Reduced expression and altered subcellular localization of the cyclin-dependent kinase inhibitor p27(Kip1) in human colon cancer

The p27(Kip1) protein is a negative regulator of the cell cycle and a poten tial tumor suppressor gene. Reduced expression of the p27(KiP1) protein has been reported in several human tumors and has been associated with higher tumor grade and increased mortality in breast, lung, colon, prostate, bladd er, and gastric cancers. On the other hand, increased expression of the p27 (Kip1) protein, in the absence of gene mutation, has been observed in prima ry colon and breast cancers. It was recently suggested that sequestration i n the cytoplasm might be an alternative way to inactivate p27(KiP1)-associa ted inhibitory activity. This study was undertaken to further evaluate p27( Kip1) expression in primary colon tumors and to verify whether differences exist between normal and cancer tissues in terms of subcellular localizatio n of this protein. Both normal and neoplastic tissues expressed variable am ounts of the p27(Kip1) protein, as assessed by western blot analyses. Altho ugh the mean values were not different between tumor and normal mucosa samp les, the expression of total p27(Kip1) was reduced in a subset of tumors. D ecreased levels of total p27(Kip1) were associated with high tumor grade (P =0.03) and stage (P=0.04). Moreover, while there was no significant differe nce in nuclear p27(Kip1) the amount of p27(Kip1) in the cytoplasmic fractio n was significantly higher in the tumor samples than in the normal mucosa s amples (P=0.0001). These results suggest that p27(Kip1) expression is lost in a subset of colorectal tumors and that alterations in the subcellular lo calization of this protein might play a role in colon carcinogenesis. (C) 1 999 Wiley-Liss, Inc.