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Erschienen in: Medical Oncology 1/2011

01.12.2011 | Original Paper

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

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

Erschienen in: Medical Oncology | Sonderheft 1/2011

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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.
Literatur
1.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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.
Zurück zum Zitat 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
Metadaten
Titel
Decreased expression of p39 is associated with a poor prognosis in human hepatocellular carcinoma
verfasst von
Jeng-Wei Lu
Jan-Gowth Chang
Kun-Tu Yeh
Rong-Ming Chen
Jeffrey J. P. Tsai
Rouh-Mei Hu
Publikationsdatum
01.12.2011
Verlag
Springer US
Erschienen in
Medical Oncology / Ausgabe Sonderheft 1/2011
Print ISSN: 1357-0560
Elektronische ISSN: 1559-131X
DOI
https://doi.org/10.1007/s12032-010-9707-9

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