Down-Regulation of p27 Is Associated with Development of Colorectal Adenocarcinoma Metastases

Abstract

The cyclin-dependent kinase inhibitor p27 is a negative regulator of the cell cycle and a potential tumor suppressor gene. Because we had previously demonstrated that loss of p27 protein is associated with aggressive behavior in colorectal adenocarcinomas, we used immunohistochemistry and in situ hybridization to evaluate the potential role of alterations in p27 expression in primary and metastatic colorectal adenocarcinomas. Parallel immunostaining was performed for Ki-67 and p53. We evaluated 13 cases of metachronous and 23 cases of synchronous primary and metastatic colorectal tumor pairs. In the synchronous subgroup (Stage IV tumors) , 57% of the primary tumor and metastases pairs did not express p27 protein and the remainder were low expressors. In the metachronous subgroup , 54% of the primary tumors were low expressors and the remainder high expressors of p27 protein. There was a significant reduction in the expression of p27 in the metachronous metastases (mean positive cells: 14.5%) when compared to the corresponding primary tumors (mean positive cells: 41.8%) , P ‫؍‬ 0.0023. All the primary and metastatic tumors in the metachronous subgroup showed high levels of p27 mRNA expression. There was no association between loss of p27 and either Ki-67 count or p53 expression. Because p27 is known to be up-regulated when epithelial cells are grown in suspension , the down-regulation of p27 in circulating tumor cells may confer the ability to grow in an environment of altered extracellular matrix or intercellular adhesion properties, two situations which may facilitate metastases. (Am J Pathol 1998, 153:681-687)

Proliferation and Cdk4 expression in microsatellite unstable colon cancers with TGFBR2 mutations

“…Cyclin D1 and cdk4 were selected as candidates because they are overexpressed in some human colon cancers, and p27 Kip1 was selected because it is underexpressed in approximately 10-80% of colon cancers, depending on the stage of the cancer. 38,47,63 Furthermore, TGF-b has been shown to regulate the expression of cyclin D1 in intestinal epithelial cells and also to regulate the transcription and translation of cdk4 in Mv1Lu cells. 26,64,65 Finally, TGF-b has also been shown to regulate the transcription and translation of p27 Kip1 in epithelial cells and to affect protein interactions of this cdk inhibitor that regulate its cellular localization.…”

“…This scoring procedure should be regarded as semiquantitative and is analogous to the immunohistochemical analysis employed in other studies of colon tumors. [47][48][49][50][51] Cell lines and plasmids…”

Overexpression of cyclin D1 and interaction between p27Kip1 and tumour thickness predict lymph node metastases occurrence in lower lip squamous cell carcinoma

“…It has been shown that patients with colorectal, 17 breast, 14 prostate, 15 or non-small cell lung cancer 12 with low or absent p27 Kip1 protein expression had a poor prognosis. It has been reported that p27…”

“…Kip1 have been shown to predict lymph node metastases in several malignancies [8][9][10]17,18 ; their role in predicting lymph node metastases in LLSCC, however, has still not been investigated. The aim of the present study was to ascertain whether the cyclin D1 and p27…”

Expression of cell cycle inhibitor p27Kip1 and its inactivator Jab1 in melanocytic lesions

“…38 Thus, we can reasonably speculate that reduced expression of p27 in metastatic melanomas might be involved in tumor progression and associated with metastatic potential. Therefore, detection of low levels of p27 may become a useful predictor of aggressive primary melanomas, as suggested in a recent study.…”