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Up-regulation of E-cadherin and β-catenin in human hepatocellular carcinoma cell lines by sodium butyrate and interferon-α

  • Cell Growth/Differentiation/Apoptosis
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Summary

Human E-cadherin is a homophilic cell adhesion molecule and its expression is well preserved in normal human hepatocytes; a decrease in its expression has been observed in poorly differentiated hepatocellular carcinoma cells. We examined the alteration of E-cadherin and catenin expressions caused by differentiation inducers in human hepatocellular carcinoma cells. Hepatocellular carcinoma cell lines, HCC-T and HCC-M, were cultured with all-trans retinoic acid (ATRA), dexamethasone (DEX), sodium butyrate, and interferon-α. E-cadherin expression was only up-regulated by butyrate and interferon-α (IFN-α) in both cell lines, studied by means of fluorescence immunostaining and flow cytometry. The localization of E-cadherin staining was shown at their cell membrane. According to the increase in E-cadherin expression, β-catenin expression appeared at the cell membrane of both cell lines when treated with butyrate and IFN-α. Such an appearance was not observed when cells were treated with ATRA and DEX. Western blotting showed that α-and γ-catenin expression was not changed, while only the expression of β-catenin increased. β-Catenin oncogenic activation as a result of amino acid substitutions or interstitial deletions within or including parts of exon 3, which has been demonstrated recently, was not detected in these cell lines by direct deoxyribonucleic acid sequencing. These results suggest that the expression and interaction between E-cadherin and wild-type β-catenin are potentially modulated by butyrate and IFN-α, and that these two agents are potent inhibitors of hepatocellular carcinoma cell invasion and metastasis.

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References

  • Aberle, H.; Buiz, S.; Stappert, J., et al. Assembly of the cadherin-catenin complex in vitro with recombinant proteins. J. Cell Sci. 107:3655–3663; 1994.

    PubMed  CAS  Google Scholar 

  • Byers, S.; Pishvaian, M.; Crockett, C., et al. Retinoids increase cell-cell adhesion strength, β-catenin protein stability, and localization to the cell membrane in a breast cancer cell line: a role for serine kinase activity. Endocrinology 137:3265–3273; 1996.

    Article  PubMed  CAS  Google Scholar 

  • Ebinuma, H.; Saito, H.; Saito, Y., et al. Antisense oligodeoxynucleotide against c-myc mRNA induces differentiation of human hepatocellular carcinoma cells. Int. J. Oncol. 15:991–999; 1999.

    PubMed  CAS  Google Scholar 

  • Funayama N.; Fagotto, F.; McCrea, P.; Gumbiner, B. Embryonic axis induction by the armadillo repeat domain of β-catenin: evidence for intracellular signaling. J. Cell Biol. 128:959–968; 1995.

    Article  PubMed  CAS  Google Scholar 

  • Hinck, L.; Näthke, I. S.; Papkoff, J.; Nelson, W. J. Dynamics of cadherin/catenin complex formation: novel protein interactions and pathways of complex assembly. J. Cell Biol. 125:1327–1340; 1994.

    Article  PubMed  CAS  Google Scholar 

  • Hirano, S.; Kimoto, N.; Shimoyama, Y., et al. Identification of a neural α-catenin as a key regulator of cadherin function and multicellular organization. Cell 70:293–301; 1992.

    Article  PubMed  CAS  Google Scholar 

  • Ihara, A.; Koizumi, H.; Hashizume, R.; Uchikoshi, T. Expression of epithelial cadherin and alpha- and beta-catenins in nontumoral livers and hepatocellular carcinomas. Hepatology 23:1441–1447; 1996.

    PubMed  CAS  Google Scholar 

  • Ilan, Y.; Saito, H.; Thummala, N. R., et al. Adenovirus-mediated gene therapy of liver diseases. Semin Liver Dis. 19:49–59; 1999.

    Article  PubMed  CAS  Google Scholar 

  • Jawkari, A.; Jordan, S.; Poole, S., et al. Abnormal immunoreactivity of the E-cadherin-catenin complex in gastric carcinoma: relationship with patient survival. Gastroenterology 112:46–54; 1997.

    Article  Google Scholar 

  • Jou, T. S.; Stewart, D. B.; Stappert, J., et al. Genetic and biochemical dissection of protein linkages in the cadherin-catenin complex. Proc. Natl. Acad. Sci. USA 92:5067–5071; 1995.

    Article  PubMed  CAS  Google Scholar 

  • Koch, A.; Denkhaus, D.; Alberecht, S., et al. Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the β-catenin gene. Cancer Res. 59:269–273; 1999.

    PubMed  CAS  Google Scholar 

  • Kozyraki, R.; Scoazec, J. Y.; Flejou, J. F., et al. Expression of cadherins and alpha-catenin in primary epithelial tumors of the liver. Gastroenterology 110:1137–1149; 1996.

    Article  PubMed  CAS  Google Scholar 

  • Leung, M.-F.; Lin, T. S.; Sartorelli, A. C. Changes in actin and actin-binding proteins during the differentiation of HL-60 leukemia cells. Cancer Res. 52:3063–3066; 1992.

    PubMed  CAS  Google Scholar 

  • Mareel, M. M.; Behrens, J.; Birchmeier, W., et al. Down-regulation of E-cadherin expression in Madin Darby canine kidney (MDCK) cells inside tumors of nude mice. Int. J. Cancer 47:922–928; 1991.

    Article  PubMed  CAS  Google Scholar 

  • Matarrese, P.; Giandomenico, V.; Fiorucci, G., et al. Antiproliferative activity of interferon a and retinoic acid in SiHa carcinoma cells: the role of cell adhesion. Int. J. Cancer 76:531–540; 1998.

    Article  PubMed  CAS  Google Scholar 

  • Miyoshi, Y.; Iwao, K.; Nagasawa, Y., et al. Activation of the β-catenin gene in primary hepatocellular carcinoma by somatic alterations involving exon 3. Cancer Res. 58:2524–2527; 1998.

    PubMed  CAS  Google Scholar 

  • Morton, R. A.; Ewing, C. M.; Nagafuchi, A., et al. Reduction of E-cadherin levels and deletion of the α-catenin gene in human prostate cancer cells. Cancer Res. 53:3585–3590; 1993.

    PubMed  CAS  Google Scholar 

  • Nagafuchi, A.; Takeichi, M. Trasmembrane control of cadherin-mediated cell adhesion: a 94-kDa protein functionally associated with a specific region of the cytoplasmic domain of E-cadherin. Cell Regul. 1:37–44; 1989.

    PubMed  CAS  Google Scholar 

  • Oyama, T.; Kanai, Y.; Ochiai, A., et al. A truncated β-catenin disrupts the interaction between E-cadherin and α-catenin: a cause of loss of intercellular adhesiveness in human cancer cell lines. Cancer Res. 54: 6282–6287; 1994.

    PubMed  CAS  Google Scholar 

  • Ozawa, M.; Baribault, H.; Kemler, R. The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species. EMBO J. 8:1711–1717; 1989.

    PubMed  CAS  Google Scholar 

  • Pavalko, F. M.; Otey, C. A. Role of adhesion molecule cytoplasmic domains in mediating interactions with the cytoskeleton. Proc. Soc. Exp. Biol. Med. 205:282–293; 1994.

    PubMed  CAS  Google Scholar 

  • Perimon, N. The genetic basis of patterned baldness in Drosophila. Cell 76: 781–784; 1994.

    Article  Google Scholar 

  • Polakis, P. The oncogenic activation of beta-catenin. Curr. Opin. Genet. Dev. 9:15–21; 1999.

    Article  PubMed  CAS  Google Scholar 

  • Saito, H.; Ebinuma, H.; Takahashi, M., et al. Loss of butyrate-induced apoptosis in human hepatocellular carcinoma cell lines HCC-M and HCC-T having substantial Bcl-2 expression. Hepatology 27:1233–1240; 1998.

    Article  PubMed  CAS  Google Scholar 

  • Saito, H.; Kagawa, T.; Tada, S., et al. Effect of dexamethasone, dimethyl-sulfoxide and sodium butyrate on a human hepatocellular carcinoma cell line PLC/PRF/5. Cancer Biochem. Biophys. 13:75–84; 1992.

    PubMed  CAS  Google Scholar 

  • Saito, H.; Morizane, T.; Watanabe, T., et al. Establishment of a human cell line (HCC-T) from a patient with hepatocellular carcinoma bearing no evidence of hepatitis B or A virus infection. Cancer 64:1054–1060; 1989.

    Article  PubMed  CAS  Google Scholar 

  • Saito, H.; Morizane, T.; Watanabe, T., et al. Differentiating effect of sodium butyrate on human hepatocellular carcinoma cell lines PLC/PRF/5, HCC-M and HCC-T. Int. J. Cancer 48:291–296; 1991.

    Article  PubMed  CAS  Google Scholar 

  • Saito, H.; Tada, S.; Ebinuma, H., et al. Changes of antigen expression on human hepatocellular carcinoma cell lines caused by sodium butyrate, a differentiation inducer. J. Gastroenterol. 29:733–739; 1994.

    Article  PubMed  CAS  Google Scholar 

  • Saunders, N.; Dicker, A.; Popa, C., et al. Histone deacetylase inhibitors as potential anti-skin cancer agents. Cancer Res. 59:399–404; 1999.

    PubMed  CAS  Google Scholar 

  • Schipper, J. H.; Unger, A.; Jahnke, K. E-cadherin as a functional marker of the differentiation and invasiveness of squamous cell carcinoma of the head and neck. Clin. Otolaryngol. 19:381–384; 1994.

    PubMed  CAS  Google Scholar 

  • Shimamura, K.; Takahashi, T.; Takeichi, T. E-cadherin expression in a particular subset of sensory neurons. Dev. Biol. 152:242–254; 1992.

    Article  PubMed  CAS  Google Scholar 

  • Shimazui, T.; Schalken, J. A.; Giroldi, L. A., et al. Prognostic values of cadherin-associated molecules (α-, β-, and γ-catenin and p120cas) in bladder tumors. Cancer Res. 56:4154–4158; 1996.

    PubMed  CAS  Google Scholar 

  • Shimoyama, Y.; Hirohashi, S.; Hirano, S. et al. Cadherin cell-adhesion molecules in human epithelial tissues and carcinomas. Cancer Res. 49: 2128–2133; 1989.

    PubMed  CAS  Google Scholar 

  • Shimoyama, Y.; Hirohashi, S. Cadherin intercellular adhesion molecule in hepatocellular carcinomas: loss of E-cadherin expression in an undifferentiated carcinoma. Cancer Lett. 57:131–135; 1991.

    Article  PubMed  CAS  Google Scholar 

  • Späth, G. F.; Weiss, M. C. Hepatocyte nuclear factor 4 provokes expression of epithelial marker genes, acting as a morphogen in dedifferentiated hepatocellular carcinoma cells. J. Cell. Biol. 140:935–946; 1998.

    Article  PubMed  Google Scholar 

  • Tabibzadeh, S.; Kong, Q. F.; Kapur, S., et al. Tumor necrosis factor-α-mediated dyscohesion of epithelial cells associated with disordered expression of cadherin/β-catenin and assembly of actin filaments Hum. Reprod. 10:994–1004; 1995.

    PubMed  CAS  Google Scholar 

  • Tada, S.; Saito, H.; Ebinuma, H., et al. Reduction of LAK-sensitivity and changes in antigen expression on hepatoma cells by sodium butyrate. Cancer Biochem. Biophys. 15:177–186; 1996.

    PubMed  CAS  Google Scholar 

  • Tada, S.; Saito, H.; Tsunematsu, S., et al. Interferon regulatory factor-1 gene abnormality and loss of growth inhibitory effect of interferon-α in human hepatoma cell lines. Int. J. Oncol. 13:1207–1216; 1998.

    PubMed  CAS  Google Scholar 

  • Takeichi, M. Cadherin cell adhesion receptors as a morphogenetic regulator. Science 251:1451–1455; 1991.

    Article  PubMed  CAS  Google Scholar 

  • Takeichi, M. Cadherin in cancer: implications for invasion and metastasis. Curr. Opin. Cell Biol. 5:806–811; 1993.

    Article  PubMed  CAS  Google Scholar 

  • Watabe, M.; Nagafuchi, A.; Tsukita, S., et al. Induction of polarized cell-cell association and retardation of growth by activation of the E-cadherin-catenin adhesion system in a dispersed carcinoma line. J. Cell Biol. 127:247–256; 1994.

    Article  PubMed  CAS  Google Scholar 

  • Watanabe, T.; Morizane, T.; Tsuchimoto, K., et al. Establishment of a cell line (HCC-M) from a human hepatocellular carcinoma. Int. J. Cancer 32: 141–146; 1983.

    Article  PubMed  CAS  Google Scholar 

  • van der Wurff, A. A. M.; Arends, J.-W.; van der Linden, E. P. M., et al. L-CAM expression in lymph node and liver metastases of colorectal carcinomas. J. Pathol. 172:177–182; 1994.

    Article  PubMed  Google Scholar 

  • Zetter, B. R. Adhesion molecules in tumor metastasis. Semin. Cancer Biol. 4:219–229; 1993.

    PubMed  CAS  Google Scholar 

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Correspondence to Hidetsugu Saito.

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Masuda, T., Saito, H., Kaneko, F. et al. Up-regulation of E-cadherin and β-catenin in human hepatocellular carcinoma cell lines by sodium butyrate and interferon-α. In Vitro Cell.Dev.Biol.-Animal 36, 387–394 (2000). https://doi.org/10.1290/1071-2690(2000)036<0387:UROECA>2.0.CO;2

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  • DOI: https://doi.org/10.1290/1071-2690(2000)036<0387:UROECA>2.0.CO;2

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