Low expression of ORF4, a dominant negative variant of peroxisome proliferator-activated receptor gamma, in colorectal adenocarcinoma.

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have been demonstrated to exert an inhibitory effect on cell growth, and to induce the cell differentiation and apoptosis of colorectal cancer cells. PPARgamma was therefore proposed as a therapeutic target. Recently, a variant of PPARgamma which functions as a dominant negative (ORF4) was described. Expression of this protein may prevent PPARgamma ligand efficiency in colon cancer treatment. In an effort to evaluate the importance of this variant, we determined the expression level of PPARgamma and that of the splicing variant ORF4 in a series of 28 human colon adenocarcinomas relative to paired normal mucosa by real-time PCR. PPARgamma expression was found to be heterogeneous among tumors. ORF4 was also expressed, but represented <10% of the PPARgamma transcripts. This low level was also found in several human colon cancer cell lines treated or not with a specific PPARgamma ligand in preparations of isolated human colonic epithelial cells and in mouse colon. We conclude that ORF4 expression is a general phenomenon, and that its low level should not affect the efficiency of selective PPARgamma modulators in colon cancer treatment.