Prognostic significance of localized p27Kip1 and potential role of Jab1/CSN5 in pancreatic cancer.
p27Kip1 belongs to the family of small polypeptides collectively termed cyclin-dependent kinase inhibitors, which negatively regulate the cell cycle progression. In various human cancers, the reduced p27Kip1 expression correlates well with poor prognosis. Recently, Jab1/CSN5, the fifth component of the COP9 signalosome complex, was found to specifically translocate p27Kip1 from the nucleus to the cytoplasm, and reduce the protein level of p27Kip1 by accelerating its degradation. In this study, we investigated the expression of p27Kip1 and Jab1 in 61 cases with pancreatic ductal adenocarcinoma. The p27Kip1 expression was positive in 41% (25/61) of the tumors. Of the 25 positive tumors, 12 cases had p27Kip1 positive expression mainly in the nucleus of the tumor cells, while 13 cases had p27Kip1 in the cytoplasm as well as in the nucleus. Among a variety of clinicopathological factors, only tumor status was inversely correlated with p27Kip1 expression (p=0.019). The Jab1 expression was detected both in the nucleus and the cytoplasm in almost all pancreatic cancer cells. The intensity of Jab1 expression in tumor cells, especially in the cytoplasm, was much stronger than in normal pancreatic ductal epithelial cells. The patients with positive p27Kip1 expression had significantly better prognosis than ones with negative p27Kip1 expression (p=0.008). Furthermore, 12 patients with exclusively nuclear p27Kip1 expression, but not 13 patients with both nuclear and cytoplasmic p27Kip1 expression, had significantly better prognosis than 36 patients with negative p27Kip1 expression (p=0.009). In multivariate survival analysis, localized p27Kip1 expression was an independent prognostic factor (p=0.016). The results of our study suggested that the mislocalization as well as the downregulation of p27Kip1 had significant prognostic value in pancreatic cancer and that Jab1 might play an important role in carcinogenesis of pancreatic cancer. Cell cycle control targeting p27Kip1 might be a promising future therapeutic modality against pancreatic cancer.
Fukumoto
Akihisa
A
First Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara-city, Nara 634-8522, Japan.
Ikeda
Naoya
N
Sho
Masayuki
M
Tomoda
Kiichiro
K
Kanehiro
Hiromichi
H
Hisanaga
Michiyoshi
M
Tsurui
Yoshikazu
Y
Tsutsumi
Masahiro
M
Kato
Jun-Ya
JY
Nakajima
Yoshiyuki
Y
D000230:Adenocarcinoma / Q000473:pathology*; D000328:Adult; D000368:Aged; D000075686:COP9 Signalosome Complex; D018797:Cell Cycle Proteins / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins / Q000032:analysis* / Q000378:metabolism*; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D010447:Peptide Hydrolases; D016016:Proportional Hazards Models; D021381:Protein Transport; D016019:Survival Analysis; D014157:Transcription Factors / Q000032:analysis* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex