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

  • Hepatobiliary and Pancreatic Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

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

  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.

    Google Scholar 

  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.

    Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  11. Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 1995;9:1149–63.

    Article  PubMed  CAS  Google Scholar 

  12. Reed SI, Bailly E, Dulic V, et al. G1 control in mammalian cells. J Cell Sci Suppl. 1994;18:69–73.

    PubMed  CAS  Google Scholar 

  13. Fero ML, Randel E, Gurley KE, et al. The murine gene p27Kip1 is haplo-insufficient for tumor suppression. Nature. 1998;396:177–80.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  23. Tomoda K, Kubota Y, Kato J. Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1. Nature. 1999;398:160–5.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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  CAS  Google Scholar 

  27. Sonoda H, Inoue H, Ogawa K, et al. Significance of Skp2 expression in primary breast cancer. Clin Cancer Res. 2006;12:1215–20.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  33. Liver Cancer Study Group of Japan. General rules for the clinical and pathological study of primary liver cancer. Tokyo: Kanehara; 2003.

    Google Scholar 

  34. Yamasaki S. Intrahepatic cholangiocarcinoma: macroscopic type and stage classification. J Hepatobiliary Pancreat Surg. 2003;10:288–91.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  40. Yamamoto M, Takasaki K, Yoshikawa T, et al. Does gross appearance indicate prognosis in intrahepatic cholangiocarcinoma? J Surg Oncol. 1998;69:162–7.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  46. Chen TC, Ng KF, Lien JM, et al. Mutational analysis of the p27kip1 gene in hepatocellular carcinoma. Cancer Lett. 2000;153:169–73.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  51. Chamovitz DA, Segal D. JAB1/CSN5 and the COP9 signalosome. A complex situation. EMBO Rep. 2001;2:96–101.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

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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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Correspondence to Shinichi Yachida MD.

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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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