Immunohistochemically detected expression of p27(Kip1) and Skp2 predicts survival in patients with intrahepatic cholangiocarcinomas

Ann Surg Oncol. 2009 Feb;16(2):395-403. doi: 10.1245/s10434-008-0236-0. Epub 2008 Nov 26.


In intrahepatic cholangiocarcinomas (ICCs), the prognostic significance of p27(Kip1), a cyclin-dependent kinase inhibitor, remains controversial, and there have been no studies of degradation pathway associated proteins, S-phase kinase-interacting protein (Skp2), and Jun activation domain-binding protein-1 (Jab1). In the present study of 74 patients with ICC-mass forming type (ICC-MF) undergoing radical surgery, we determined immunohistochemical expression of p27(Kip1), Skp2, and Jab1 and examined relationships with clinicopathologic findings and patient survival. On the basis of the average of labeling indices, we set cutoff values to define high and low expressors and divided the cases into two groups. A statistically significant correlation was found between low p27(Kip1) expression and lymph node metastasis (P = .009). Patient survival in the low p27(Kip1) expression group (n = 25) was also significantly worse than that in the high p27(Kip1) expression group (n = 49, P = .0007). A significant inverse correlation was found between p27(Kip1) and Skp2 expression (P = .016). High Skp2 expression (n = 36) was significantly associated with poor prognosis (P = .0046). High Jab1 expression was observed in 32 cases, but there was no statistically significant relationship with clinicopathologic findings or patient survival. The multivariate analysis revealed that low p27(Kip1) and high Skp2 expression are independent and significant factors of poor prognosis. The results suggest that low p27(Kip1) and high Skp2 expression are associated with aggressive tumor behavior, and these cell-cycle regulators are useful markers to predict outcome of patients with ICC-MF.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Bile Duct Neoplasms / metabolism
  • Bile Duct Neoplasms / mortality*
  • Bile Duct Neoplasms / pathology
  • Bile Ducts, Intrahepatic*
  • Biomarkers, Tumor / metabolism
  • COP9 Signalosome Complex
  • Cholangiocarcinoma / metabolism
  • Cholangiocarcinoma / mortality*
  • Cholangiocarcinoma / pathology
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism*
  • Female
  • Hepatocytes / metabolism
  • Humans
  • Immunoenzyme Techniques
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lymphatic Metastasis
  • Male
  • Middle Aged
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Peptide Hydrolases / metabolism
  • Prognosis
  • S-Phase Kinase-Associated Proteins / metabolism*
  • Survival Rate


  • Biomarkers, Tumor
  • Intracellular Signaling Peptides and Proteins
  • S-Phase Kinase-Associated Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Peptide Hydrolases
  • COPS5 protein, human
  • COP9 Signalosome Complex