Jun Activation Domain Binding Protein 1 is Overexpressed from the Very Early Stages of Hepatocarcinogenesis
Purchase on Springer.com
$39.95 / €34.95 / £29.95*
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.
As is known for many types of human cancers, the hepatocellular carcinoma (HCC) associated with chronic liver disease shows an obvious multistage process of tumor progression. Despite the demonstrated importance of cell-cycle regulators in tumor biology, there have only been a few studies of their role in multistep hepatocarcinogenesis. Recently, we reported that a high level of p27Kip1 expression is evident from the very early stages of hepatocarcinogenesis.
In the present study, expression of p27Kip1 and Jun activation domain binding protein-1 (Jab1), which is a key molecule involved in posttranslational regulation of p27Kip1, was evaluated in surgically resected specimens of 8 dysplastic nodules (DNs), 16 early HCCs, and 126 classical HCCs.
Immunohistochemistry revealed no Jab1 expression in the majority of hepatocytes in noncancerous normal liver tissue and cases of chronic hepatitis or cirrhosis. In contrast, Jab1 was overexpressed in 50% (4/8) and 50% (8/16) of DNs and early HCCs, respectively, and the labeling index was increased in line with the degree of loss of differentiation in classical HCCs. Real-time quantitative reverse transcription polymerase chain reactions revealed the Jab1 mRNA levels in all tested early and well-differentiated HCCs to be increased compared with matched nontumorous liver specimens. The Spearman coefficient pointed to a high correlation between p27Kip1 and Jab1 mRNA expression levels (P = 0.0014).
Jab1 expression, as well as p27Kip1 upregulation, is evident from the very early stages of hepatocarcinogenesis, suggesting that Jab1 could be a diagnostic marker and a treatment target for precancerous lesions and early HCCs.
- Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–49. CrossRef
- Sakamoto M, Hirohashi S, Shimosato Y. Early stages of multistep hepatocarcinogenesis: adenomatous hyperplasia and early hepatocellular carcinoma. Human Pathol. 1991;22:172–8. CrossRef
- Sakamoto M, Hirohashi S. Natural history and prognosis of adenomatous hyperplasia and early hepatocellular carcinoma: multi-institutional analysis of 53 nodules followed up for more than 6 months and 141 patients with single early hepatocellular carcinoma treated by surgical resection or percutaneous ethanol injection. Jpn J Clin Oncol. 1998;28:604–8. CrossRef
- Oikawa T, Ojima H, Yamasaki S, Takayama T, Hirohashi S, Sakamoto M. Multistep and multicentric development of hepatocellular carcinoma: histological analysis of 980 resected nodules. J Hepatol. 2005;42:225–9. CrossRef
- Takayama T, Makuuchi M, Hirohashi S, et al. Malignant transformation of adenomatous hyperplasia to hepatocellular carcinoma. Lancet. 1990;336:1150–3. CrossRef
- Takayama T, Makuuchi M, Kojiro M, et al. Early hepatocellular carcinoma: pathology, imaging, and therapy. Ann Surg Oncol. 2008;15:972–8. CrossRef
- Hirohashi S, Ishak KG, Kojiro M, et al. Hepatocellular carcinoma. In: Hamilton SR, Aaltonen LA, eds. Pathology and genetics of tumors of the digestive system. Lyon: IARC Press, 2000:159–72.
- Morimitsu Y, Hsia CC, Kojiro M, Tabor E. Nodules of less-differentiated tumor within or adjacent to hepatocellular carcinoma: reactive expression of transforming growth factor-alpha and its receptor in the different areas of tumor. Human Pathol. 1995;26:1126–32. CrossRef
- Fero ML, Randel E, Gurley KE, Roberts JM, Kemp CJ. The murine gene p27Kip1 is heplo-insufficient for tumor suppression. Nature. 1998;396:177–80. CrossRef
- Lee MH, Reynisdottir I, Massagué J. Cloning of p57KIP2, A cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev. 1995;9:639–49. CrossRef
- Polyak K, Lee MH, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P, Massagué J. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell. 1994;78:59–66. CrossRef
- Yachida S, Sakamoto M, Imaida K, et al. p27Kip1 is overexpressed in very early stages of hepatocarcinogenesis. Cancer Sci. 2008;99:2152–9. CrossRef
- Carrano AC, Eytan E, Hershko A, Pagano M. Skp2 is required for ubiquitin-mediated degradation of Cdk inhibitor p27. Nat Cell Biol. 1999;1:193–7. CrossRef
- Sutterlüty H, Chatelain E, Marti A, Wirbelauer C, Senften M, Müller U, Krek W. p45Skp2 promotes p27Kip1 degradation and induces S phase in quiescent cells. Nat Cell Biol. 1999;1:207–14. CrossRef
- Tomoda K, Kubota Y, Kato J. Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1. Nature. 1999;398:160–5. CrossRef
- 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. CrossRef
- Wei N, Deng XW. The COP9 signalosome. Annu Rev Cell Dev Biol. 2003;19:261–86. CrossRef
- Chamovitz DA, Segal D. JAB1/CSN5 and the COP9 signalosome. A complex situation. EMBO Rep. 2001;2:96–101. CrossRef
- Shintani S, Li C, Mihara M, Hino S, Nakashirio K, Hamakawa H. Skp2 and Jab1 expression are associated with inverse expression of p27KIP1 and poor prognosis in oral squamous cell carcinomas. Oncology. 2003;65:355–62. CrossRef
- Kouvaraki MA, Rassidakis GZ, Tian L, Kumar R, Kittas C, Claret FX. Jun activation domain-binding protein 1 expression in breast cancer inversely correlates with the cell cycle inhibitor p27Kip1. Cancer Res. 2003;63:2977–81.
- Wang F, Wang Y, Yu X, et al. Significance of Jab1 expression in human esophageal squamous cell carcinoma. J Clin Gastroenterol. 2009;43:520–6. CrossRef
- 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. CrossRef
- Dong Y, Sui L, Watanabe Y, Yamaguchi F, Hatano N, Tokuda M. Prognostic significance of Jab1 expression in laryngeal squamous cell carcinomas. Clin Cancer Res. 2005;11:259–66. CrossRef
- Osoegawa A, Yoshino I, Kometani T, Yamaguchi M, Kameyama T, Yohena T, Maehara Y. 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. CrossRef
- 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. CrossRef
- 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. 2009;16:395–403. CrossRef
- 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. CrossRef
- Liver Cancer Study Group of Japan. General rules for the clinical and pathological study of primary liver cancer. Tokyo: Kanehara, 2003.
- Ito Y, Matsuura N, Sakon M, et al. Expression and prognostic roles of the G1-S modulators in hepatocellular carcinoma: p27 independently predicts the recurrence. Hepatology. 1999;30:90–9. CrossRef
- Tannapfel A, Grund D, Katalinic A, et al. Decreased expression of p27 protein is associated with advanced tumor stage in hepatocellular carcinoma. Int J Cancer. 2000;89:350–5. CrossRef
- Fiorentino M, Altimari A, D’Errico A, Cukor B, Barozzi C, Loda M, Grigioni WF. Acquired expression of p27 is a favorable prognostic indicator in patients with hepatocellular carcinoma. Clin Cancer Res. 2000;6:3966–72.
- Armengol C, Boix L, Bachs O, et al. p27Kip1 is an independent predictor of recurrence after surgical resection in patients with small hepatocellular carcinoma. J Hepatol. 2003;38:591–7. CrossRef
- Chuma M, Sakamoto M, Yamazaki K, Ohta T, Ohki M, Asaka M, Hirohashi S. Expression profiling in multistage hepatocarcinogenesis: identification of HSP70 as a molecular marker of early hepatocellular carcinoma. Hepatology. 2003;37:198–207. CrossRef
- Viglietto G, Motti ML, Bruni P, et al. Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27Kip1 by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med. 2002;8:1136–44. CrossRef
- Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J, Arteaga CL. PKB/Akt mediates cell-cycle progression by phosphorylation of p27Kip1 at threonine 157 and modulation of its cellular localization. Nat Med. 2002;8:1145–52. CrossRef
- Liang J, Zubovitz J, Petrocelli T, et al. PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med. 2002;8:1153–60. CrossRef
- Takami T, Terai S, Yokoyama Y, et al. Human homologue of maid is a useful marker protein in hepatocarcinogenesis. Gastroenterology. 2005;128:1369–80. CrossRef
- 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. CrossRef
- Hsu MC, Huang CC, Chang HC, Hu TH, Hung WC. Overexpression of Jab1 in hepatocellular carcinoma and its inhibition by peroxisome proliferator-activated receptor γ ligands in vitro and in vivo. Clin Cancer Res. 2008;14:4045–52. CrossRef
- 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. CrossRef
- 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. CrossRef
- Cope GA, Suh GS, Aravind L, Schwarz SE, Zipursky SL, Koonin EV, Deshales RJ. Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of Nedd8 from Cul1. Science. 2002;298:608–11. CrossRef
- Bech-Otschir D, Kraft R, Huang X, Henklein P, Kapelari B, Pollmann C, Dubiel W. COP9 signalosome-specific phosphorylation targets p53 to degradation by the ubiquitin system. EMBO J. 2001;20:1630–9. CrossRef
- Eferl R, Ricci R, Kenner L, Zenz R, David JP, Rath M, Wagner EF. Liver tumor development: c-Jun antagonizes the proapoptotic activity of p53. Cell. 2003;112:181–92. CrossRef
- Wan M, Cao X, Wu Y, et al. Jab1 Antagonizes TGF-beta signaling by inducing Smad4 degradation. EMBO Rep. 2002;3:171–6. CrossRef
- Wang B, Hsu SH, Majumder S, Kutay H, Huang W, Jacob ST, Ghoshai K. TGFbeta-mediated upregulation of hepatic miR-181b promotes hepatocarcinogenesis by targeting TIMP3. Oncogene. 2010 (in press).
- Tanaka Y, Kanai F, Ichimura T, et al. The Hepatitis B Virus X `rotein Enhances AP-1 Activation through Interaction with Jab1. Oncogene. 2006; 25:633–42. CrossRef
- Jun Activation Domain Binding Protein 1 is Overexpressed from the Very Early Stages of Hepatocarcinogenesis
Annals of Surgical Oncology
Volume 17, Issue 12 , pp 3386-3393
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- Industry Sectors
- Author Affiliations
- 1. Department of Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan
- 4. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
- 2. Department of Pathology and Host-Defense, Kagawa University, Kagawa, Japan
- 3. Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan