1. ¹Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL, USA
2. ²Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA

Correspondence: Dr EA Thompson or Dr AP Fields, Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Griffin Cancer Research Building, RM310, Jacksonville, FL 32224, USA. E-mails: thompson.aubrey@mayo.edu or fields.alan@mayo.edu

Received 23 September 2005; Revised 1 December 2005; Accepted 14 December 2005; Published online 6 February 2006.

Abstract

In hematopoietic cells the transforming potential of the ecotropic viral integration site 1 (Evi1) oncogene is thought to be dependent upon the ability to inhibit TGF signaling. Although Evi1 has recently been implicated in certain epithelial cancers, the effects of Evi1 on transformation and TGF signaling in epithelial cells are not completely understood. Herein, we have determined the effects of Evi1 on TGF signaling in intestinal epithelial cells. Stable expression of Evi1 in non-transformed intestinal epithelial cells inhibited induction of some Smad3-dependent TGF target genes, such as PAI1. However, TGF-mediated induction of cellular adhesion signaling components such as integrin1 and paxillin was not inhibited by Evi1; nor did Evi1 inhibit TGF-mediated epithelial to mesenchymal transition. Likewise, Evi1 did not inhibit TGF-mediated downregulation of cyclin D1 or block TGF-mediated growth inhibition. However, Evi1 did inhibit TGF-mediated apoptosis by a process that involves phosphoinositide-3-kinase (PI3K) and its downstream effector AKT. The ability of Evi1 to suppress apoptosis is not restricted to TGF-mediated cell death, since Evi1 also protects intestinal epithelial cells from taxol-mediated apoptosis. Evi1 is overexpressed in some human colon cancer cell lines, and overexpression is associated with amplification of the Evi1 gene. Knockdown of Evi1 by siRNA inhibited AKT phosphorylation in HT-29 human colon cancer cells and increased their sensitivity to taxol-mediated apoptosis. These data indicate that Evi1 functions as a survival gene in intestinal epithelial cells and colon cancer cells, activating PI3K/AKT and conveying resistance to both physiological and therapeutic apoptotic stimuli.