Decreased P27 Kip1 Expression Research Articles

Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2+/- cells.

Tuberous sclerosis complex (TSC) is an autosomal dominant tumor predisposition syndrome characterized by benign proliferations (hamartomas). In the brain, individuals with TSC develop autism, mental retardation and seizures associated with focal cortical dysplasias, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs). We hypothesize that dysregulated astrocyte function due to mutations in the tumor suppressor genes, TSC1 and TSC2, may contribute to the pathogenesis of these brain abnormalities. In this report, we demonstrate that mice heterozygous for a targeted defect in either the Tsc1 or Tsc2 genes(Tsc1+/- and Tsc2+/- mice) exhibit a 1.5-fold increase in the number of astrocytes in vivo. Whereas increased astrocyte numbers in vivo were suggestive of a proliferative advantage, Tsc2+/- primary astrocyte cultures did not show a cell-autonomous growth advantage, anchorage-independent growth, increased saturation density, or increased fluid-phase endocytosis compared to wild type astrocytes. Tsc2 null mouse embryonic fibroblasts (MEFs) however, did exhibit increased saturation density compared to Tsc2 wild type controls. In both Tsc2+/- astrocytes and Tsc2 null mouse embryonic fibroblasts, p27-Kip1 expression was decreased compared to wild type cells, and was reversed by tuberin re-expression in Tsc2-/- MEFs. In contrast, no change in endocytosis was observed upon tuberin re-expression in Tsc2-/- MEFs. Collectively, these results suggest Tsc heterozygosity may provide a non-cell-autonomous growth advantage for astrocytes that may involve p27-Kip1 expression.

The combined evaluation of p27Kip1 and Ki-67 expression provides independent information on overall survival of ovarian carcinoma patients.

Considering the limited and controversial information on the significance of the cyclin-dependent kinase inhibitor p27Kip1 in ovarian cancer, we conducted a retrospective investigation to clarify the relationships of this protein to proliferation rate, clinicopathologic variables, and prognosis of epithelial ovarian tumors. Paraffin-embedded tissue from 43 ovarian tumors of low malignant potential (LMP) and 80 primary ovarian adenocarcinomas was stained immunohistochemically for p27Kip1, Ki-67 antigen (a marker of cell proliferation), and p53 protein. Expression of these markers was correlated with clinicopathologic features and with overall survival of patients with adenocarcinomas. p27Kip1 levels were significantly higher in LMP tumors as well as in low-grade, early-stage, slowly proliferating adenocarcinomas and those associated with minimal residual disease (P < 0.001). Decreased p27Kip1 expression was related to poor overall survival on its own (P = 0.0304) and, when combined, to increased proliferation rate (P = 0.0232). More importantly, in multivariate analysis, p27Kip1/Ki-67 status was independently related to survival (P = 0.040) along with histologic type and FIGO stage. Decreased p27Kip1 expression is related to several clinicopathologic indicators of aggressiveness in ovarian adenocarcinomas and is a major player in cell cycle control in these neoplasms. On the contrary, deregulation of the protein does not seem to participate in the pathogenesis of LMP tumors. Furthermore, combined p27Kip1/Ki-67 expression is a better prognostic marker than expression of p27Kip1 or Ki-67 alone and supplements the prognostic information gained from traditional prognosticators.

Decreased p27(Kip1) expression and cyclin D1 overexpression, alone and in combination, influence recurrence and survival of patients with resectable extrahepatic bile duct carcinoma.

This study was undertaken to identify potential abnormalities of p27(Kip1) and cyclin D1 expression in extrahepatic bile duct carcinomas and to assess the prognostic significance of p27(Kip1) and cyclin D1 levels for patients with this disease. Decreased p27(Kip1) expression (<50% nuclei staining) and cyclin D1 overexpression (>5% nuclei staining) was observed immunohistochemically in 19 (56%) and 23 (68%) of the 34 tumors examined, respectively. Both decreased p27(Kip1) and cyclin D1 overexpression were associated with relapse (P =.0005 for p27(Kip1) and P =.0004 for cyclin D1). Kaplan-Meier curves showed that both decreased p27(Kip1) and cyclin D1 overexpression correlate significantly with shortened survival rates (for p27(Kip1), P =.0419 and P =.002 for overall and disease-free survival; for cyclin D1, P =.0392 and P =.0021 for overall and disease-free survival). Cox regression model analyses identified decreased p27(Kip1) and cyclin D1 overexpression as independent markers predicting death from relapse (P =.0371, risk ratio: 3.891 for p27(Kip1); P =.0429, risk ratio: 8.31 for cyclin D1). Decreased p27(Kip1) was associated with cyclin D1 overexpression (P =.0202), and coincident abnormalities of the 2 proteins occurred in 16 of the 34 (47%) tumors, indicating that extrahepatic bile duct carcinoma progression may require synchronous dysfunction of p27(Kip1) and cyclin D1 in about half of patients. Patients with tumors showing coincident abnormalities of p27(Kip1) and cyclin D1 showed even more frequent recurrence than patients with an alteration in only 1 of the 2 proteins. In conclusion, decreased p27(Kip1) expression and cyclin D1 overexpression, alone and in combination, predict poor prognosis in patients with resectable extrahepatic bile duct carcinoma.

Impact of the expression of cyclin-dependent kinase inhibitor p27Kip1 and apoptosis in tumor cells on the overall survival of patients with non-Early stage gastric carcinoma

The expression of p27Kip1 and apoptosis have been implicated in tumor aggressiveness and proved to be prognostic predictors for several human malignancies. In this study, the authors sought to investigate the expression of p27Kip1 and apoptosis and their potential significance in determining the prognosis of patients with non-early stage gastric carcinoma. Primary gastric tumor specimens from 225 patients were investigated by immunohistochemistry with anti-p27Kip1 and anti-Ki-67 antibodies, and their apoptotic indices were determined with the use of an Apop-Tag in situ detection kit. The median p27Kip1 labeling index (LI) was 48.4%. There was a significant association between the p27 LIs and the apoptotic indices (Als). However, there was no association between the p27 LIs and the Ki-67 LIs. p27 LI was demonstrated to be one of the most significant and independent prognostic factors in multivariate analysis. Although AI was found to be prognostically significant in univariate analysis, it failed to retain an independent and significant value regarding overall survival in multivariate analysis. Decreased expression of p27Kip1 and reduction of apoptotic potential were two of the most important factors in predicting a poor prognosis for patients with non-early stage gastric carcinoma. These findings support the hypothesis that decreased p27Kip1 expression, which may reflect a decreased rate of apoptosis, is closely related to the aggressiveness of gastric carcinoma. Therefore, the assessment of p27Kip1 expression and apoptotic potential may prove valuable in identifying patients with gastric carcinoma who are at high risk for recurrence and would benefit from adjuvant therapy.