Journal of Cancer Research and Clinical Oncology

, Volume 134, Issue 2, pp 179–186 | Cite as

Down-regulation of β-centractin might be involved in dendritic cells dysfunction and subsequent hepatocellular carcinoma immune escape: a proteomic study

  • Yong-Qiang Weng
  • Shuang-Jian Qiu
  • Yin-Kun Liu
  • Jia Fan
  • Qiang Gao
  • Zhao-You TangEmail author
Original Paper



Proteomic study was used to clarify the mechanism of hepatocellular carcinoma (HCC) immune escape concerning Dendritic cells (DCs’) dysfunction and their association with HCC invasion.


Human peripheral blood mononuclear cells (PBMCs) derived DCs from healthy donors were pulsed with soluble cell lysates prepared from different metastatic potential human HCC cell lines. The total protein of these DCs was analyzed by two-dimensional electrophoresis and Electro-Spray Mass Spectrometry. The allostimulatoy capacity and phenotype of these DCs were also evaluated. The clinical significance of β-centractin, one of the largest quantitative changed spot, down-regulation in DCs was further evaluated in autologous PBMCs derived DCs pulsed with auto-tumor lysates in 26 HCC patients.


The expression of β-centractin was found to be considerably lower either in DCs pulsed with HCCLM6 (high metastatic potential HCC cell line) lysates, accompanied by down-regulation of CD86 molecule and impaired allostimulatory capacity, than those of DCs pulsed with lysates from HCC cell lines with low or without metastatic potential or in DCs pulsed with lysates from HCC with invasiveness than those without invasiveness.


The down-regulation of β-centractin in DCs pulsed with high metastatic potential HCC lysates might associate with DCs dysfunction and HCC invasiveness.


Hepatocellular carcinoma (HCC) Dendritic cells (DCs) β-centractin Proteomics 



Hepatocellular carcinoma


Dendritic cell


Peripheral blood mononuclear cells




Antigen presenting cell


T-cell receptor



This work was supported by a grant from the National Natural Science Foundation of China (No. 30200268). We thank Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences for helping with the Proteomic analysis, and Shanghai Fudan-Yueda Bio-Tech Co. Ltd., for helping with Western blot analysis of β-centractin expression.

Supplementary material

432_2007_267_MOESM1_ESM.doc (40 kb)
(DOC 39 kb)


  1. Al-Alwan MM, Rowden G, Lee TD, West KA (2001) The dendritic cell cytoskeleton is critical for the formation of the immunological synapse. J Immunol 166:1452–1456PubMedGoogle Scholar
  2. Al-Alwan MM, Liwski RS, Haeryfar SM, Baldridge WH, Hoskin DW, Rowden G, West KA (2003) Cutting edge: dendritic cell actin cytoskeletal polarization during immunological synapse formation is highly antigen-dependent. J Immunol 171:4479–4483PubMedGoogle Scholar
  3. Aspengren S, Wallin M (2004) A role for spectrin in dynactin-dependent melanosome transport in xenopus laevis melanophores. Pigment Cell Res 17:295–301PubMedCrossRefGoogle Scholar
  4. Andrews DM, Andoniou CE, Scalzo AA, van Dommelen SL, Wallace ME, Smyth MJ, Degli-Esposti MA (2005) Cross-talk between dendritic cells and natural killer cells in viral infection. Mol Immunol 42:547–555PubMedCrossRefGoogle Scholar
  5. Bingham JB, Schroer TA (1999) Self-regulated polymerization of the actin-related protein Arp1. Curr Biol 9:223–226PubMedCrossRefGoogle Scholar
  6. Bromley SK, Burack WR, Johnson KG, Somersalo K, Sims TN, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML (2001) The immunological synapse. Annu Rev Immunol 19:375–396PubMedCrossRefGoogle Scholar
  7. Beckebaum S, Zhang X, Chen X, Yu Z, Frilling A, Dworacki G, Grosse-Wilde H, Broelsch CE, Gerken G, Cicinnati VR (2004) Increased levels of interleukin-10 in serum from patients with hepatocellular carcinoma correlate with profound numerical deficiencies and immature phenotype of circulating dendritic cell subsets. Clin Cancer Res 10:7260–7269PubMedCrossRefGoogle Scholar
  8. Bohnenkamp HR, Coleman J, Burchell JM, Taylor-Papadimitriou J, Noll T (2004) Breast carcinoma cell lysate-pulsed dendritic cells cross-prime MUC1-specific CD8+ T cells identified by peptide-MHC-class-I tetramers. Cell Immunol 231:112–125PubMedCrossRefGoogle Scholar
  9. Creusot RJ, Mitchison NA, Terazzini NM (2002) The immunological synapse. Mol Immunol 38:997–1002PubMedCrossRefGoogle Scholar
  10. Clark SW, Meyer DI (1992) Centractin is an actin homologue associated with the centrosome. Nature 359:246–250PubMedCrossRefGoogle Scholar
  11. Clark SW, Staub O, Clark IB, Holzbaur EL, Paschal BM, Vallee RB, Meyer DI (1994) Beta-centractin: characterization and distribution of a new member of the centractin family of actin-related proteins. Mol Biol Cell 5:1301–1310PubMedGoogle Scholar
  12. Clark IB, Meyer DI (1999) Overexpression of normal and mutant Arp1alpha (centractin) differentially affects microtubule organization during mitosis and interphase. J Cell Sci 112:3507–3518PubMedGoogle Scholar
  13. Cuadrado-Tejedor M, Sesma MT, Gimenez-Amaya JM, Ortiz L (2005) Changes in cytoskeletal gene expression linked to MPTP-treatment in Mice. Neurobiol Dis 20:666–672PubMedCrossRefGoogle Scholar
  14. Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21:137–148PubMedCrossRefGoogle Scholar
  15. Dustin ML, Tseng SY, Varma R, Campi G (2006) T cell-dendritic cell immunological synapses. Curr Opin Immunol 18:512–516PubMedCrossRefGoogle Scholar
  16. Elsea SH, Clark IB, Juyal RC, Meyer DJ, Meyer DI, Patel PI (1999) Assignment of beta-centractin (CTRN2) to human chromosome 2 bands q11.1–>q11.2 with somatic cell hybrids and in situ hybridization. Cytogenet Cell Genet 84:48–49PubMedCrossRefGoogle Scholar
  17. Eaton BA, Fetter RD, Davis GW (2002) Dynactin is necessary for synapse stabilization. Neuron 34:729–741PubMedCrossRefGoogle Scholar
  18. Friedman KM, Fox BA (2004) The promising future of proteomics in cancer diagnosis and treatment. Eur J Gastroenterol Hepatol 17:701–703CrossRefGoogle Scholar
  19. Feng JT, Shang S, Beretta L (2006) Proteomics for the early detection and treatment of hepatocellular carcinoma. Oncogene 25:3810–3817PubMedCrossRefGoogle Scholar
  20. Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML (1999) The immunological synapse: a molecular machine controlling T cell activation. Science 285:221–227PubMedCrossRefGoogle Scholar
  21. Gregoire M, Ligeza-Poisson C, Juge-Morineau N, Spisek R (2003) Anti-cancer therapy using dendritic cells and apoptotic tumour cells: pre-clinical data in human mesothelioma and acute myeloid leukaemia. Vaccine 21:791–794PubMedCrossRefGoogle Scholar
  22. Gabrilovich D (2004) Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol 4:941–952PubMedCrossRefGoogle Scholar
  23. Holleran EA, Tokito MK, Karki S, Holzbaur EL (1996) Centractin (ARP1) associates with spectrin revealing a potential mechanism to link dynactin to intracellular organelles. J Cell Biol 135:1815–1829PubMedCrossRefGoogle Scholar
  24. Kiertscher SM, Luo J, Dubinett SM, Roth MD (2000) Tumors promote altered maturation and early apoptosis of monocyte-derived dendritic cells. J Immunol 164:1269–1276PubMedGoogle Scholar
  25. Kotera Y, Shimizu K, Mule JJ (2001) Comparative analysis of necrotic and apoptotic tumor cells as a source of antigen(s) in dendritic cell-based immunization. Cancer Res 61:8105–8109PubMedGoogle Scholar
  26. Lees-Miller JP, Helfman DM, Schroer TA (1992) A vertebrate actin-related protein is a component of a multisubunit complex involved in microtubule-based vesicle motility. Nature 359:244–246PubMedCrossRefGoogle Scholar
  27. Lanzavecchia A, Sallusto F (2001) Antigen decoding by T lymphocytes: from synapses to fate determination. Nat Immunol 2:487–492PubMedCrossRefGoogle Scholar
  28. Li Y, Tang ZY, Ye SL, Liu YK, Chen J, Xue Q, Chen J, Gao DM, Bao WH (2001) Establishment of cell clones with different metastatic potential from the metastatic hepatocellular carcinoma cell line MHCC97. World J Gastroenterol 7:630–636PubMedGoogle Scholar
  29. Li Y, Tian B, Yang J, Zhao L, Wu X, Ye SL, Liu YK, Tang ZY (2004) Stepwise metastatic human hepatocellular carcinoma cell model system with multiple metastatic potentials established through consecutive in vivo selection and studies on metastatic characteristics. J Cancer Res Clin Oncol 130:460–468PubMedCrossRefGoogle Scholar
  30. Li MS, Ma QL, Chen Q, Liu XH, Li PF, Du GG, Li G (2005) Alpha-fetoprotein triggers hepatoma cells escaping from immune surveillance through altering the expression of Fas/FasL and tumor necrosis factor related apoptosis-inducing ligand and its receptor of lymphocytes and liver cancer cells. World J Gastroenterol 11:2564–2569PubMedGoogle Scholar
  31. Nagao M, Nakajima Y, Kanehiro H, Hisanaga M, Aomatsu Y, Ko S, Tatekawa Y, Ikeda N, Kanokogi H, Urizono Y, Kobayashi T, Shibaji T, Kanamura T, Ogawa S, Nakano H (2000) The impact of interferon gamma receptor expression on the mechanism of escape from host immune surveillance in hepatocellular carcinoma. Hepatology 32:491–500PubMedCrossRefGoogle Scholar
  32. Plamann M, Minke PF, Tinsley JH, Bruno KS (1994) Cytoplasmic dynein and actin-related protein Arp1 are required for normal nuclear distribution in filamentous fungi. J Cell Biol 127:139–149PubMedCrossRefGoogle Scholar
  33. Pardoll DM (2002) Spinning molecular immunology into successful immunotherapy. Nat Rev Immunol 2:227–238PubMedCrossRefGoogle Scholar
  34. Posadas EM, Simpkins F, Liotta LA, MacDonald C, Kohn EC (2005) Proteomic analysis for the early detection and rational treatment of cancer—realistic hope? Ann Oncol 16:16–22PubMedCrossRefGoogle Scholar
  35. Pereira SR, Faca VM, Gomes GG, Chammas R, Fontes AM, Covas DT, Greene LJ (2005) Changes in the proteomic profile during differentiation and maturation of human monocyte-derived dendritic cells stimulated with granulocyte macrophage colony stimulating factor/interleukin-4 and lipopolysaccharide. Proteomics 5:1186–1198PubMedCrossRefGoogle Scholar
  36. Pizzo P, Viola A (2005) Lipid-based membrane microdomains in T cell activation. Curr Immunol Rev 1:7–12CrossRefGoogle Scholar
  37. Richards J, Le, Naour F, Hanash S, Beretta L (2002) Integrated genomic and proteomic analysis of signaling pathways in dendritic cell differentiation and maturation. Ann NY Acad Sci 975:91–100PubMedCrossRefGoogle Scholar
  38. Schroer TA (1994) New insights into the interaction of cytoplasmic dynein with the actin-related protein, Arp 1. J Cell Biol 127:1–4PubMedCrossRefGoogle Scholar
  39. Schafer DA, Gill SR, Cooper JA, Heuse JE, Schroer TA (1994) Ultrastructural analysis of the dynactin complex:an actin-related protein is a component of a filament that resembles F-actin. J Cell Biol 126:403–412PubMedCrossRefGoogle Scholar
  40. Steinman RM, Turley S, Mellman I, Inaba K (2000) The induction of tolerance by dendritic cells that have captured apoptotic cells. J Exp Med 191:411–416PubMedCrossRefGoogle Scholar
  41. Steinman RM, Nussenzweig MC (2002) Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc Natl Acad Sci USA 99:351–358PubMedCrossRefGoogle Scholar
  42. Schnurr M, Galambos P, Scholz C, Then F, Dauer M, Endres S, Eigler A (2001) Tumor cell lysate-pulsed human dendritic cells induce a T-cell response against pancreatic carcinoma cells: an in vitro model for the assessment of tumor vaccines. Cancer Res 61:6445–6450PubMedGoogle Scholar
  43. Seliger B, Maeurer MJ, Ferrone S (2000) Antigen-processing machinery breakdown and tumor growth. Immunol Today 21:455–464PubMedCrossRefGoogle Scholar
  44. Slingluff CL Jr, Engelhard VH, Ferrone S (2000) Peptide and dendritic cell vaccines. Clin Cancer Res 12:2342s–2345sCrossRefGoogle Scholar
  45. Srivastava PK (2000) Immunotherapy of human cancer: lessons from mice. Nat Immunol 1:363–366PubMedCrossRefGoogle Scholar
  46. Um SH, Mulhall C, Alisa A, Ives AR, Karani J, Williams R, Bertoletti A, Behboudi S (2004) Alpha-fetoprotein impairs APC function and induces their apoptosis. J Immunol 1731:1772–1778Google Scholar
  47. Vallee RB, Sheetz MP (1996) Targeting of motor proteins. Science 271:1539–1544PubMedCrossRefGoogle Scholar
  48. Way M, Weeds A (1990) Actin-binding proteins. Cytoskeletal ups and downs. Nature 344:292–294PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Yong-Qiang Weng
    • 1
  • Shuang-Jian Qiu
    • 1
  • Yin-Kun Liu
    • 1
  • Jia Fan
    • 1
  • Qiang Gao
    • 1
  • Zhao-You Tang
    • 1
    Email author
  1. 1.Liver Cancer Institute and Zhong Shan HospitalFudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, Ministry of EducationShanghaiPeople’s Republic of China

Personalised recommendations