p27Kip1 expression in normal epithelia, precancerous lesions, and carcinomas of the gallbladder: Association with cancer progression and prognosis

Abstract

p27 Kip1 is a cyclin-dependent kinase inhibitor that negatively regulates cell proliferation. This study was designed to evaluate the roles of p27 Kip1 in gallbladder carcinogenesis and the prognostic value of p27 Kip1 in patients with gallbladder carcinoma. p27 Kip1 expression was examined immunohistochemically in surgically resected specimens of 8 normal epithelia, 8 adenomyomatosis lesions, 6 precancerous adenomas, and 37 carcinomas of the gallbladder. Decreased p27 Kip1 expression (F50% nuclear staining) was observed in 16 of the 37 (43%) gallbladder carcinomas, but not in any specimen of normal epithelium, adenomyomatosis, or adenoma. The fact that all of the adenomas showed normal p27 Kip1 expression suggests that decreased p27 Kip1 expression is probably not an early event in gallbladder carcinogenesis. Decreased p27 Kip1 expression was significantly associated with less marked tumor cell differentiation (P ‫؍‬ .017), lymphatic invasion (P ‫؍‬ .046), lymph node metastasis (P ‫؍‬ .007), and advanced TNM stage (stage IV vs. stage I, P ‫؍‬ .026; stage IV vs. stage II, P ‫؍‬ .005). This suggests that down-regulation of p27 Kip1 expression is a late event in gallbladder carcinogenesis, possibly promoting tumor progression and metastasis. Kaplan-Meier curves showed that decreased p27 Kip1 expression was significantly associated with shorter overall survival (P ‫؍‬ .001) in patients with gallbladder carcinomas who had undergone radical surgery. Cox's proportional hazards model revealed decreased p27 Kip1 expression to be an independent predictor for death (P ‫؍‬ .034; risk ratio, 3.9; 95% confidence interval, 1.1-13.7). In conclusion, decreased p27 Kip1 expression significantly correlates with tumor progression and predicts poor prognosis in gallbladder carcinomas. (HEPATOLOGY 2000;31:1068-1072.)

Skp2 is an independent prognosticator of gallbladder carcinoma among p27Kip1-interacting cell cycle regulators: an immunohistochemical study of 62 cases by tissue microarray

“…Actually, a considerable proportion of these stage I gallbladder carcinomas were incidentally found and treated by simple cholecystectomy for other clinical manifestations. This was different from the series of Hui et al 20 and Filpits et al, 19 which respectively enrolled as high as 70 and 92% of gallbladder carcinomas with advanced presenting stage.…”

“…19,20 This discrepancy might be ascribed to the following reasons. First, we found 20% reactivity of p27…”

“…19,20 Insufficient formalin fixation in some specimens has been shown to result in artificial reduced labeling of p27 Kip1 in TMA, which might therefore hamper its scoring wherein a loss or decrease in nuclear staining is interpreted as aberrant. 34 More likely, the root cause might stem from the distribution of presenting stages in different study cohorts.…”

“…9,13 Reduced expression of p27 Kip1 protein was recently found correlated with tumor progression and prognosis in gallbladder carcinoma. 19,20 However, downregulation of p27 Kip1 mRNA is rarely observed in human malignancies. 9 Instead, it becomes apparent that aberrant loss of p27 Kip1 protein in malignant diseases results mainly from enhanced ubiquitin-mediated proteolysis regulated by Skp2, a member of the F-box protein family, which targets Thr 187 -phosphorylated p27 Kip1 for degradation.…”

Factors That Influence the Measurement of Prostate Cancer DNA Ploidy and Proliferation in Paraffin Embedded Tissue Evaluated by Flow Cytometry

“…Therefore, our statistical power to detect a significant association between the amount of tumor in the block and DNA ploidy in the subset of tetraploid and aneuploid cases was limited. Proliferation as a prognostic marker in prostate cancer, although less well defined, has also been shown to be a marker for outcome (22,(37)(38)(39). We wanted to investigate what, if any, impact the above-noted histologic features had on the proliferation indices (%S and %S ϩ %G2M) quantified by FCM.…”