Cancer Therapy

You have full text access to this OnlineOpen article

High expression levels of IKKα and IKKβ are necessary for the malignant properties of liver cancer

  1. Runqiu Jiang,
  2. Yongxiang Xia,
  3. Jun Li,
  4. Lei Deng,
  5. Liang Zhao,
  6. Jian Shi,
  7. Xuehao Wang†,*,
  8. Beicheng Sun†,*

Article first published online: 2 SEP 2009

DOI: 10.1002/ijc.24854

Issue

International Journal of Cancer

International Journal of Cancer

Volume 126, Issue 5, pages 1263–1274, 1 March 2010

Additional Information

How to Cite

Jiang, R., Xia, Y., Li, J., Deng, L., Zhao, L., Shi, J., Wang, X. and Sun, B. (2010), High expression levels of IKKα and IKKβ are necessary for the malignant properties of liver cancer. Int. J. Cancer, 126: 1263–1274. doi: 10.1002/ijc.24854

Author Information

  1. Liver Transplantation Center of the First Affiliated Hospital and Cancer Center, Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China

  1. †

    Fax: 86-25-86560946

*Liver Transplantation Center of the First Affiliated Hospital and Cancer Center, Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, People's Republic of China

Publication History

  1. Issue published online: 27 DEC 2009
  2. Article first published online: 2 SEP 2009
  3. Accepted manuscript online: 2 SEP 2009 12:00AM EST
  4. Manuscript Accepted: 18 AUG 2009
  5. Manuscript Received: 24 APR 2009

Funded by

  • Jiangsu Province's Outstanding Medical Academic Leader Program. Grant Number: RC2007057
  • Jiangsu Province's Key Medical Center
  • Natural Science Foundation of China. Grant Numbers: 30672367, 30772003
  • Ministry of Health, China. Grant Number: Wkj2006-2-021
  • Jiangsu Province “Six adults just” high peak. Grant Number: 06-B-032

SEARCH

SEARCH BY CITATION

ARTICLE TOOLS

View Full Article (HTML) Get PDF (1031K)

References

  • 1
    Luedde T, Beraza N, Kotsikoris V, van Loo G, Nenci A, De Vos R, Roskams T, Trautwein C, Pasparakis M. Deletion of NEMO/IKKγ in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 2007; 11: 119–32.
  • 2
    Maeda S, Chang L, Li ZW, Luo JL, Leffert H, Karin M. IKKβ is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha. Immunity 2003; 19: 725–37.
  • 3
    Maeda S, Kamata H, Luo JL, Leffert H, Karin M. IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 2005; 121: 977–90.
  • 4
    Sakurai T, He G, Matsuzawa A, Yu GY, Maeda S, Hardiman G, Karin M. Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 2008; 14: 156–65.
  • 5
    Sakurai T, Maeda S, Chang L, Karin M. Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc Natl Acad Sci U S A 2006; 103: 10544–51.
  • 6
    Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben-Neriah Y. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 2004; 431: 461–6.
  • 7
    Takeda K, Takeuchi O, Tsujimura T, Itami S, Adachi O, Kawai T, Sanjo H, Yoshikawa K, Terada N, Akira S. Limb and skin abnormalities in mice lacking IKKα. Science 1999; 284: 313–16.
  • 8
    Hu Y, Baud V, Delhase M, Zhang P, Deerinck T, Ellisman M, Johnson R, Karin M. Abnormal morphogenesis but intact IKK activation in mice lacking the IKKα subunit of IkappaB kinase. Science 1999; 284: 316–20.
  • 9
    Luo JL, Tan W, Ricono JM, Korchynskyi O, Zhang M, Gonias SL, Cheresh DA, Karin M. Nuclear cytokine-activated IKKα controls prostate cancer metastasis by repressing Maspin. Nature 2007; 446: 690–4.
  • 10
    Cao Y, Bonizzi G, Seagroves TN, Greten FR, Johnson R, Schmidt EV, Karin M. IKKα provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development. Cell 2001; 107: 763–75.
  • 11
    Cao Y, Luo JL, Karin M. IkappaB kinase alpha kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells. Proc Natl Acad Sci U S A 2007; 104: 15852–7.
  • 12
    Horie R, Watanabe T, Umezawa K. Blocking NF-kappaB as a potential strategy to treat adult T-cell leukemia/lymphoma. Drug News Perspect 2006; 19: 201–9.
  • 13
    Guan YS, He Q, Wang MQ, Li P. Nuclear factor kappa B and hepatitis viruses. Expert Opin Ther Targets 2008; 12: 265–80.
  • 14
    Greten FR, Karin M. The IKK/NF-kappaB activation pathway—a target for prevention and treatment of cancer. Cancer Lett 2004; 206: 193–9.
  • 15
    Kim HJ, Hawke N, Baldwin AS. NF-kappaB and IKK as therapeutic targets in cancer. Cell Death Differ 2006; 13: 738–47.
  • 16
    Schon M, Wienrich BG, Kneitz S, Sennefelder H, Amschler K, Vohringer V, Weber O, Stiewe T, Ziegelbauer K, Schon MP. KINK-1, a novel small-molecule inhibitor of IKKβ, and the susceptibility of melanoma cells to antitumoral treatment. J Natl Cancer Inst 2008; 100: 862–75.
  • 17
    Miller RE, Roudier M, Jones J, Armstrong A, Canon J, Dougall WC. RANK ligand inhibition plus docetaxel improves survival and reduces tumor burden in a murine model of prostate cancer bone metastasis. Mol Cancer Ther 2008; 7: 2160–9.
  • 18
    Wiznerowicz M, Trono D. Conditional suppression of cellular genes: lentivirus vector-mediated drug-inducible RNA interference. J Virol 2003; 77: 8957–61.
  • 19
    Fang J, Hodivala-Dilke K, Johnson BD, Du LM, Hynes RO, White GCII, Wilcox DA. Therapeutic expression of the platelet-specific integrin, alphaIIbbeta3, in a murine model for Glanzmann thrombasthenia. Blood 2005; 106: 2671–9.
  • 20
    Sun B, Chen M, Hawks CL, Pereira-Smith OM, Hornsby PJ. The minimal set of genetic alterations required for conversion of primary human fibroblasts to cancer cells in the subrenal capsule assay. Neoplasia 2005; 7: 585–93.
  • 21
    Yang JY, Zeng XY, Ma BR. Effect of NF-kappa B pathway on apoptosis of hepatic carcinoma cell line-7721 induced by TNF-alpha. Ai Zheng 2002; 21: 974–8.
  • 22
    Armstrong AP, Miller RE, Jones JC, Zhang J, Keller ET, Dougall WC. RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes. Prostate 2008; 68: 92–104.
  • 23
    Canon JR, Roudier M, Bryant R, Morony S, Stolina M, Kostenuik PJ, Dougall WC. Inhibition of RANKL blocks skeletal tumor progression and improves survival in a mouse model of breast cancer bone metastasis. Clin Exp Metastasis 2008; 25: 119–29.
  • 24
    Chen EI, Yates JR. Maspin and tumor metastasis. IUBMB Life 2006; 58: 25–9.
  • 25
    Ignatoski KM, Escara-Wilke JF, Dai JL, Lui A, Dougall W, Daignault S, Yao Z, Zhang J, Day ML, Sargent EE, Keller ET. RANKL inhibition is an effective adjuvant for docetaxel in a prostate cancer bone metastases model. Prostate 2008; 68: 820–9.
  • 26
    Li Q, Van Antwerp D, Mercurio F, Lee KF, Verma IM. Severe liver degeneration in mice lacking the IkappaB kinase 2 gene. Science 1999; 284: 321–5.
  • 27
    Rudolph D, Yeh WC, Wakeham A, Rudolph B, Nallainathan D, Potter J, Elia AJ, Mak TW. Severe liver degeneration and lack of NF-kappaB activation in NEMO/IKKγ-deficient mice. Genes Dev 2000; 14: 854–62.
  • 28
    Mendez O, Martin B, Sanz R, Aragues R, Moreno V, Oliva B, Stresing V, Sierra A. Underexpression of transcriptional regulators is common in metastatic breast cancer cells overexpressing Bcl-xL. Carcinogenesis 2006; 27: 1169–79.
  • 29
    Fernandez Y, Gu B, Martinez A, Torregrosa A, Sierra A. Inhibition of apoptosis in human breast cancer cells: role in tumor progression to the metastatic state. Int J Cancer 2002; 101: 317–26.
  • 30
    Heijink DM, Kleibeuker JH, Jalving M, Boersma-van Ek W, Koornstra JJ, Wesseling J, de Jong S. Independent induction of caspase-8 and cFLIP expression during colorectal carcinogenesis in sporadic and HNPCC adenomas and carcinomas. Cell Oncol 2007; 29: 409–19.
  • 31
    Li X, Pan X, Zhang H, Lei D, Liu D, Xu F, Luan X. Overexpression of cFLIP in head and neck squamous cell carcinoma and its clinicopathologic correlations. J Cancer Res Clin Oncol 2008; 134: 609–15.
  • 32
    Hyer ML, Sudarshan S, Kim Y, Reed JC, Dong JY, Schwartz DA, Norris JS. Downregulation of c-FLIP sensitizes DU145 prostate cancer cells to Fas-mediated apoptosis. Cancer Biol Ther 2002; 1: 401–6.
  • 33
    Deverman BE, Cook BL, Manson SR, Niederhoff RA, Langer EM, Rosova I, Kulans LA, Fu X, Weinberg JS, Heinecke JW, Roth KA, Weintraub SJ. Bcl-xL deamidation is a critical switch in the regulation of the response to DNA damage. Cell 2002; 111: 51–62.
  • 34
    Takehara T, Liu X, Fujimoto J, Friedman SL, Takahashi H. Expression and role of Bcl-xL in human hepatocellular carcinomas. Hepatology 2001; 34: 55–61.
  • 35
    Rae C, Langa S, Tucker SJ, MacEwan DJ. Elevated NF-kappaB responses and FLIP levels in leukemic but not normal lymphocytes: reduction by salicylate allows TNF-induced apoptosis. Proc Natl Acad Sci U S A 2007; 104: 12790–5.
  • 36
    Wong BR, Josien R, Lee SY, Vologodskaia M, Steinman RM, Choi Y. The TRAF family of signal transducers mediates NF-kappaB activation by the TRANCE receptor. J Biol Chem 1998; 273: 28355–9.
  • 37
    Kim HH, Lee DE, Shin JN, Lee YS, Jeon YM, Chung CH, Ni J, Kwon BS, Lee ZH. Receptor activator of NF-kappaB recruits multiple TRAF family adaptors and activates c-Jun N-terminal kinase. FEBS Lett 1999; 443: 297–302.
  • 38
    Darnay BG, Haridas V, Ni J, Moore PA, Aggarwal BB. Characterization of the intracellular domain of receptor activator of NF-kappaB (RANK). Interaction with tumor necrosis factor receptor-associated factors and activation of NF-kappab and c-Jun N-terminal kinase. J Biol Chem 1998; 273: 20551–5.
  • 39
    Galibert L, Tometsko ME, Anderson DM, Cosman D, Dougall WC. The involvement of multiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-kappaB, a member of the TNFR superfamily. J Biol Chem 1998; 273: 34120–7.
  • 40
    Zou Z, Anisowicz A, Hendrix MJ, Thor A, Neveu M, Sheng S, Rafidi K, Seftor E, Sager R. Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells. Science 1994; 263: 526–9.
  • 41
    Sheng S, Carey J, Seftor EA, Dias L, Hendrix MJ, Sager R. Maspin acts at the cell membrane to inhibit invasion and motility of mammary and prostatic cancer cells. Proc Natl Acad Sci U S A 1996; 93: 11669–74.
  • 42
    Zhang M, Volpert O, Shi YH, Bouck N. Maspin is an angiogenesis inhibitor. Nat Med 2000; 6: 196–9.
  • 43
    Jiang N, Meng Y, Zhang S, Mensah-Osman E, Sheng S. Maspin sensitizes breast carcinoma cells to induced apoptosis. Oncogene 2002; 21: 4089–98.
  • 44
    Le NH, Franken P, Fodde R. Tumour-stroma interactions in colorectal cancer: converging on beta-catenin activation and cancer stemness. Br J Cancer 2008; 98: 1886–93.
  • 45
    Albini A, Sporn MB. The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer 2007; 7: 139–47.
  • 46
    Chua HL, Bhat-Nakshatri P, Clare SE, Morimiya A, Badve S, Nakshatri H. NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2. Oncogene 2007; 26: 711–24.
View Full Article (HTML) Get PDF (1031K)