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Arsenic trioxide: marked suppression of tumor metastasis potential by inhibiting the transcription factor Twist in vivo and in vitro

  • Original Article – Cancer Research
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Abstract

Purpose

Arsenic trioxide (ATO) has been found effective in several types of cancer cells, including acute promyelocytic leukemia, and recently in hepatocellular carcinoma (HCC). In this study, we investigated the role of ATO in regulating the invasive activity of HCC after transarterial embolization (TAE).

Methods

Cell migration and invasion were observed using Transwell and wound-healing assay. The molecular changes in E-cadherin, N-cadherin, and Vimentin of surviving tumor cells were determined by Western blotting. The effects of ATO on Twist activity of the tumor cells were further analyzed. In animal study, 40 male buffalo rats implanted with McA-RH7777 tumor in the liver were randomly divided into four groups: control, TAE, ATO, and TAE + ATO. TAE procedures were performed on the 14th day after implantation. Lung metastases were observed using fluorescence imaging, and the molecular changes in residual tumor cells were evaluated by Western blotting or immunohistochemistry. Tumor growth and survival analysis were also evaluated.

Results

Arsenic trioxide markedly reduced cell migration and invasiveness, which were enhanced by hypoxia after TAE. Western blot analysis revealed ATO inhibited the expression of epithelial–mesenchymal transition (EMT) markers by suppressing Twist. The marked suppression effect of ATO on invasiveness and metastatic potential related to EMT was also shown in tissue.

Conclusion

The results of this study demonstrated that ATO is an effective anticancer agent in combination with TAE in the treatment of HCC, by suppressing tumor progression and metastasis via selectively inducing tumor cell apoptosis and arresting EMT by inhibiting the Twist activation.

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References

  • Abou-Alfa GK (2011) TACE and sorafenib: a good marriage? J Clin Oncol 29(30):3949–3952. doi:10.1200/JCO.2011.37.9651

    Article  CAS  PubMed  Google Scholar 

  • Chen C, Wang J, Liu R, Qian S (2012) RNA interference of hypoxia-inducible factor-1 alpha improves the effects of transcatheter arterial embolization in rat liver tumors. Tumour Biol 33(4):1095–1103. doi:10.1007/s13277-012-0349-8

    Article  CAS  PubMed  Google Scholar 

  • Fei M, Lu M, Wang Y, Zhao Y, He S, Gao S, Ke Q, Liu Y, Li P, Cui X, Shen A, Cheng C (2009) Arsenic trioxide-induced growth arrest of human hepatocellular carcinoma cells involving FOXO3a expression and localization. Med Oncol 26(2):178–185. doi:10.1007/s12032-008-9105-8

    Article  CAS  PubMed  Google Scholar 

  • Forner A, Llovet JM, Bruix J (2012) Hepatocellular carcinoma. Lancet 379(9822):1245–1255. doi:10.1016/S0140-6736(11)61347-0

    Article  PubMed  Google Scholar 

  • Friedl P, Wolf K (2003) Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 3(5):362–374. doi:10.1038/nrc1075

    Article  CAS  PubMed  Google Scholar 

  • Gupta GP, Massague J (2006) Cancer metastasis: building a framework. Cell 127(4):679–695. doi:10.1016/j.cell.2006.11.001

    Article  CAS  PubMed  Google Scholar 

  • Jiang H, Meng Q, Tan H, Pan S, Sun B, Xu R, Sun X (2007) Antiangiogenic therapy enhances the efficacy of transcatheter arterial embolization for hepatocellular carcinomas. Int J Cancer 121(2):416–424. doi:10.1002/ijc.22655

    Article  CAS  PubMed  Google Scholar 

  • Kito M, Akao Y, Ohishi N, Yagi K, Nozawa Y (2002) Arsenic trioxide-induced apoptosis and its enhancement by buthionine sulfoximine in hepatocellular carcinoma cell lines. Biochem Biophys Res Commun 291(4):861–867. doi:10.1006/bbrc.2002.6525

    Article  CAS  PubMed  Google Scholar 

  • Lewandowski RJ, Geschwind JF, Liapi E, Salem R (2011) Transcatheter intraarterial therapies: rationale and overview. Radiology 259(3):641–657. doi:10.1148/radiol.11081489

    Article  PubMed Central  PubMed  Google Scholar 

  • Liu B, Pan S, Dong X, Qiao H, Jiang H, Krissansen GW, Sun X (2006) Opposing effects of arsenic trioxide on hepatocellular carcinomas in mice. Cancer Sci 97(7):675–681. doi:10.1111/j.1349-7006.2006.00230.x

    Article  CAS  PubMed  Google Scholar 

  • Llovet JM, Bruix J (2003) Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 37(2):429–442. doi:10.1053/jhep.2003.50047

    Article  CAS  PubMed  Google Scholar 

  • Llovet JM, Schwartz M, Mazzaferro V (2005) Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis 25(2):181–200. doi:10.1055/s-2005-871198

    Article  PubMed  Google Scholar 

  • Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J, Group SIS (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390. doi:10.1056/NEJMoa0708857

    Article  CAS  PubMed  Google Scholar 

  • Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, Fan ST, Wong J (2002) Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 35(5):1164–1171. doi:10.1053/jhep.2002.33156

    Article  CAS  PubMed  Google Scholar 

  • Maataoui A, Qian J, Mack MG, Khan MF, Oppermann E, Roozru M, Schmidt S, Bechstein WO, Vogl TJ (2005a) Liver metastases in rats: chemoembolization combined with interstitial laser ablation for treatment. Radiology 237(2):479–484. doi:10.1148/radiol.2372041494

    Article  PubMed  Google Scholar 

  • Maataoui A, Qian J, Vossoughi D, Khan MF, Oppermann E, Bechstein WO, Vogl TJ (2005b) Transarterial chemoembolization alone and in combination with other therapies: a comparative study in an animal HCC model. Eur Radiol 15(1):127–133. doi:10.1007/s00330-004-2517-8

    Article  CAS  PubMed  Google Scholar 

  • Maeda H, Hori S, Ohizumi H, Segawa T, Kakehi Y, Ogawa O, Kakizuka A (2004) Effective treatment of advanced solid tumors by the combination of arsenic trioxide and L-buthionine-sulfoximine. Cell Death Differ 11(7):737–746. doi:10.1038/sj.cdd.4401389

    Article  CAS  PubMed  Google Scholar 

  • Mendez O, Zavadil J, Esencay M, Lukyanov Y, Santovasi D, Wang SC, Newcomb EW, Zagzag D (2010) Knock down of HIF-1alpha in glioma cells reduces migration in vitro and invasion in vivo and impairs their ability to form tumor spheres. Mol Cancer 9(133). doi:10.1186/1476-4598-1189-1133

  • Othumpangat S, Kashon M, Joseph P (2005) Sodium arsenite-induced inhibition of eukaryotic translation initiation factor 4E (eIF4E) results in cytotoxicity and cell death. Mol Cell Biochem 279(1–2):123–131. doi:10.1007/s11010-005-8284-2

    Article  CAS  PubMed  Google Scholar 

  • Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9(4):265–273. doi:10.1038/nrc2620

    Article  CAS  PubMed  Google Scholar 

  • Ramsey DE, Kernagis LY, Soulen MC, Geschwind JF (2002) Chemoembolization of hepatocellular carcinoma. J Vasc Interv Radiol 13(9 Pt 2):S211–S221

    Article  PubMed  Google Scholar 

  • Sergio A, Cristofori C, Cardin R, Pivetta G, Ragazzi R, Baldan A, Girardi L, Cillo U, Burra P, Giacomin A, Farinati F (2008) Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness. Am J Gastroenterol 103(4):914–921. doi:10.1111/j.1572-0241.2007.01712.x

    Article  PubMed  Google Scholar 

  • Shim JH, Park JW, Kim JH, An M, Kong SY, Nam BH, Choi JI, Kim HB, Lee WJ, Kim CM (2008) Association between increment of serum VEGF level and prognosis after transcatheter arterial chemoembolization in hepatocellular carcinoma patients. Cancer Sci 99(10):2037–2044. doi:10.1111/j.1349-7006.2008.00909.x

    CAS  PubMed  Google Scholar 

  • Tang ZY (2001) Hepatocellular carcinoma-cause, treatment and metastasis. World J Gastroenterol 7(4):445–454

    CAS  PubMed  Google Scholar 

  • TC EASL-EOR (2012) Clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 56(4):908–943. doi:10.1016/j.jhep.2011.12.001

    Google Scholar 

  • Thiery JP (2002) Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2(6):442–454. doi:10.1038/nrc822

    Article  CAS  PubMed  Google Scholar 

  • Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial–mesenchymal transitions. Nat Rev Mol Cell Biol 7(2):131–142. doi:10.1038/nrm1835

    Article  CAS  PubMed  Google Scholar 

  • Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial–mesenchymal transitions in development and disease. Cell 139(5):871–890. doi:10.1016/j.cell.2009.11.007

    Article  CAS  PubMed  Google Scholar 

  • Tomuleasa C, Soritau O, Fischer-Fodor E, Pop T, Susman S, Mosteanu O, Petrushev B, Aldea M, Acalovschi M, Irimie A, Kacso G (2011) Arsenic trioxide plus cisplatin/interferon alpha-2b/doxorubicin/capecitabine combination chemotherapy for unresectable hepatocellular carcinoma. Hematol Oncol Stem Cell Ther 4(2):60–66

    CAS  PubMed  Google Scholar 

  • Trevisani F, Cantarini MC, Wands JR, Bernardi M (2008) Recent advances in the natural history of hepatocellular carcinoma. Carcinogenesis 29(7):1299–1305. doi:10.1093/carcin/bgn113

    Article  CAS  PubMed  Google Scholar 

  • Virmani S, Rhee TK, Ryu RK, Sato KT, Lewandowski RJ, Mulcahy MF, Kulik LM, Szolc-Kowalska B, Woloschak GE, Yang GY, Salem R, Larson AC, Omary RA (2008) Comparison of hypoxia-inducible factor-1 alpha expression before and after transcatheter arterial embolization in rabbit VX2 liver tumors. J Vasc Interv Radiol 19(10):1483–1489. doi:10.1016/j.jvir.2008.06.017

    Article  PubMed Central  PubMed  Google Scholar 

  • Wang B, Xu H, Gao ZQ, Ning HF, Sun YQ, Cao GW (2008) Increased expression of vascular endothelial growth factor in hepatocellular carcinoma after transcatheter arterial chemoembolization. Acta Radiol 49(5):523–529. doi:10.1080/02841850801958890

    Article  CAS  PubMed  Google Scholar 

  • Wang GZ, Fang ZT, Zhang W, Qu XD, Qian S, Liu R, Wang JH (2014) Increased metastatic potential of residual carcinoma after transarterial embolization in rat with McARH7777 hepatoma. Oncol Rep 31(1):95–102. doi:10.3892/or.2013.2820

    PubMed  Google Scholar 

  • Zheng QS, Zhang YT, Zheng RL (2002) Ascorbic acid induces redifferentiation and growth inhibition in human hepatoma cells by increasing endogenous hydrogen peroxide. Pharmazie 57(11):753–757

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by grants from National Natural Sciences Foundation of China (No. 81350031) and in part by 863 National High Technology Research and Development Program of China (No. 2012AA022701).

Conflict of interest

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Intervention Radiology, Zhongshan Hospital Fudan University, No. 180 Fenglin Road, Xuhui, Shanghai, China

    Guang-Zhi Wang, Wei Zhang, Zhu-Ting Fang, Wen Zhang, Min-Jie Yang, Guo-Wei Yang, Shuo Li, Lian Zhu, Li-Li Wang, Wei-Sheng Zhang, Rong Liu, Sheng Qian, Jian-Hua Wang & Xu-Dong Qu

  2. Department of Intervention Radiology, Provincial Hospital of Fujian Province, Teaching Hospital of Fujian Medical University, Fuzhou, China

    Zhu-Ting Fang

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  1. Guang-Zhi Wang
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Correspondence to Jian-Hua Wang or Xu-Dong Qu.

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Guang-Zhi Wang, Wei Zhang and Zhu-Ting Fang have contributed equally to this article.

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Wang, GZ., Zhang, W., Fang, ZT. et al. Arsenic trioxide: marked suppression of tumor metastasis potential by inhibiting the transcription factor Twist in vivo and in vitro. J Cancer Res Clin Oncol 140, 1125–1136 (2014). https://doi.org/10.1007/s00432-014-1659-6

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  • DOI: https://doi.org/10.1007/s00432-014-1659-6

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