Skip to main content

Advertisement

SpringerLink
Log in

Metastatic tumor antigen in hepatocellular carcinoma: golden roads toward personalized medicine

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Hepatocellular carcinoma (HCC), a prototype of hypervascular tumors, is one of the most common malignancies in the world, especially hyperendemic in the Far East where chronic hepatitis B virus (HBV) infection is highly prevalent. It is characterized by the clinical feature of a poor prognosis or a high mortality due to its already far advanced stages at diagnosis. It is so multifactorial that hepatocarcinogenesis cannot be explained by a single molecular mechanism. To date, a number of pathways have been known to contribute to the development, growth, angiogenesis, and even metastasis of HCC. Among the various factors, metastatic tumor antigens (MTAs) or metastasis-associated proteins have been vigorously investigated as an intriguing target in the field of hepatocarcinogenesis. According to recent studies including ours, MTAs are not only involved in the HCC development and growth (molecular carcinogenesis), but also closely associated with the post-operative recurrence and a poor prognosis or a worse response to post-operative anti-cancer therapy (clinical significance). Herein, we review MTAs in light of their essential structure, functions, and molecular mechanism in hepatocarcinogenesis. We will also focus in detail on the interaction between hepatitis B x protein (HBx) of HBV and MTA in order to clarify the HBV-associated HCC development. Finally, we will discuss the prognostic significance and clinical application of MTA in HCC. We believe that this review will help clinicians to understand the meaning and use of the detection of MTA in order to more effectively manage their HCC patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Bosch, F. X., Ribes, J., Diaz, M., & Cleries, R. (2004). Primary liver cancer: worldwide incidence and trends. Gastroenterology, 127(5 Suppl 1), S5–S16.

    PubMed  Google Scholar 

  2. Kiyosawa, K., Umemura, T., Ichijo, T., Matsumoto, A., Yoshizawa, K., Gad, A., et al. (2004). Hepatocellular carcinoma: recent trends in Japan. Gastroenterology, 127(5 Suppl 1), S17–S26.

    PubMed  Google Scholar 

  3. El-serag, H. B. (2004). Hepatocellular carcinoma: recent trends in the United States. Gastroenterology, 127(5 Suppl 1), S27–S34.

    PubMed  Google Scholar 

  4. Chen, M. F., Hwang, T. L., Jeng, L. B., Jan, Y. Y., Wang, C. S., & Chou, F. F. (1989). Hepatic resection in 120 patients with hepatocellular carcinoma. Archives of Surgery, 124(9), 1025–1028.

    CAS  PubMed  Google Scholar 

  5. Tsuzuki, T., Sugioka, A., Ueda, M., Iida, S., Kanai, T., Yoshii, H., et al. (1990). Hepatic resection for hepatocellular carcinoma. Surgery, 107(5), 511–520.

    CAS  PubMed  Google Scholar 

  6. Nagorney, D. M., van Heerden, J. A., Ilstrup, D. M., & Adson, M. A. (1989). Primary hepatic malignancy: surgical management and determinants of survival. Surgery, 106(4), 740–748.

    CAS  PubMed  Google Scholar 

  7. Llovet, J. M., Fuster, J., & Bruix, J. (1999). Intention-to treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology, 30(6), 1434–1440.

    CAS  PubMed  Google Scholar 

  8. Okada, S., Shimada, K., Yamamoto, J., Takayama, T., Kosuge, T., Yamasaki, S., et al. (1994). Predictive factors for postoperative recurrence of hepatocellular carcinoma. Gastroenterology, 106(6), 1618–1624.

    CAS  PubMed  Google Scholar 

  9. Adachi, E., Maeda, T., Matsumata, T., Shirabe, K., Kinukawa, N., Sugimachi, K., et al. (1995). Risk factors for intrahepatic recurrence in human small hepatocellular carcinoma. Gastroenterology, 108(3), 768–775.

    CAS  PubMed  Google Scholar 

  10. Kumada, T., Nakano, S., Takeda, I., Sugiyama, K., Osada, T., Kiriyama, S., et al. (1997). Patterns of recurrence after initial treatment in patients with small hepatocellular carcinoma. Hepatology, 25(1), 87–92.

    CAS  PubMed  Google Scholar 

  11. Mahoney, M. G., Simpson, A., Jost, M., Noe, M., Kari, C., Pepe, D., et al. (2002). Metastasis-associated protein (MTA) 1 enhances migration, invasion, and anchorage-independent survival of immortalized human keratinocytes. Oncogene, 21(14), 2161–2170.

    CAS  PubMed  Google Scholar 

  12. Hofer, M. D., Menke, A., Genze, F., Gierschik, P., & Giehl, K. (2004). Expression of MTA1 promotes motility and invasiveness of PNAC-1 pancreatic carcinoma cells. British Journal of Cancer, 90(2), 455–462.

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Nicolson, G. L., Nawa, A., Toh, Y., Taniguchi, S., Nishimori, K., & Moustafa, A. (2003). Tumor metastasis-associated human MTA1 gene and its MTA1 protein product: role in epithelial cancer invasion, proliferation and nuclear regulation. Clinical and Experimental Metastasis, 20(1), 19–24.

    CAS  PubMed  Google Scholar 

  14. Moon, H. E., Cheon, H., Chun, K. H., Lee, S. K., Kim, Y. S., Jung, B. K., et al. (2006). Metastasis-associated protein 1 enhances angiogenesis by stabilization of HIF-1alpha. Oncology Reports, 16(4), 929–935.

    CAS  PubMed  Google Scholar 

  15. Yoo, Y. G., Kong, G., & Lee, M. O. (2006). Metastasis-associated protein 1 enhances stability of hypoxia-inducible factor-1alpha protein by recruiting histone deacetylase 1. EMBO Journal, 25(6), 1231–1241.

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Kim, S. H., Jeong, J. W., Park, J. A., Lee, J. W., Seo, J. H., Jung, B. K., et al. (2007). Regulation of the HIF-1alpha stability by histone deacetylases. Oncology Reports, 17(3), 647–651.

    CAS  PubMed  Google Scholar 

  17. Jang, K. S., Paik, S. S., Chung, H. K., Oh, Y. H., & Kong, G. (2006). MTA1 overexpression correlates significantly with tumor grade and angiogenesis in human breast cancer. Cancer Science, 97(5), 374–379.

    CAS  PubMed  Google Scholar 

  18. Martin, M. D., Hilsenbeck, S. G., Mohsin, S. K., Hopp, T. A., Clark, G. M., Osborne, C. K., et al. (2006). Breast tumors that overexpress nuclear metastasis-associated 1 (MTA1) protein have high recurrence risks but enhanced responses to systemic therapies. Breast Cancer Research and Treatment, 95(1), 7–12.

    CAS  PubMed  Google Scholar 

  19. Hofer, M. D., Kuefer, R., Varambally, S., Li, H., Ma, J., Shapiro, G. I., et al. (2004). The role of metastasis-associated protein 1 in prostate cancer progression. Cancer Research, 64(3), 825–829.

    CAS  PubMed  Google Scholar 

  20. Toh, Y., Ohga, T., Endo, K., Adachi, E., Kusumoto, H., Haraguchi, M., et al. (2004). Expression of the metastasis-associated MTA1 protein and its relationship to deacetylation of the histone H4 in esophageal squamous cell carcinomas. International Journal of Cancer, 110(3), 362–367.

    CAS  Google Scholar 

  21. Balasenthil, S., Broaddus, R. R., & Kumar, R. (2006). Expression of metastasis-associated protein 1 (MTA1) in benign endometrium and endometrial adenocarcinomas. Human Pathology, 37(6), 656–661.

    CAS  PubMed  Google Scholar 

  22. Toh, Y., Oki, E., Oda, S., Tokunaga, E., Ohno, S., Maehara, Y., et al. (1997). Overexpression of the MTA1 gene in gastrointestinal carcinomas: correlation with invasion and metastasis. International Journal of Cancer, 74(4), 459–463.

    CAS  Google Scholar 

  23. Sasaki, H., Moriyama, S., Nakashima, Y., Kobayashi, Y., Yukiue, H., Kaji, M., et al. (2002). Expression of the MTA1 mRNA in advanced lung cancer. Lung Cancer, 35(2), 149–154.

    PubMed  Google Scholar 

  24. Kumar, R., Wang, R. A., & Bagheri-Yarmand, R. (2003). Emerging roles of MTA family members in human cancers. Seminars in Oncology, 30(5 suppl 16), 30–37.

    CAS  PubMed  Google Scholar 

  25. Moon, W. S., Chang, K., & Tarnawski, A. S. (2004). Overexpression of metastatic tumor antigen 1 in hepatocellular carcinoma: relationship to vascular invasion and estrogen receptor-α. Human Pathology, 35(4), 424–429.

    CAS  PubMed  Google Scholar 

  26. Hamatsu, T., Rikimaru, T., Yamashita, Y., Aishima, S., Tanaka, S., Shirabe, K., et al. (2003). The role of MTA1 gene expression in human hepatocellular carcinoma. Oncology Reports, 10(3), 599–604.

    CAS  PubMed  Google Scholar 

  27. Ryu, S. H., Chung, Y. H., Lee, H., Kim, J. A., Shin, H. D., Min, H. J., et al. (2008). Metastatic tumor antigen 1 is closely associated with frequent post-operative recurrence and poor survival in patients with hepatocellular carcinoma. Hepatology, 47(3), 929–936.

    PubMed  Google Scholar 

  28. Lee, H., Ryu, S. H., Hong, S. S., Seo, D. D., Min, H. J., Jang, M. K., et al. (2009). Overexpression of metastasis-associated protein 2 is associated with hepatocellular carcinoma size and differentiation. Journal of Gastroenterology and Hepatology, 24(8), 1445–1450.

    PubMed  Google Scholar 

  29. Lee, S. H., Chung, Y. H., Kim, J. A., Lee, D., Jin, Y. J., Shim, J. H., et al. (2011). Single nucleotide polymorphisms associated with metastatic tumor antigen 1 overexpression in patients with hepatocellular carcinoma. Liver International, 32(3), 457–466.

    PubMed  Google Scholar 

  30. Jin, Y. J., Chung, Y. H., Kim, J. A., Park, W. H., Lee, D., Seo, D. D., et al. (2012). Factors predisposing metastatic tumor antigen 1 overexpression in hepatitis B virus associated hepatocellular carcinoma. Digestive Diseases and Sciences, 57(11), 2917–2923.

    CAS  PubMed  Google Scholar 

  31. Lee, D., Chung, Y. H., Kim, J. A., Park, W. H., Jin, Y. J., Shim, J. H., et al. (2013). Safety and efficacy of adjuvant pegylated interferon therapy for metastatic tumor antigen 1-positive hepatocellular carcinoma. Cancer, 119(12), 2239–2246.

    CAS  PubMed  Google Scholar 

  32. Yao, Y. L., & Yang, W. M. (2003). The metastasis-associated proteins 1 and 2 form distinct protein complexes with histone deacetylase activity. Journal of Biological Chemistry, 278(43), 42560–42568.

    CAS  PubMed  Google Scholar 

  33. Toh, Y., Pencil, S. D., & Nicolson, G. L. (1995). Analysis of the complete sequence of the novel metastasis-associated candidate gene, mta1, differentially expressed in mammary adenocarcinoma and breast cancer cell lines. Gene, 159(1), 97–104.

    CAS  PubMed  Google Scholar 

  34. Pencil, S. D., Toh, Y., & Nicolson, G. L. (1993). Candidate metastasis-associated genes of the rat 13762NF mammary adenocarcinoma. Breast Cancer Research and Treatment, 25(2), 165–174.

    CAS  PubMed  Google Scholar 

  35. Toh, Y., & Nicolson, G. L. (2009). The role of the MTA family and their encoded proteins in human cancers: molecular functions and clinical implications. Clinical and Experimental Metastasis, 26(3), 215–227.

    CAS  PubMed  Google Scholar 

  36. Manavathi, B., & Kumar, R. (2007). Metastasis tumor antigens, an emerging family of multifaceted master coregulators. Journal of Biological Chemistry, 282(3), 1529–1533.

    CAS  PubMed  Google Scholar 

  37. Nawa, A., Nishimori, K., Lin, P., Maki, Y., Moue, K., Sawada, H., et al. (2000). Tumor metastasis-associated human MTA1 gene: its deduced protein sequence, localization, and association with breast cancer cell proliferation using antisense phosphorothioate oligonucleotides. Journal of Cellular Biochemistry, 79(2), 202–212.

    CAS  PubMed  Google Scholar 

  38. Singh, R. R., & Kumar, R. (2007). MTA family of transcriptional metaregulators in mammary gland morphogenesis and breast cancer. Journal of Mammary Gland Biology and Neoplasia, 12(2–3), 115–125.

    PubMed  Google Scholar 

  39. Pawson, T., & Schlessingert, J. (1993). SH2 and SH3 domains. Current Biology, 3(7), 434–442.

    CAS  PubMed  Google Scholar 

  40. Bar-Sagi, D., Rotin, D., Batzer, A., Mandiyan, V., & Schlessinger, J. (1993). SH3 domains direct cellular localization of signaling molecules. Cell, 74(1), 83–91.

    CAS  PubMed  Google Scholar 

  41. Weng, Z., Taylor, J. A., Turner, C. E., Brugge, J. S., & Seidel-Dugan, C. (1993). Detection of Src homology 3-binding proteins, including paxillin, in normal and v-Src-transformed Balb/c 3T3 cells. Journal of Biological Chemistry, 268(20), 14956–14963.

    CAS  PubMed  Google Scholar 

  42. Toh, Y., Pencil, S. D., & Nicolson, G. L. (1994). A novel candidate metastasis-associated gene, mta1, differentially expressed in highly metastatic mammary adenocarcinoma cell lines. cDNA cloning, expression, and protein analyses. Journal of Biological Chemistry, 269(37), 22958–22963.

    CAS  PubMed  Google Scholar 

  43. Kumar, R., Wang, R. A., Mazumdar, A., Talukder, A. H., Mandal, M., Yang, Z., et al. (2002). A naturally occurring MTA1 variant sequesters oestrogen receptor-alpha in the cytoplasm. Nature, 418(6898), 654–657.

    CAS  PubMed  Google Scholar 

  44. Li, W., Ma, L., Zhao, J., Liu, X., Li, Z., & Zhang, Y. (2009). Expression profile of MTA1 in adult mouse tissues. Tissue and Cell, 41(6), 390–399.

    CAS  PubMed  Google Scholar 

  45. Liu, J., Xu, D., Wang, H., Zhang, Y., Chang, Y., Zhang, J., et al. (2014). The subcellular distribution and function of MTA1 in cancer differentiation. Oncotarget, 5(13), 5153–5164.

    PubMed Central  PubMed  Google Scholar 

  46. Nagaraj S. R., Shilpa P., Rachaiah K., Salimath B.P. (2013). Crosstalk between VEGF and MTA1 signaling pathways contribute to aggressiveness of breast carcinoma. Molecular Carcinogenesis, 2013 Nov 22. doi: 10.1002/mc.22104

  47. Neuveut, C., Wei, Y., & Buendia, M. A. (2010). Mechanisms of HBV-related hepatocarcinogenesis. Journal of Hepatology, 52(4), 594–604.

    CAS  PubMed  Google Scholar 

  48. Murakami, S. (2001). Hepatitis B virus X protein: a multifunctional viral regulator. Journal of Gastroenterology, 36(10), 651–660.

    CAS  PubMed  Google Scholar 

  49. Zhang, X., Zhang, H., & Ye, L. (2006). Effects of hepatitis B virus X protein on the development of liver cancer. Journal of Laboratory and Clinical Medicine, 147(2), 58–66.

    CAS  PubMed  Google Scholar 

  50. Yun, C., Um, H. R., Jin, Y. H., Wang, J. H., Lee, M. O., Park, S., et al. (2002). NF-kappaB activation by hepatitis B virus X (HBx) protein shifts the cellular fate toward survival. Cancer Letters, 184(1), 97–104.

    CAS  PubMed  Google Scholar 

  51. Chan, D. W., & Ng, I. O. (2006). Knock-down of hepatitis B virus X protein reduces the tumorigenicity of hepatocellular carcinoma cells. Journal of Pathology, 208(3), 372–380.

    CAS  PubMed  Google Scholar 

  52. Yoo, Y. G., Na, T. Y., Seo, H. W., Seong, J. K., Park, C. K., Shin, Y. K., et al. (2008). Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells. Oncogene, 27(24), 3405–3413.

    CAS  PubMed  Google Scholar 

  53. Feitelson, M. A., & Lee, J. (2007). Hepatitis B virus integration, fragile sites, and hepatocarcinogenesis. Cancer Letters, 252(2), 157–170.

    CAS  PubMed  Google Scholar 

  54. Liu, B., Wen, X., Huang, C., & Wei, Y. (2013). Unraveling the complexity of hepatitis B virus: from molecular understanding to therapeutic strategy in 50 years. International Journal of Biochemistry and Cell Biology, 45(9), 1987–1996.

    CAS  PubMed  Google Scholar 

  55. Wang, F., Zhou, H., Yang, Y., Xia, X., Sun, Q., Luo, J., et al. (2012). Hepatitis B virus X protein promotes the growth of hepatocellular carcinoma by modulation of the Notch signaling pathway. Oncology Reports, 27(4), 1170–1176.

    PubMed Central  PubMed  Google Scholar 

  56. Lara-Pezzi, E., Roche, S., Andrisani, O. M., Sánchez-Madrid, F., & López-Cabrera, M. (2001). The hepatitis B virus HBx protein induces adherens junction disruption in a src-dependent manner. Oncogene, 20(26), 3323–3331.

    CAS  PubMed  Google Scholar 

  57. Lara-Pezzi, E., Majano, P. L., Yáñez-Mó, M., Gómez-Gonzalo, M., Carretero, M., Moreno-Otero, R., et al. (2001). Effect of the hepatitis B virus HBx protein on integrin-mediated adhesion to and migration on extracellular matrix. Journal of Hepatology, 34(3), 409–415.

    CAS  PubMed  Google Scholar 

  58. Lara-Pezzi, E., Gómez-Gaviro, M. V., Gálvez, B. G., Mira, E., Iñiguez, M. A., Fresno, M., et al. (2002). The hepatitis B virus X protein promotes tumor cell invasion by inducing membrane-type matrix metalloproteinase-1 and cyclooxygenase-2 expression. Journal of Clinical Investigation, 110(12), 1831–1838.

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Chung, T. W., Lee, Y. C., & Kim, C. H. (2004). Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: involvement of invasive potential. FASEB Journal, 18(10), 1123–1125.

    CAS  PubMed  Google Scholar 

  60. Yu, F. L., Liu, H. J., Lee, J. W., Liao, M. H., & Shih, W. L. (2005). Hepatitis B virus X protein promotes cell migration by inducing matrix metalloproteinase-3. Journal of Hepatology, 42(4), 520–527.

    CAS  PubMed  Google Scholar 

  61. Ou, D. P., Tao, Y. M., Chang, Z. G., Tang, F. Q., & Yang, L. Y. (2006). Hepatocellular carcinoma cells containing hepatitis B virus X protein have enhanced invasive potential conditionally. Digestive and Liver Disease, 38(4), 262–267.

    CAS  PubMed  Google Scholar 

  62. Ou, D. P., Tao, Y. M., Tang, F. Q., & Yang, L. Y. (2007). The hepatitis B virus X protein promotes hepatocellular carcinoma metastasis by upregulation of matrix metalloproteinases. International Journal of Cancer, 120(6), 1208–1214.

    CAS  Google Scholar 

  63. Zhang, X., Liu, S., Hu, T., Liu, S., He, Y., & Sun, S. (2009). Up-regulated microRNA-143 transcribed by nuclear factor kappa B enhances hepatocarcinoma metastasis by repressing fibronectin expression. Hepatology, 50(2), 490–499.

    CAS  PubMed  Google Scholar 

  64. Manavathi, B., Singh, K., & Kumar, R. (2007). MTA family of coregulators in nuclear receptor biology and pathology. Nuclear Receptor Signaling, 5, e010.

    PubMed Central  PubMed  Google Scholar 

  65. Bui-Nguyen, T. M., Pakala, S. B., Sirigiri, R. D., Xia, W., Hung, M. C., Sarin, S. K., et al. (2010). NF-kappaB signaling mediates the induction of MTA1 by hepatitis B virus transactivator protein HBx. Oncogene, 29(8), 1179–1189.

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Jung, J. K., Park, S. H., & Jang, K. L. (2010). Hepatitis B virus X protein overcomes the growth-inhibitory potential of retinoic acid by downregulating retinoic acid receptor-beta2 expression via DNA methylation. Journal of General Virology, 91(Pt 2), 493–500.

    CAS  PubMed  Google Scholar 

  67. Park, I. Y., Sohn, B. H., Yu, E., Suh, D. J., Chung, Y. H., Lee, J. H., et al. (2007). Aberrant epigenetic modifications in hepatocarcinogenesis induced by hepatitis B virus X protein. Gastroenterology, 132(4), 1476–1494.

    CAS  PubMed  Google Scholar 

  68. Lee, M. H., Na, H., Na, T. Y., Shin, Y. K., Seong, J. K., & Lee, M. O. (2012). Epigenetic control of metastasis-associated protein 1 gene expression by hepatitis B virus X protein during hepatocarcinogenesis. Oncogenesis, 1, e25.

    PubMed Central  PubMed  Google Scholar 

  69. Reddy, S. D., Pakala, S. B., Ohshiro, K., Rayala, S. K., & Kumar, R. (2009). MicroRNA-661, a c/EBPalpha target, inhibits metastatic tumor antigen 1 and regulates its functions. Cancer Research, 69(14), 5639–5642.

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Bui-Nguyen, T. M., Pakala, S. B., Sirigiri, D. R., Martin, E., Murad, F., & Kumar, R. (2010). Stimulation of inducible nitric oxide by hepatitis B virus transactivator protein HBx requires MTA1 coregulator. Journal of Biological Chemistry, 285(10), 6980–6986.

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Aboobaker, A. A., Tomancak, P., Patel, N., Rubin, G. M., & Lai, E. C. (2005). Drosophila microRNAs exhibit diverse spatial expression patterns during embryonic development. Proceedings of the National Academy of Sciences of the United States of America, 102(50), 18017–18022.

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Iorio, M. V., Ferracin, M., Liu, C. G., Veronese, A., Spizzo, R., Sabbioni, S., et al. (2005). MicroRNA gene expression deregulation in human breast cancer. Cancer Research, 65(16), 7065–7070.

    CAS  PubMed  Google Scholar 

  73. Makeyev, E. V., & Maniatis, T. (2008). Multilevel regulation of gene expression by microRNAs. Science, 319(5871), 1789–1790.

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Behm-Ansmant, I., Rehwinkel, J., & Izaurralde, E. (2006). MicroRNAs silence gene expression by repressing protein expression and/or by promoting mRNA decay. Cold Spring Harbor Symposia on Quantitative Biology, 71, 523–530.

    CAS  PubMed  Google Scholar 

  75. Ma, L., Teruya-Feldstein, J., & Weinberg, R. A. (2007). Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature, 449(7163), 682–688.

    CAS  PubMed  Google Scholar 

  76. Reddy, S. D., Ohshiro, K., Rayala, S. K., & Kumar, R. (2008). MicroRNA-7, a homeobox D10 target, inhibits p21-activated kinase 1 and regulates its functions. Cancer Research, 68(20), 8195–8200.

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Kefas, B., Godlewski, J., Comeau, L., Li, Y., Abounader, R., Hawkinson, M., et al. (2008). microRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma. Cancer Research, 68(10), 3566–3572.

    CAS  PubMed  Google Scholar 

  78. Li, S., Tian, H., Yue, W., Li, L., Gao, C., Si, L., et al. (2013). Down-regulation of MTA1 protein leads to the inhibition of migration, invasion, and angiogenesis of non-small-cell lung cancer cell line. Acta Biochimica et Biophysica Sinica, 45(2), 115–122.

    CAS  PubMed  Google Scholar 

  79. Mazure, N. M., Brahimi-Horn, M. C., Berta, M. A., Benizri, E., Bilton, R. L., Dayan, F., et al. (2004). HIF-1: master and commander of the hypoxic world. A pharmacological approach to its regulation by siRNAs. Biochemical Pharmacology, 68(6), 971–980.

    CAS  PubMed  Google Scholar 

  80. Bruick, R. K., & McKnight, S. L. (2001). A conserved family of prolyl-4-hydroxylases that modify HIF. Science, 294(5545), 1337–1340.

    CAS  PubMed  Google Scholar 

  81. Epstein, A. C., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O’Rourke, J., Mole, D. R., et al. (2001). C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell, 107(1), 43–54.

    CAS  PubMed  Google Scholar 

  82. Semenza, G. L. (2003). Targeting HIF-1 for cancer therapy. Nature Reviews Cancer, 3(10), 721–732.

    CAS  PubMed  Google Scholar 

  83. Jeong, J. W., Bae, M. K., Ahn, M. Y., Kim, S. H., Sohn, T. K., Bae, M. H., et al. (2002). Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation. Cell, 111(5), 709–720.

    CAS  PubMed  Google Scholar 

  84. Côté, J., Quinn, J., Workman, J. L., & Peterson, C. L. (1994). Stimulation of GAL4 derivative binding to nucleosomal DNA by the yeast SWI/SNF complex. Science, 265(5168), 53–60.

    PubMed  Google Scholar 

  85. Kwon, H., Imbalzano, A. N., Khavari, P. A., Kingston, R. E., & Green, M. R. (1994). Nucleosome disruption and enhancement of activator binding by a human SW1/SNF complex. Nature, 370(6489), 477–481.

    CAS  PubMed  Google Scholar 

  86. Tsukiyama, T., & Wu, C. (1995). Purification and properties of an ATP-dependent nucleosome remodeling factor. Cell, 83(6), 1011–1020.

    CAS  PubMed  Google Scholar 

  87. Cairns, B. R., Lorch, Y., Li, Y., Zhang, M., Lacomis, L., Erdjument-Bromage, H., et al. (1996). RSC, an essential, abundant chromatin-remodeling complex. Cell, 87(7), 1249–1260.

    CAS  PubMed  Google Scholar 

  88. Wang, W., Chi, T., Xue, Y., Zhou, S., Kuo, A., & Crabtree, G. R. (1998). Architectural DNA binding by a high-mobility-group/kinesin-like subunit in mammalian SWI/SNF-related complexes. Proceedings of the National Academy of Sciences of the United States of America, 95(2), 492–498.

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Varga-Weisz, P. D., Wilm, M., Bonte, E., Dumas, K., Mann, M., & Becker, P. B. (1997). Chromatin-remodelling factor CHRAC contains the ATPases ISWI and topoisomerase II. Nature, 388(6642), 598–602.

    CAS  PubMed  Google Scholar 

  90. Xue, Y., Wong, J., Moreno, G. T., Young, M. K., Côté, J., & Wang, W. (1998). NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Molecular Cell, 2(6), 851–861.

    CAS  PubMed  Google Scholar 

  91. Nair, S. S., Bommana, A., Bethony, J. M., Lyon, A. J., Ohshiro, K., Pakala, S. B., et al. (2011). The metastasis-associated protein-1 gene encodes a host permissive factor for schistosomiasis, a leading global cause of inflammation and cancer. Hepatology, 54(1), 285–295.

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Ghanta, K. S., Pakala, S. B., Reddy, S. D., Li, D. Q., Nair, S. S., & Kumar, R. (2011). MTA1 coregulation of transglutaminase 2 expression and function during inflammatory response. Journal of Biological Chemistry, 286(9), 7132–7138.

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Pakala, S. B., Bui-Nguyen, T. M., Reddy, S. D., Li, D. Q., Peng, S., Rayala, S. K., et al. (2010). Regulation of NF-kappaB circuitry by a component of the nucleosome remodeling and deacetylase complex controls inflammatory response homeostasis. Journal of Biological Chemistry, 285(31), 23590–23597.

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Pakala, S. B., Reddy, S. D., Bui-Nguyen, T. M., Rangparia, S. S., Bommana, A., & Kumar, R. (2010). MTA1 coregulator regulates LPS response via MyD88-dependent signaling. Journal of Biological Chemistry, 285(43), 32787–32792.

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Li, D. Q., Pakala, S. B., Reddy, S. D., Ohshiro, K., Peng, S. H., Lian, Y., et al. (2010). Revelation of p53-independent function of MTA1 in DNA damage response via modulation of the p21 WAF1-proliferating cell nuclear antigen pathway. Journal of Biological Chemistry, 285(13), 10044–10052.

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Van Rechem, C., Boulay, G., Pinte, S., Stankovic-Valentin, N., Guérardel, C., & Leprince, D. (2010). Differential regulation of HIC1 target genes by CtBP and NuRD, via an acetylation/SUMOylation switch, in quiescent versus proliferating cells. Molecular and Cellular Biology, 30(16), 4045–4059.

    PubMed Central  PubMed  Google Scholar 

  97. Wales, M. M., Biel, M. A., el Deiry, W., Nelkin, B. D., Issa, J. P., Cavenee, W. K., et al. (1995). p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Nature Medicine, 1(6), 570–577.

    CAS  PubMed  Google Scholar 

  98. El-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., et al. (1993). WAF1, a potential mediator of p53 tumor suppression. Cell, 75(4), 817–825.

    CAS  PubMed  Google Scholar 

  99. Vitari, A. C., Leong, K. G., Newton, K., Yee, C., O’Rourke, K., Liu, J., et al. (2011). COP1 is a tumour suppressor that causes degradation of ETS transcription factors. Nature, 474(7351), 403–406.

    CAS  PubMed  Google Scholar 

  100. Migliorini, D., Bogaerts, S., Defever, D., Vyas, R., Denecker, G., Radaelli, E., et al. (2011). Cop1 constitutively regulates c-Jun protein stability and functions as a tumor suppressor in mice. Journal of Clinical Investigation, 121(4), 1329–1343.

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Li, D. Q., Ohshiro, K., Reddy, S. D., Pakala, S. B., Lee, M. H., Zhang, Y., et al. (2009). E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1. Proceedings of the National Academy of Sciences of the United States of America, 106(41), 17493–17498.

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Luo, J., Su, F., Chen, D., Shiloh, A., & Gu, W. (2000). Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature, 408(6810), 377–381.

    CAS  PubMed  Google Scholar 

  103. Ohshiro, K., Rayala, S. K., Wigerup, C., Pakala, S. B., Natha, R. S., Gururaj, A. E., et al. (2010). Acetylation-dependent oncogenic activity of metastasis-associated protein 1 co-regulator. EMBO Reports, 11(9), 691–697.

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Denslow, S. A., & Wade, P. A. (2007). The human Mi-2/NuRD complex and gene regulation. Oncogene, 26(37), 5433–5438.

    CAS  PubMed  Google Scholar 

  105. Mazumdar, A., Wang, R. A., Mishra, S. K., Adam, L., Bagheri-Yarmand, R., Mandal, M., et al. (2001). Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor. Nature Cell Biology, 3(1), 30–37.

    CAS  PubMed  Google Scholar 

  106. Hay, E. D. (1995). An overview of epithelio-mesenchymal transformation. Acta Anatomica, 154(1), 8–20.

    CAS  PubMed  Google Scholar 

  107. Lamouille, S., Xu, J., & Derynck, R. (2014). Molecular mechanisms of epithelial-mesenchymal transition. Nature Reviews Molecular Cell Biology, 15(3), 178–196.

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Medici, D., & Kalluri, R. (2012). Endothelial-mesenchymal transition and its contribution to the emergence of stem cell phenotype. Seminars in Cancer Biology, 22(5–6), 379–384.

    CAS  PubMed Central  PubMed  Google Scholar 

  109. van Meeteren, L. A., & ten Dijke, P. (2012). Regulation of endothelial cell plasticity by TGF-β. Cell and Tissue Research, 347(1), 177–186.

    PubMed Central  PubMed  Google Scholar 

  110. Zeisberg, E. M., Potenta, S., Xie, L., Zeisberg, M., & Kalluri, R. (2007). Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Research, 67(21), 10123–10128.

    CAS  PubMed  Google Scholar 

  111. Lee, S. W., Won, J. Y., Kim, W. J., Lee, J., Kim, K. H., Youn, S. W., et al. (2013). Snail as a potential target molecule in cardiac fibrosis: paracrine action of endothelial cells on fibroblasts through snail and CTGF axis. Molecular Therapy, 21(9), 1767–1777.

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Medici, D., Shore, E. M., Lounev, V. Y., Kaplan, F. S., Kalluri, R., & Olsen, B. R. (2010). Conversion of vascular endothelial cells into multipotent stem-like cells. Nature Medicine, 16(12), 1400–1406.

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Wong, L. L., Chang, C. F., Koay, E. S., & Zhang, D. (2009). Tyrosine phosphorylation of PP2A is regulated by HER-2 signalling and correlates with breast cancer progression. International Journal of Oncology, 34(5), 1291–1301.

    CAS  PubMed  Google Scholar 

  114. Kim, R., Arihiro, K., Emi, M., Tanabe, K., & Osaki, A. (2006). Potential role of HER-2; in primary breast tumor with bone metastasis. Oncology Reports, 15(6), 1477–1484.

    CAS  PubMed  Google Scholar 

  115. Jiang, W. G., Lloyds, D., Puntis, M. C., Nakamura, T., & Hallett, M. B. (1993). Regulation of spreading and growth of colon cancer cells by hepatocyte growth factor. Clinical and Experimental Metastasis, 11(3), 235–242.

    CAS  PubMed  Google Scholar 

  116. Jiang, W., Hiscox, S., Matsumoto, K., & Nakamura, T. (1999). Hepatocyte growth factor/scatter factor, its molecular, cellular and clinical implications in cancer. Critical Reviews in Oncology/Hematology, 29(3), 209–248.

    CAS  PubMed  Google Scholar 

  117. Stoker, M., & Perryman, M. (1985). An epithelial scatter factor released by embryo fibroblasts. Journal of Cell Science, 77, 209–223.

    CAS  PubMed  Google Scholar 

  118. Savagner, P., Yamada, K. M., & Thiery, J. P. (1997). The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition. Journal of Cell Biology, 137(6), 1403–1419.

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Grotegut, S., von Schweinitz, D., Christofori, G., & Lehembre, F. (2006). Hepatocyte growth factor induces cell scattering through MAPK/Egr-1-mediated upregulation of Snail. EMBO Journal, 25(15), 3534–3545.

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Hiscox, S., & Jiang, W. G. (1999). Association of the HGF/SF receptor, c-met, with the cell-surface adhesion molecule, E-cadherin, and catenins in human tumor cells. Biochemical and Biophysical Research Communications, 261(2), 406–411.

    CAS  PubMed  Google Scholar 

  121. Pakala, S. B., Singh, K., Reddy, S. D., Ohshiro, K., Li, D. Q., Mishra, L., et al. (2011). TGF-β1 signaling targets metastasis-associated protein 1, a new effector in epithelial cells. Oncogene, 30(19), 2230–2241.

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Thiery, J. P. (2002). Epithelial-mesenchymal transitions in tumour progression. Nature Reviews Cancer, 2(6), 442–454.

    CAS  PubMed  Google Scholar 

  123. Dannenmann, C., Shabani, N., Friese, K., Jeschke, U., Mylonas, I., & Brüning, A. (2008). The metastasis-associated gene MTA1 is upregulated in advanced ovarian cancer, represses ERbeta, and enhances expression of oncogenic cytokine GRO. Cancer Biology and Therapy, 7(9), 1460–1467.

    CAS  PubMed  Google Scholar 

  124. Batlle, E., Sancho, E., Francí, C., Domínguez, D., Monfar, M., Baulida, J., et al. (2000). The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nature Cell Biology, 2(2), 84–89.

    CAS  PubMed  Google Scholar 

  125. Polyak, K., & Weinberg, R. A. (2009). Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nature Reviews Cancer, 9(4), 265–273.

    CAS  PubMed  Google Scholar 

  126. Moon, E. J., Jeong, C. H., Jeong, J. W., Kim, K. R., Yu, D. Y., Murakami, S., et al. (2004). Hepatitis B virus X protein induces angiogenesis by stabilizing hypoxia-inducible factor-1α. FASEB Journal, 18(2), 382–384.

    CAS  PubMed  Google Scholar 

  127. Zhang, X. Y., DeSalle, L. M., Patel, J. H., Capobianco, A. J., Yu, D., Thomas-Tikhonenko, A., et al. (2005). Metastasis-associated protein I (MTA1) is an essential downstream effector of the c-MYC oncoprotein. Proceedings of the National Academy of Sciences of the United States of America, 102(39), 13968–13973.

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Terradillos, O., Billet, O., Renard, C. A., Levy, R., Molina, T., Briand, P., et al. (1997). The hepatitis B virus X gene potentiates c-MYC induced liver oncogenesis in transgenic mice. Oncogene, 14(4), 395–404.

    CAS  PubMed  Google Scholar 

  129. Ou, D. P., Tao, Y. M., Tang, F. Q., & Yang, L. Y. (2007). The hepatitis B virus X protein promotes hepatocellular carcinoma metastasis by upregulation of matrix metalloproteinases. International Journal of Cancer, 120(6), 1208–1214.

    CAS  Google Scholar 

  130. Zhang, Y., Ng, H. H., Erdjument-Bromage, H., Tempst, P., Bird, A., & Reinberg, D. (1999). Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes and Development, 13(15), 1924–1935.

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Park, N. H., Song, I. H., & Chung, Y. H. (2006). Chronic hepatitis B in hepatocarcinogenesis. Postgraduate Medical Journal, 82(970), 507–51.

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Yamaguchi, R., Yano, H., Iemura, A., Ogasawara, S., Haramaki, M., & Kojiro, M. (1998). Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology, 28(1), 68–77.

    CAS  PubMed  Google Scholar 

  133. Pang, R., & Poon, R. T. (2006). Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma. Cancer Letters, 242(2), 151–167.

    CAS  PubMed  Google Scholar 

  134. Song, B. C., Chung, Y. H., Kim, J. A., Lee, H. C., Yoon, H. K., Sung, K. B., et al. (2001). Association between insulin-like growth factor-2 and metastases after transcatheter arterial chemoembolization in patients with hepatocellular carcinoma: a prospective study. Cancer, 91(12), 2386–2393.

    CAS  PubMed  Google Scholar 

  135. Li, H., Sun, L., Xu, Y., Li, Z., Luo, W., Tang, Z., et al. (2013). Overexpression of MTA3 correlates with tumor progression in non-small cell lung cancer. Plos One, 8(6), 1–8.

    Google Scholar 

  136. Zhang, H., Stephens, L. C., & Kumar, R. (2006). Metastasis tumor antigen family proteins during breast cancer progression and metastasis in a reliable mouse model for human breast cancer. Clinical Cancer Research, 12(5), 1479–1486.

    CAS  PubMed  Google Scholar 

  137. Dong, H., Guo, H., Xie, L., Wang, G., Zhong, X., Khoury, T., et al. (2013). The metastasis-associated gene MTA3, a component of the Mi-2/NuRD transcriptional repression complex, predicts prognosis of gastroesophageal junction adenocarcinoma. PloS One, 8(5), e62986.

    CAS  PubMed Central  PubMed  Google Scholar 

  138. Chu, H., Chen, X., Wang, H., Du, Y., Wang, Y., Zang, W., et al. (2014). MiR-495 regulates proliferation and migration in NSCLC by targeting MTA3. Tumour Biology, 35(4), 3487–3494.

    CAS  PubMed  Google Scholar 

  139. Zhong, J. H., Ma, L., & Li, L. Q. (2014). Postoperative therapy options for hepatocellular carcinoma. Scandivian Journal of Gastroenterology, 49(6), 649–661.

    CAS  Google Scholar 

  140. Shin, J. W., & Chung, Y. H. (2013). Molecular targeted therapy for hepatocellular carcinoma: current and future. World Journal of Gastroenterology, 19(37), 6144–6155.

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Ikeda, K., Saitoh, S., Suzuki, Y., Kobayashi, M., Tsubota, A., Fukuda, M., et al. (1998). Interferon decreases hepatocellular carcinogenesis in patients with cirrhosis caused by the hepatitis B virus: a pilot study. Cancer, 82(5), 827–835.

    CAS  PubMed  Google Scholar 

  142. Yoshida, H., Shiratori, Y., Moriyama, M., Arakawa, Y., Ide, T., Sata, M., et al. (1999). Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group Inhibition of Hepatocarcinogenesis by Interferon Therapy. Annals of Internal Medicine, 131(3), 174–181.

    CAS  PubMed  Google Scholar 

  143. Sun, H. C., Tang, Z. Y., Wang, L., Qin, L. X., Ma, Z. C., Ye, Q. H., et al. (2006). Postoperative interferon alpha treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial. Journal of Cancer Research and Clinical Oncology, 132(7), 458–465.

    CAS  PubMed  Google Scholar 

  144. Kudo, M. (2008). Impact of interferon therapy after curative treatment of hepatocellular carcinoma. Oncology, 75(suppl 1), 30–41.

    CAS  PubMed  Google Scholar 

  145. Zeisberg, M., Yang, C., Martino, M., Duncan, M. B., Rieder, F., Tanjore, H., et al. (2007). Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. Journal of Biological Chemistry, 282(32), 23337–23347.

    CAS  PubMed  Google Scholar 

  146. Kim, K. H., Lee, W. R., Kang, Y. N., Chang, Y. C., & Park, K. K. (2014). Inhibitory effect of nuclear factor-κB decoy oligodeoxynucleotide on liver fibrosis through regulation of the epithelial-mesenchymal transition. Human Gene Therapy, 25(8), 721–729.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Inje University College of Medicine, Seoul Paik Hospital, Seoul, South Korea

    Soo Hyung Ryu

  2. Department of Internal Medicine, Hallym University College of Medicine, Kangdong Sacred Heart Hospital, Seoul, South Korea

    Myoung Kuk Jang

  3. National Research Center for Sexual Medicine, Inha University College of Medicine, Inha University Hospital, Inchon, South Korea

    Woo Jean Kim

  4. Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, South Korea

    Danbi Lee & Young-Hwa Chung

Authors
  1. Soo Hyung Ryu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Myoung Kuk Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Woo Jean Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Danbi Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Young-Hwa Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Young-Hwa Chung.

Additional information

Soo Hyung Ryu, Myoung Kuk Jang, and Woo Jean Kim contributed equally to the article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ryu, S.H., Jang, M.K., Kim, W.J. et al. Metastatic tumor antigen in hepatocellular carcinoma: golden roads toward personalized medicine. Cancer Metastasis Rev 33, 965–980 (2014). https://doi.org/10.1007/s10555-014-9522-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-014-9522-4

Keywords

Search

Navigation