Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 2/2009

01-02-2009 | Hepatobiliary and Pancreatic Tumors

Immunohistochemically Detected Expression of p27Kip1 and Skp2 Predicts Survival in Patients with Intrahepatic Cholangiocarcinomas

Authors: Nozomi Hashimoto, MD, Shinichi Yachida, MD, Keiichi Okano, MD, Hisao Wakabayashi, MD, Katsumi Imaida, MD, Kazutaka Kurokohchi, MD, Tsutomu Masaki, MD, Hisoka Kinoshita, MD, Masahiro Tominaga, MD, Tetsuo Ajiki, MD, Yonson Ku, MD, Takehiro Okabayashi, MD, Kazuhiro Hanazaki, MD, Makoto Hiroi, MD, Sadanobu Izumi, MD, Shohei Mano, MD, Setsuo Okada, MD, Yukihiko Karasawa, MD, Takashi Maeba, MD, Yasuyuki Suzuki, MD

Published in: Annals of Surgical Oncology | Issue 2/2009

Login to get access

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.
Literature
1.
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.
2.
Liver Cancer Study Group of Japan. Primary liver cancer in Japan: clinicopathologic features and results of surgical treatment. Ann Surg. 1990;211:277–87.
3.
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.PubMedCrossRef
4.
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.PubMedCrossRef
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.PubMedCrossRef
6.
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.PubMed
7.
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.PubMedCrossRef
8.
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.PubMed
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.PubMedCrossRef
10.
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.PubMedCrossRef
11.
Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 1995;9:1149–63.PubMedCrossRef
12.
Reed SI, Bailly E, Dulic V, et al. G1 control in mammalian cells. J Cell Sci Suppl. 1994;18:69–73.PubMed
13.
Fero ML, Randel E, Gurley KE, et al. The murine gene p27Kip1 is haplo-insufficient for tumor suppression. Nature. 1998;396:177–80.PubMedCrossRef
14.
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.PubMedCrossRef
15.
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.PubMedCrossRef
16.
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.PubMedCrossRef
17.
Yachida S, Sakamoto M, Imaida K, et al. p27Kip1 is overexpressed in very early stages of hepatocarcinogenesis. Cancer Sci. 2008 (in press).
18.
Lei PP, Zhang ZJ, Shen LJ, et al. Expression and hypermethylation of p27 kip1 in hepatocarcinogenesis. World J Gastroenterol. 2005;29:4587–91.
19.
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.PubMedCrossRef
20.
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.PubMedCrossRef
21.
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.PubMedCrossRef
22.
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.PubMedCrossRef
23.
Tomoda K, Kubota Y, Kato J. Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1. Nature. 1999;398:160–5.PubMedCrossRef
24.
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.PubMedCrossRef
25.
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.PubMedCrossRef
26.
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.PubMed
27.
Sonoda H, Inoue H, Ogawa K, et al. Significance of Skp2 expression in primary breast cancer. Clin Cancer Res. 2006;12:1215–20.PubMedCrossRef
28.
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.PubMedCrossRef
29.
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.PubMedCrossRef
30.
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.PubMedCrossRef
31.
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.PubMedCrossRef
32.
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.PubMedCrossRef
33.
Liver Cancer Study Group of Japan. General rules for the clinical and pathological study of primary liver cancer. Tokyo: Kanehara; 2003.
34.
Yamasaki S. Intrahepatic cholangiocarcinoma: macroscopic type and stage classification. J Hepatobiliary Pancreat Surg. 2003;10:288–91.PubMedCrossRef
35.
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.PubMedCrossRef
36.
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.PubMedCrossRef
37.
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.PubMedCrossRef
38.
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.PubMedCrossRef
39.
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.PubMedCrossRef
40.
Yamamoto M, Takasaki K, Yoshikawa T, et al. Does gross appearance indicate prognosis in intrahepatic cholangiocarcinoma? J Surg Oncol. 1998;69:162–7.PubMedCrossRef
41.
Yeh TS, Chen TC, Chen MF. Dedifferentiation of human hepatocellular carcinoma up-regulates telomerase and Ki-67 expression. Arch Surg. 2000;135:1334–9.PubMedCrossRef
42.
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.PubMedCrossRef
43.
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.PubMed
44.
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.PubMedCrossRef
45.
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.PubMedCrossRef
46.
Chen TC, Ng KF, Lien JM, et al. Mutational analysis of the p27kip1 gene in hepatocellular carcinoma. Cancer Lett. 2000;153:169–73.PubMedCrossRef
47.
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.PubMedCrossRef
48.
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.PubMedCrossRef
49.
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.PubMedCrossRef
50.
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.PubMedCrossRef
51.
Chamovitz DA, Segal D. JAB1/CSN5 and the COP9 signalosome. A complex situation. EMBO Rep. 2001;2:96–101.PubMedCrossRef
52.
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.PubMedCrossRef
53.
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.PubMedCrossRef
54.
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.PubMedCrossRef
55.
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.PubMedCrossRef
56.
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.PubMedCrossRef
57.
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.PubMedCrossRef
Metadata
Title
Immunohistochemically Detected Expression of p27Kip1 and Skp2 Predicts Survival in Patients with Intrahepatic Cholangiocarcinomas
Authors
Nozomi Hashimoto, MD
Shinichi Yachida, MD
Keiichi Okano, MD
Hisao Wakabayashi, MD
Katsumi Imaida, MD
Kazutaka Kurokohchi, MD
Tsutomu Masaki, MD
Hisoka Kinoshita, MD
Masahiro Tominaga, MD
Tetsuo Ajiki, MD
Yonson Ku, MD
Takehiro Okabayashi, MD
Kazuhiro Hanazaki, MD
Makoto Hiroi, MD
Sadanobu Izumi, MD
Shohei Mano, MD
Setsuo Okada, MD
Yukihiko Karasawa, MD
Takashi Maeba, MD
Yasuyuki Suzuki, MD
Publication date
01-02-2009
Publisher
Springer-Verlag
Published in
Annals of Surgical Oncology / Issue 2/2009
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-008-0236-0

Other articles of this Issue 2/2009

Annals of Surgical Oncology 2/2009 Go to the issue

Gastrointestinal Oncology

Patterns of Local Recurrence in Rectal Cancer: A Single-Center Experience

Healthcare Policy and Outcomes

How Good is Endoscopic Ultrasound in Differentiating Various T Stages of Rectal Cancer? Meta-Analysis and Systematic Review

Gastrointestinal Oncology

Polymorphisms of p16, p27, p73, and MDM2 Modulate Response and Survival of Pancreatic Cancer Patients Treated with Preoperative Chemoradiation

Gastrointestinal Oncology

Extracapsular Lymph Node Involvement Differs Between Squamous Cell and Adenocarcinoma of the Esophagus

Gastrointestinal Oncology

Evaluation of Preoperative Computed Tomography in Estimating Peritoneal Cancer Index in Colorectal Peritoneal Carcinomatosis

Gastrointestinal Oncology

Adenocarcinoma of the Esophagogastric Junction: The Role of Abdominal-Transhiatal Resection