Skip to main content
Top
Published in: Medical Oncology 1/2011

01-12-2011 | Original Paper

Decreased expression of p39 is associated with a poor prognosis in human hepatocellular carcinoma

Authors: Jeng-Wei Lu, Jan-Gowth Chang, Kun-Tu Yeh, Rong-Ming Chen, Jeffrey J. P. Tsai, Rouh-Mei Hu

Published in: Medical Oncology | Special Issue 1/2011

Login to get access

Abstract

The aims of this study are to investigate the relationship between p39 expression and clinicopathological parameters of hepatocellular carcinoma (HCC) and to evaluate the prognostic value of p39 for HCC patients. Real-time quantitative PCR and immunohistochemistry was used to measure p39 expression in tumor and adjacent nontumor samples. Relationships of p39 expression with clinical parameters and patient survival were analyzed. Real-time quantitative RT–PCR showed that the quantity of p39 mRNA in cancerous tissue was significantly lower than that in nontumor tissue (P < 0.001). Immunohistochemistry data confirmed that p39 protein was reduced in 64% of HCC. p39 expression was not influenced by chronic alcohol exposure or cirrhosis. Reduction in p39 was correlated with the HBV (P = 0.039), HCV (P = 0.011), and histological grade (P < 0.001). HCC patients with lower p39 expression had poorer overall survival rate than that with high expression (HR, 2.868; 95% CI, 1.451–5.670; P = 0.002). Together with other results, these results reveal that p39 expression was reduced in HCC tissue. p39 could be a useful clinical prognostic marker for hepatocellular carcinoma patients.
Literature
1.
go back to reference Sung JL. Hepatitis B virus infection and its sequelae in Taiwan. Gastroenterol Jpn. 1984;4:363–6. Sung JL. Hepatitis B virus infection and its sequelae in Taiwan. Gastroenterol Jpn. 1984;4:363–6.
2.
go back to reference El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;7:2557–76.CrossRef El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;7:2557–76.CrossRef
3.
go back to reference Marrero CR, Marrero JA. Viral hepatitis and hepatocellular carcinoma. Arch Med Res. 2007;6:612–20.CrossRef Marrero CR, Marrero JA. Viral hepatitis and hepatocellular carcinoma. Arch Med Res. 2007;6:612–20.CrossRef
4.
go back to reference McGlynn KA, London WT. Epidemiology and natural history of hepatocellular carcinoma. Best Practice Res. 2005;1:3–23.CrossRef McGlynn KA, London WT. Epidemiology and natural history of hepatocellular carcinoma. Best Practice Res. 2005;1:3–23.CrossRef
5.
go back to reference Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology. 2004;5:87–96.CrossRef Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology. 2004;5:87–96.CrossRef
6.
go back to reference Seeff LB, Hoofnagle JH. Epidemiology of hepatocellular carcinoma in areas of low hepatitis B and hepatitis C endemicity. Oncogene. 2006;27:3771–7.CrossRef Seeff LB, Hoofnagle JH. Epidemiology of hepatocellular carcinoma in areas of low hepatitis B and hepatitis C endemicity. Oncogene. 2006;27:3771–7.CrossRef
7.
go back to reference Lin TY, Lee CS, Chen KM, Chen CC. Role of surgery in the treatment of primary carcinoma of the liver: a 31-year experience. Br J Surg. 1987;9:839–42.CrossRef Lin TY, Lee CS, Chen KM, Chen CC. Role of surgery in the treatment of primary carcinoma of the liver: a 31-year experience. Br J Surg. 1987;9:839–42.CrossRef
8.
go back to reference El-Serag HB, Mason AC, Key C. Trends in survival of patients with hepatocellular carcinoma between 1977 and 1996 in the United States. Hepatology. 2001;1:62–5.CrossRef El-Serag HB, Mason AC, Key C. Trends in survival of patients with hepatocellular carcinoma between 1977 and 1996 in the United States. Hepatology. 2001;1:62–5.CrossRef
9.
go back to reference Bosch FX, Ribes J, Borras J. Epidemiology of primary liver cancer. Semin Liver Dis. 1999;3:271–85.CrossRef Bosch FX, Ribes J, Borras J. Epidemiology of primary liver cancer. Semin Liver Dis. 1999;3:271–85.CrossRef
10.
go back to reference Mor E, Kaspa RT, Sheiner P, Schwartz M. Treatment of hepatocellular carcinoma associated with cirrhosis in the era of liver transplantation. Ann Intern Med. 1998;8:643–53. Mor E, Kaspa RT, Sheiner P, Schwartz M. Treatment of hepatocellular carcinoma associated with cirrhosis in the era of liver transplantation. Ann Intern Med. 1998;8:643–53.
11.
go back to reference Lalioti V, Pulido D, Sandoval IV. Cdk5, the multifunctional surveyor. Cell Cycle. 2010;9:284–311.PubMedCrossRef Lalioti V, Pulido D, Sandoval IV. Cdk5, the multifunctional surveyor. Cell Cycle. 2010;9:284–311.PubMedCrossRef
12.
go back to reference Dhariwala FA, Rajadhyaksha MS. An unusual member of the Cdk family: Cdk5. Cell Mol Neurobiol. 2008;3:351–69.CrossRef Dhariwala FA, Rajadhyaksha MS. An unusual member of the Cdk family: Cdk5. Cell Mol Neurobiol. 2008;3:351–69.CrossRef
13.
go back to reference Rosales JL, Lee KY. Extraneuronal roles of cyclin-dependent kinase 5. Bioessays. 2006;10:1023–34.CrossRef Rosales JL, Lee KY. Extraneuronal roles of cyclin-dependent kinase 5. Bioessays. 2006;10:1023–34.CrossRef
14.
go back to reference Paglini G, Caceres A. The role of the Cdk5–p35 kinase in neuronal development. Eur J Biochem. 2001;6:1528–33.CrossRef Paglini G, Caceres A. The role of the Cdk5–p35 kinase in neuronal development. Eur J Biochem. 2001;6:1528–33.CrossRef
15.
go back to reference Tang D, Yeung J, Lee KY, Matsushita M, Matsui H, Tomizawa K, et al. An isoform of the neuronal cyclin-dependent kinase 5 (Cdk5) activator. J Biol Chem. 1995;45:26897–903. Tang D, Yeung J, Lee KY, Matsushita M, Matsui H, Tomizawa K, et al. An isoform of the neuronal cyclin-dependent kinase 5 (Cdk5) activator. J Biol Chem. 1995;45:26897–903.
16.
go back to reference Hisanaga S, Saito T. The regulation of cyclin-dependent kinase 5 activity through the metabolism of p35 or p39 Cdk5 activator. Neurosignals. 2003;4:221–9.CrossRef Hisanaga S, Saito T. The regulation of cyclin-dependent kinase 5 activity through the metabolism of p35 or p39 Cdk5 activator. Neurosignals. 2003;4:221–9.CrossRef
17.
go back to reference Ko J, Humbert S, Bronson RT, Takahashi S, Kulkarni AB, Li E, et al. p35 and p39 are essential for cyclin-dependent kinase 5 function during neurodevelopment. J Neurosci. 2001;17:6758–71. Ko J, Humbert S, Bronson RT, Takahashi S, Kulkarni AB, Li E, et al. p35 and p39 are essential for cyclin-dependent kinase 5 function during neurodevelopment. J Neurosci. 2001;17:6758–71.
18.
go back to reference Tsai LH, Takahashi T, Caviness VS Jr, Harlow E. Activity and expression pattern of cyclin-dependent kinase 5 in the embryonic mouse nervous system. Development. 1993;4:1029–40. Tsai LH, Takahashi T, Caviness VS Jr, Harlow E. Activity and expression pattern of cyclin-dependent kinase 5 in the embryonic mouse nervous system. Development. 1993;4:1029–40.
19.
go back to reference Lazaro JB, Kitzmann M, Poul MA, Vandromme M, Lamb NJ, Fernandez A. Cyclin dependent kinase 5, cdk5, is a positive regulator of myogenesis in mouse C2 cells. J Cell Sci. 1997;10:1251–60. Lazaro JB, Kitzmann M, Poul MA, Vandromme M, Lamb NJ, Fernandez A. Cyclin dependent kinase 5, cdk5, is a positive regulator of myogenesis in mouse C2 cells. J Cell Sci. 1997;10:1251–60.
20.
go back to reference Gao CY, Zakeri Z, Zhu Y, He H, Zelenka PS. Expression of Cdk5, p35, and Cdk5-associated kinase activity in the developing rat lens. Dev Genet. 1997;3:267–75.CrossRef Gao CY, Zakeri Z, Zhu Y, He H, Zelenka PS. Expression of Cdk5, p35, and Cdk5-associated kinase activity in the developing rat lens. Dev Genet. 1997;3:267–75.CrossRef
21.
go back to reference Session DR, Fautsch MP, Avula R, Jones WR, Nehra A, Wieben ED. Cyclin-dependent kinase 5 is expressed in both Sertoli cells and metaphase spermatocytes. Fertil Steril. 2001;4:669–73.CrossRef Session DR, Fautsch MP, Avula R, Jones WR, Nehra A, Wieben ED. Cyclin-dependent kinase 5 is expressed in both Sertoli cells and metaphase spermatocytes. Fertil Steril. 2001;4:669–73.CrossRef
22.
go back to reference Chen F, Studzinski GP. Expression of the neuronal cyclin-dependent kinase 5 activator p35Nck5a in human monocytic cells is associated with differentiation. Blood. 2001;12:3763–7.CrossRef Chen F, Studzinski GP. Expression of the neuronal cyclin-dependent kinase 5 activator p35Nck5a in human monocytic cells is associated with differentiation. Blood. 2001;12:3763–7.CrossRef
23.
go back to reference Lilja L, Yang SN, Webb DL, Juntti-Berggren L, Berggren PO, Bark C. Cyclin-dependent kinase 5 promotes insulin exocytosis. J Biol Chem. 2001;36:34199–205.CrossRef Lilja L, Yang SN, Webb DL, Juntti-Berggren L, Berggren PO, Bark C. Cyclin-dependent kinase 5 promotes insulin exocytosis. J Biol Chem. 2001;36:34199–205.CrossRef
24.
go back to reference Mao D, Hinds PW. p35 is required for CDK5 activation in cellular senescence. J Biol Chem. 2010;19:14671–80.CrossRef Mao D, Hinds PW. p35 is required for CDK5 activation in cellular senescence. J Biol Chem. 2010;19:14671–80.CrossRef
25.
go back to reference Tian B, Yang Q, Mao Z. Phosphorylation of ATM by Cdk5 mediates DNA damage signalling and regulates neuronal death. Nat Cell Biol. 2009;2:211–8.CrossRef Tian B, Yang Q, Mao Z. Phosphorylation of ATM by Cdk5 mediates DNA damage signalling and regulates neuronal death. Nat Cell Biol. 2009;2:211–8.CrossRef
26.
go back to reference Alexander K, Yang HS, Hinds PW. Cellular senescence requires CDK5 repression of Rac1 activity. Mol Cell Biol. 2004;7:2808–19.CrossRef Alexander K, Yang HS, Hinds PW. Cellular senescence requires CDK5 repression of Rac1 activity. Mol Cell Biol. 2004;7:2808–19.CrossRef
27.
go back to reference Yang HS, Alexander K, Santiago P, Hinds PW. ERM proteins and Cdk5 in cellular senescence. Cell Cycle. 2003;6:517–20.CrossRef Yang HS, Alexander K, Santiago P, Hinds PW. ERM proteins and Cdk5 in cellular senescence. Cell Cycle. 2003;6:517–20.CrossRef
28.
go back to reference Kuo HS, Hsu FN, Chiang MC, You SC, Chen MC, Lo MJ, et al. The role of Cdk5 in retinoic acid-induced apoptosis of cervical cancer cell line. Chin J Physiol. 2009;1:23–30.CrossRef Kuo HS, Hsu FN, Chiang MC, You SC, Chen MC, Lo MJ, et al. The role of Cdk5 in retinoic acid-induced apoptosis of cervical cancer cell line. Chin J Physiol. 2009;1:23–30.CrossRef
29.
go back to reference Lin H, Juang JL, Wang PS. Involvement of Cdk5/p25 in digoxin-triggered prostate cancer cell apoptosis. J Biol Chem. 2004;28:29302–7.CrossRef Lin H, Juang JL, Wang PS. Involvement of Cdk5/p25 in digoxin-triggered prostate cancer cell apoptosis. J Biol Chem. 2004;28:29302–7.CrossRef
30.
go back to reference Sandal T, Stapnes C, Kleivdal H, Hedin L, Doskeland SO. A novel, extraneuronal role for cyclin-dependent protein kinase 5 (CDK5): modulation of cAMP-induced apoptosis in rat leukemia cells. J Biol Chem. 2002;23:20783–93.CrossRef Sandal T, Stapnes C, Kleivdal H, Hedin L, Doskeland SO. A novel, extraneuronal role for cyclin-dependent protein kinase 5 (CDK5): modulation of cAMP-induced apoptosis in rat leukemia cells. J Biol Chem. 2002;23:20783–93.CrossRef
31.
go back to reference Gao CY, Stepp MA, Fariss R, Zelenka P. Cdk5 regulates activation and localization of Src during corneal epithelial wound closure. J Cell Sci. 2004;117:4089–98.PubMedCrossRef Gao CY, Stepp MA, Fariss R, Zelenka P. Cdk5 regulates activation and localization of Src during corneal epithelial wound closure. J Cell Sci. 2004;117:4089–98.PubMedCrossRef
32.
go back to reference Pareek TK, Kulkarni AB. Cdk5: a new player in pain signaling. Cell Cycle. 2006;6:585–8.CrossRef Pareek TK, Kulkarni AB. Cdk5: a new player in pain signaling. Cell Cycle. 2006;6:585–8.CrossRef
33.
go back to reference Lin H, Chen MC, Chiu CY, Song YM, Lin SY. Cdk5 regulates STAT3 activation and cell proliferation in medullary thyroid carcinoma cells. J Biol Chem. 2007;5:2776–84. Lin H, Chen MC, Chiu CY, Song YM, Lin SY. Cdk5 regulates STAT3 activation and cell proliferation in medullary thyroid carcinoma cells. J Biol Chem. 2007;5:2776–84.
34.
go back to reference Feldmann G, Mishra A, Hong SM, Bisht S, Strock CJ, Ball DW, et al. Inhibiting the cyclin-dependent kinase CDK5 blocks pancreatic cancer formation and progression through the suppression of Ras-Ral signaling. Cancer Res. 2010;11:4460–9.CrossRef Feldmann G, Mishra A, Hong SM, Bisht S, Strock CJ, Ball DW, et al. Inhibiting the cyclin-dependent kinase CDK5 blocks pancreatic cancer formation and progression through the suppression of Ras-Ral signaling. Cancer Res. 2010;11:4460–9.CrossRef
35.
go back to reference Strock CJ, Park JI, Nakakura EK, Bova GS, Isaacs JT, Ball DW, et al. Cyclin-dependent kinase 5 activity controls cell motility and metastatic potential of prostate cancer cells. Cancer Res. 2006;15:7509–15.CrossRef Strock CJ, Park JI, Nakakura EK, Bova GS, Isaacs JT, Ball DW, et al. Cyclin-dependent kinase 5 activity controls cell motility and metastatic potential of prostate cancer cells. Cancer Res. 2006;15:7509–15.CrossRef
36.
go back to reference Liu JL, Wang XY, Huang BX, Zhu F, Zhang RG, Wu G. Expression of CDK5/p35 in resected patients with non-small cell lung cancer: relation to prognosis. Med Oncol. 2010;10:9510–7. Liu JL, Wang XY, Huang BX, Zhu F, Zhang RG, Wu G. Expression of CDK5/p35 in resected patients with non-small cell lung cancer: relation to prognosis. Med Oncol. 2010;10:9510–7.
37.
go back to reference Yamada M, Saito T, Sato Y, Kawai Y, Sekigawa A, Hamazumi Y, et al. Cdk5–p39 is a labile complex with the similar substrate specificity to Cdk5–p35. J Neurochem. 2007;5:1477–87.CrossRef Yamada M, Saito T, Sato Y, Kawai Y, Sekigawa A, Hamazumi Y, et al. Cdk5–p39 is a labile complex with the similar substrate specificity to Cdk5–p35. J Neurochem. 2007;5:1477–87.CrossRef
38.
go back to reference Chen X, Cheung ST, So S, Fan ST, Barry C, Higgins J, et al. Gene expression patterns in human liver cancers. Mol Biol Cell. 2002;6:1929–39.CrossRef Chen X, Cheung ST, So S, Fan ST, Barry C, Higgins J, et al. Gene expression patterns in human liver cancers. Mol Biol Cell. 2002;6:1929–39.CrossRef
39.
go back to reference Hirohashi S, Ishak KG, Kojiro M, Puig PL, Wanless IR, Fischer HP, Theise ND, Sakamoto M, Tsukuma H. Hepatocellular carcinoma. In: Hamilton SR, Aaltonen LA, editors. Pathology and genetics of tumours of the digestive system. Lyon: IARC Press; 2000. p. 159–72. Hirohashi S, Ishak KG, Kojiro M, Puig PL, Wanless IR, Fischer HP, Theise ND, Sakamoto M, Tsukuma H. Hepatocellular carcinoma. In: Hamilton SR, Aaltonen LA, editors. Pathology and genetics of tumours of the digestive system. Lyon: IARC Press; 2000. p. 159–72.
40.
go back to reference Lippincott-Raven P. Digestive system. In: American Joint Committee on Cancer, editor. AJCC cancer staging manual. New York: Springer; 2009. p. 191–200. Lippincott-Raven P. Digestive system. In: American Joint Committee on Cancer, editor. AJCC cancer staging manual. New York: Springer; 2009. p. 191–200.
41.
go back to reference Yeh KT, Yang MY, Liu TC, Chen JC, Chan WL, Lin SF, et al. Abnormal expression of period 1 (PER1) in endometrial carcinoma. J Pathol. 2005;1:111–20.CrossRef Yeh KT, Yang MY, Liu TC, Chen JC, Chan WL, Lin SF, et al. Abnormal expression of period 1 (PER1) in endometrial carcinoma. J Pathol. 2005;1:111–20.CrossRef
42.
go back to reference Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;6:1101–8.CrossRef Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;6:1101–8.CrossRef
43.
go back to reference Tseng HH, Hwang YH, Yeh KT, Chang JG, Chen YL, Yu HS. Reduced expression of C/EBP alpha protein in hepatocellular carcinoma is associated with advanced tumor stage and shortened patient survival. J Cancer Res Clin Oncol. 2009;2:241–7.CrossRef Tseng HH, Hwang YH, Yeh KT, Chang JG, Chen YL, Yu HS. Reduced expression of C/EBP alpha protein in hepatocellular carcinoma is associated with advanced tumor stage and shortened patient survival. J Cancer Res Clin Oncol. 2009;2:241–7.CrossRef
44.
go back to reference Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966;3:163–70. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966;3:163–70.
45.
go back to reference Wu DC, Yu YP, Lee NT, Yu AC, Wang JH, Han YF. The expression of Cdk5, p35, p39, and Cdk5 kinase activity in developing, adult, and aged rat brains. Neurochem Res. 2000;7:923–9.CrossRef Wu DC, Yu YP, Lee NT, Yu AC, Wang JH, Han YF. The expression of Cdk5, p35, p39, and Cdk5 kinase activity in developing, adult, and aged rat brains. Neurochem Res. 2000;7:923–9.CrossRef
46.
go back to reference Humbert S, Dhavan R, Tsai L. p39 activates cdk5 in neurons, and is associated with the actin cytoskeleton. J Cell Sci. 2000;6:975–83. Humbert S, Dhavan R, Tsai L. p39 activates cdk5 in neurons, and is associated with the actin cytoskeleton. J Cell Sci. 2000;6:975–83.
47.
go back to reference Ledee DR, Tripathi BK, Zelenka PS. The CDK5 activator, p39, binds specifically to myosin essential light chain. Biochem Biophys Res Commun. 2007;4:1034–9.CrossRef Ledee DR, Tripathi BK, Zelenka PS. The CDK5 activator, p39, binds specifically to myosin essential light chain. Biochem Biophys Res Commun. 2007;4:1034–9.CrossRef
48.
go back to reference Ledee DR, Gao CY, Seth R, Fariss RN, Tripathi BK, Zelenka PS. A specific interaction between muskelin and the cyclin-dependent kinase 5 activator p39 promotes peripheral localization of muskelin. J Biol Chem. 2005;22:21376–83.CrossRef Ledee DR, Gao CY, Seth R, Fariss RN, Tripathi BK, Zelenka PS. A specific interaction between muskelin and the cyclin-dependent kinase 5 activator p39 promotes peripheral localization of muskelin. J Biol Chem. 2005;22:21376–83.CrossRef
49.
go back to reference Ajay AK, Upadhyay AK, Singh S, Vijayakumar MV, Kumari R, Pandey V, et al. Cdk5 phosphorylates non-genotoxically overexpressed p53 following inhibition of PP2A to induce cell cycle arrest/apoptosis and inhibits tumor progression. Mol Cancer. 2010;9:204–19.PubMedCrossRef Ajay AK, Upadhyay AK, Singh S, Vijayakumar MV, Kumari R, Pandey V, et al. Cdk5 phosphorylates non-genotoxically overexpressed p53 following inhibition of PP2A to induce cell cycle arrest/apoptosis and inhibits tumor progression. Mol Cancer. 2010;9:204–19.PubMedCrossRef
50.
go back to reference Zhang J, Krishnamurthy PK, Johnson GV. Cdk5 phosphorylates p53 and regulates its activity. J Neurochem. 2002;2:307–13.CrossRef Zhang J, Krishnamurthy PK, Johnson GV. Cdk5 phosphorylates p53 and regulates its activity. J Neurochem. 2002;2:307–13.CrossRef
51.
go back to reference Lee JH, Jeong MW, Kim W, Choi YH, Kim KT. Cooperative roles of c-Abl and Cdk5 in regulation of p53 in response to oxidative stress. J Biol Chem. 2008;28:19826–35.CrossRef Lee JH, Jeong MW, Kim W, Choi YH, Kim KT. Cooperative roles of c-Abl and Cdk5 in regulation of p53 in response to oxidative stress. J Biol Chem. 2008;28:19826–35.CrossRef
Metadata
Title
Decreased expression of p39 is associated with a poor prognosis in human hepatocellular carcinoma
Authors
Jeng-Wei Lu
Jan-Gowth Chang
Kun-Tu Yeh
Rong-Ming Chen
Jeffrey J. P. Tsai
Rouh-Mei Hu
Publication date
01-12-2011
Publisher
Springer US
Published in
Medical Oncology / Issue Special Issue 1/2011
Print ISSN: 1357-0560
Electronic ISSN: 1559-131X
DOI
https://doi.org/10.1007/s12032-010-9707-9

Other articles of this Special Issue 1/2011

Medical Oncology 1/2011 Go to the issue