2008/12/10
Y1 - 2008/12/10
N2 - The Krüppel-like factor 4 (KLF4) transcription factor suppresses tumorigenesis in gastrointestinal epithelium. Thus, its expression is decreased in gastric and colon cancers. Moreover, KLF4 regulates both differentiation and growth that is likely fundamental to its tumor suppressor activity. We dissected the expression of Klf4 in the normal mouse intestinal epithelium along the crypt-villus and cephalo-caudal axes. Klf4 reached its highest level in differentiated cells of the villus, with levels in the duodenum > jejunum > ileum, in inverse relation to the representation of goblet cells in these regions, the lineage previously linked to KLF4. In parallel, in vitro studies using HT29cl.16E and Caco2 colon cancer cell lines clarified that KLF4 increased coincident with differentiation along both the goblet and absorptive cell lineages, respectively, and that KLF4 levels also increased during differentiation induced by the short chain fatty acid butyrate, independently of cell fate. Moreover, we determined that lower levels of KLF4 expression in the proliferative compartment of the intestinal epithelium are regulated by the transcription factors TCF4 and SOX9, an effector and a target, respectively, of β-catenin/Tcf signaling, and independently of CDX2. Thus, reduced levels of KLF4 tumor suppressor activity in colon tumors may be driven by elevated β-catenin/Tcf signaling.
AB - The Krüppel-like factor 4 (KLF4) transcription factor suppresses tumorigenesis in gastrointestinal epithelium. Thus, its expression is decreased in gastric and colon cancers. Moreover, KLF4 regulates both differentiation and growth that is likely fundamental to its tumor suppressor activity. We dissected the expression of Klf4 in the normal mouse intestinal epithelium along the crypt-villus and cephalo-caudal axes. Klf4 reached its highest level in differentiated cells of the villus, with levels in the duodenum > jejunum > ileum, in inverse relation to the representation of goblet cells in these regions, the lineage previously linked to KLF4. In parallel, in vitro studies using HT29cl.16E and Caco2 colon cancer cell lines clarified that KLF4 increased coincident with differentiation along both the goblet and absorptive cell lineages, respectively, and that KLF4 levels also increased during differentiation induced by the short chain fatty acid butyrate, independently of cell fate. Moreover, we determined that lower levels of KLF4 expression in the proliferative compartment of the intestinal epithelium are regulated by the transcription factors TCF4 and SOX9, an effector and a target, respectively, of β-catenin/Tcf signaling, and independently of CDX2. Thus, reduced levels of KLF4 tumor suppressor activity in colon tumors may be driven by elevated β-catenin/Tcf signaling.
KW - Differentiation
KW - Epithelium
KW - Intestine
KW - KLF4
KW - Sox9
KW - Wnt
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U2 - 10.1016/j.yexcr.2008.10.004
DO - 10.1016/j.yexcr.2008.10.004
M3 - Article
C2 - 18977346
AN - SCOPUS:56249119515
SN - 0014-4827
VL - 314
SP - 3712
EP - 3723
JO - Experimental Cell Research
JF - Experimental Cell Research
IS - 20
ER -