Abstract
In intrahepatic cholangiocarcinomas (ICCs), the prognostic significance of p27Kip1, 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 p27Kip1, 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 p27Kip1 expression and lymph node metastasis (P = .009). Patient survival in the low p27Kip1 expression group (n = 25) was also significantly worse than that in the high p27Kip1 expression group (n = 49, P = .0007). A significant inverse correlation was found between p27Kip1 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 p27Kip1 and high Skp2 expression are independent and significant factors of poor prognosis. The results suggest that low p27Kip1 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.
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References
Nakanuma Y, Sripa B, Vatanasapt V, et al. Intrahepatic cholangiocarcinoma. In: Hamilton SR, Aaltonen LA, editors. Pathology and genetics of tumours of the digestive system. Lyon: IARC Press; 2000. p. 173–80.
Liver Cancer Study Group of Japan. Primary liver cancer in Japan: clinicopathologic features and results of surgical treatment. Ann Surg. 1990;211:277–87.
Sano T, Shimada K, Sakamoto Y, et al. Prognosis of perihilar cholangiocarcinoma: hilar bile duct cancer versus intrahepatic cholangiocarcinoma involving the hepatic hilus. Ann Surg Oncol. 2008;15:590–9.
Shimada K, Sano T, Sakamoto Y, et al. Clinical impact of the surgical margin status in hepatectomy for solitary mass-forming type intrahepatic cholangiocarcinoma without lymph node metastases. J Surg Oncol. 2007;96:160–5.
Miwa S, Miyagawa S, Kobayashi A, et al. Predictive factors for intrahepatic cholangiocarcinoma recurrence in the liver following surgery. J Gastroenterol. 2006;41:893–900.
Hanazaki K, Kajikawa S, Shimozawa N, et al. Prognostic factors of intrahepatic cholangiocarcinoma after hepatic resection: univariate and multivariate analysis. Hepatogastroenterology. 2002;49:311–6.
Taguchi K, Aishima S, Asayama Y, et al. The role of p27kip1 protein expression on the biological behavior of intrahepatic cholangiocarcinoma. Hepatology. 2001;33:1118–23.
Fiorentino M, Altimari A, D’Errico A, et al. Low p27 expression is an independent predictor of survival for patients with either hilar or peripheral intrahepatic cholangiocarcinoma. Clin Cancer Res. 2001;7:3994–9.
Shibahara H, Tamada S, Higashi M, et al. MUC4 is a novel prognostic factor of intrahepatic cholangiocarcinoma-mass forming type. Hepatology. 2004;39:220–9.
Polyak K, Lee MH, Erdjument-Bromage H, et al. Cloning p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell. 1994;78:59–66.
Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 1995;9:1149–63.
Reed SI, Bailly E, Dulic V, et al. G1 control in mammalian cells. J Cell Sci Suppl. 1994;18:69–73.
Fero ML, Randel E, Gurley KE, et al. The murine gene p27Kip1 is haplo-insufficient for tumor suppression. Nature. 1998;396:177–80.
Lee MH, Reynisdottir I, Massague J. Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev. 1995;9:639–49.
Nozoe T, Oyama T, Takenoyama M, et al. Significance of immunohistochemical expression of p27 and involucrin as the marker of cellular differentiation of squamous cell carcinoma of the esophagus. Oncology. 2006;71:402–10.
Galizia G, Lieto E, Ferraraccio F, et al. Prognostic significance of epidermal growth factor receptor expression in colon cancer patients undergoing curative surgery. Ann Surg Oncol. 2006;13:823–35.
Yachida S, Sakamoto M, Imaida K, et al. p27Kip1 is overexpressed in very early stages of hepatocarcinogenesis. Cancer Sci. 2008 (in press).
Lei PP, Zhang ZJ, Shen LJ, et al. Expression and hypermethylation of p27 kip1 in hepatocarcinogenesis. World J Gastroenterol. 2005;29:4587–91.
Shintani S, Li C, Mihara M, et al. Skp2 and Jab1 expression is associated with inverse expression of p27KIP1 and poor prognosis in oral squamous cell carcinomas. Oncology. 2003;65:355–62.
Goto A, Niki T, Moriyama S, et al. Immunohistochemical study of Skp2 and Jab1, two key molecules in the degradation of P27, in lung adenocarcinoma. Pathol Int. 2004;54:675–81.
Carrano AC, Eytan E, Hershko A, et al. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol. 1999;1:193–9.
Sutterlüty H, Chatelain E, Marti A, et al. p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells. Nat Cell Biol. 1999;1:207–14.
Tomoda K, Kubota Y, Kato J. Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1. Nature. 1999;398:160–5.
Tomoda K, Kubota Y, Arata Y, et al. The cytoplasmic shuttling and subsequent degradation of p27Kip1 mediated by Jab1/CSN5 and the COP9 signalosome complex. J Biol Chem. 2002;277:2302–10.
Gstaiger M, Jordan R, Lim M, et al. Skp2 is oncogenic and overexpressed in human cancers. Proc Natl Acad Sci USA. 2001;98:5043–8.
Masuda T, Inoue H, Sonoda H, et al. Clinical and biological significance of S-phase kinase-associated protein 2 (Skp2) gene expression in gastric carcinoma: modulation of malignant phenotype by Skp2 overexpression, possibly via p27 proteolysis. Cancer Res. 2002;62:3819–25.
Sonoda H, Inoue H, Ogawa K, et al. Significance of Skp2 expression in primary breast cancer. Clin Cancer Res. 2006;12:1215–20.
Seki R, Okamura T, Koga H, et al. Prognostic significance of the F-box protein Skp2 expression in diffuse large B-cell lymphoma. Am J Hematol. 2003;73:230–5.
Osoegawa A, Yoshino I, Kometani T, et al. Overexpression of Jun activation domain-binding protein 1 in nonsmall cell lung cancer and its significance in p27 expression and clinical features. Cancer. 2006;107:154–61.
Berg JP, Zhou Q, Breuhahn K, et al. Inverse expression of Jun activation domain binding protein 1 and cell cycle inhibitor p27Kip1: influence on proliferation in hepatocellular carcinoma. Hum Pathol. 2007;38:1621–7.
Patil MA, Gütgemann I, Zhang J, et al. Array-based comparative genomic hybridization reveals recurrent chromosomal aberrations and Jab1 as a potential target for 8q gain in hepatocellular carcinoma. Carcinogenesis. 2005;26:2050–7.
Kouvaraki MA, Korapati AL, Rassidakis GZ, et al. Potential role of Jun activation domain-binding protein 1 as a negative regulator of p27kip1 in pancreatic adenocarcinoma. Cancer Res. 2006;66:8581–9.
Liver Cancer Study Group of Japan. General rules for the clinical and pathological study of primary liver cancer. Tokyo: Kanehara; 2003.
Yamasaki S. Intrahepatic cholangiocarcinoma: macroscopic type and stage classification. J Hepatobiliary Pancreat Surg. 2003;10:288–91.
Shimada K, Sano T, Sakamoto Y, et al. Surgical outcomes of the mass-forming plus periductal infiltration types of intrahepatic cholangiocarcinoma: a comparative study with the typical mass-forming type of intrahepatic cholangiocarcinoma. World J Surg. 2007;31:2016–22.
Morimoto Y, Tanaka Y, Ito T, et al. Long-term survival and prognostic factors in the surgical treatment for intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg. 2003;10:432–40.
Ohashi K, Nakajima Y, Kanehiro H, et al. Ki-ras mutations and p53 protein expressions in intrahepatic cholangiocarcinomas: relation to gross tumor morphology. Gastroenterology. 1995;109:1612–7.
Suh KS, Chang SH, Lee HJ, et al. Clinical outcomes and apomucin expression of intrahepatic cholangiocarcinoma according to gross morphology. J Am Coll Surg. 2002;195:782–9.
Ohtsuka M, Ito H, Kimura F, et al. Results of surgical treatment for intrahepatic cholangiocarcinoma and clinicopathological factors influencing survival. Br J Surg. 2002;89:1525–31.
Yamamoto M, Takasaki K, Yoshikawa T, et al. Does gross appearance indicate prognosis in intrahepatic cholangiocarcinoma? J Surg Oncol. 1998;69:162–7.
Yeh TS, Chen TC, Chen MF. Dedifferentiation of human hepatocellular carcinoma up-regulates telomerase and Ki-67 expression. Arch Surg. 2000;135:1334–9.
Okabayashi T, Yamamoto J, Kosuge T, et al. A new staging system for mass-forming intrahepatic cholangiocarcinoma: analysis of preoperative and postoperative variables. Cancer. 2001;92:2374–83.
Masciullo V, Susini T, Zamparelli A, et al. Frequent loss of expression of the cyclin-dependent kinase inhibitor p27Kip1 in estrogen-related endometrial adenocarcinomas. Clin Cancer Res. 2003;9:5332–8.
Rodolico V, Cabibi D, Pizzolanti G, et al. BRAFV600E mutation and p27 kip1 expression in papillary carcinomas of the thyroid < or = 1 cm and their paired lymph node metastases. Cancer. 2007;110:1218–26.
Gao Y, Kitagawa K, Hiramatsu Y, et al. Up-regulation of GPR48 induced by down-regulation of p27Kip1 enhances carcinoma cell invasiveness and metastasis. Cancer Res. 2006;66:11623–31.
Chen TC, Ng KF, Lien JM, et al. Mutational analysis of the p27kip1 gene in hepatocellular carcinoma. Cancer Lett. 2000;153:169–73.
Timmerbeul I, Garrett-Engele CM, Kossatz U, et al. Testing the importance of p27 degradation by the SCFskp2 pathway in murine models of lung and colon cancer. Proc Natl Acad Sci USA. 2006;103:14009–14.
Li SH, Li CF, Sung MT, et al. Skp2 is an independent prognosticator of gallbladder carcinoma among p27Kip1-interacting cell cycle regulators: an immunohistochemical study of 62 cases by tissue microarray. Mod Pathol. 2007;20:497–507.
Nakayama K, Nagahama H, Minamishima YA, et al. Targeted disruption of Skp2 results in accumulation of cyclin E and p27Kip1, polyploidy and centrosome overduplication. EMBO J. 2000;19:2069–81.
Chiappetta G, De Marco C, Quintiero A, et al. Overexpression of the S-phase kinase-associated protein 2 in thyroid cancer. Endocr Relat Cancer. 2007;14:405–20.
Chamovitz DA, Segal D. JAB1/CSN5 and the COP9 signalosome. A complex situation. EMBO Rep. 2001;2:96–101.
Bianchi E, Denti S, Granata A, et al. Integrin LFA-1 interacts with the transcriptional co-activator JAB1 to modulate AP-1 activity. Nature. 2000;404:617–21.
Kleemann R, Hausser A, Geiger G, et al. Intracelluar action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1. Nature. 2000;408:211–6.
Cope GA, Suh GS, Aravind L, et al. Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of Nedd8 from Cul1. Science. 2002;298:608–11.
Bech-Otschir D, Kraft R, Huang X, et al. COP9 signalosome-specific phosphorylation targets p53 to degradation by the ubiquitin system. EMBO J. 2001;20:1630–9.
Hara T, Kamura T, Nakayama K, et al. Degradation of p27Kip1 at the G0–G1 transition mediated by a Skp2-independent ubiquitination pathway. J Biol Chem. 2001;276:48937–43.
Kotoshiba S, Kamura T, Hara T, et al. Molecular dissection of the interaction between p27 and Kip1 ubiquitylation-promoting complex, the ubiquitin ligase that regulates proteolysis of p27 in G1 phase. J Biol Chem. 2005;280:17694–700.
Acknowledgments
We thank Dr. Kousuke Saoo, Kagawa University, for access to archival material. We also thank Yukie Yoshino, Satomi Saijo, Mizuho Kuroda, and Aya Hashimoto for their expert technical assistance. This work was supported by a Grant-in-Aid for Scientific Research (15790717, 17790919) from the Ministry of Education, Science and Culture of Japan.
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Hashimoto, N., Yachida, S., Okano, K. et al. Immunohistochemically Detected Expression of p27Kip1 and Skp2 Predicts Survival in Patients with Intrahepatic Cholangiocarcinomas. Ann Surg Oncol 16, 395–403 (2009). https://doi.org/10.1245/s10434-008-0236-0
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DOI: https://doi.org/10.1245/s10434-008-0236-0