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

Abstract

The p27(Kip1) protein is a negative regulator of the cell cycle and a potential 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, bladder, and gastric cancers. On the other hand, increased expression of the p27(Kip1) protein, in the absence of gene mutation, has been observed in primary colon and breast cancers. It was recently suggested that sequestration in the cytoplasm might be an alternative way to inactivate p27(Kip1)-associated 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 localization of this protein. Both normal and neoplastic tissues expressed variable amounts of the p27(Kip1) protein, as assessed by western blot analyses. Although the mean values were not different between tumor and normal mucosa samples, the expression of total p27(Kip1) was reduced in a subset of tumors. Decreased 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 difference in nuclear p27(Kip1), the amount of p27(Kip1) in the cytoplasmic fraction was significantly higher in the tumor samples than in the normal mucosa samples (P=0.0001). These results suggest that p27(Kip1) expression is lost in a subset of colorectal tumors and that alterations in the subcellular localization of this protein might play a role in colon carcinogenesis.