Digestive Diseases and Sciences

, Volume 54, Issue 10, pp 2128–2136 | Cite as

Antitumoral Activity of Rapamycin Mediated Through Inhibition of HIF-1alpha and VEGF in Hepatocellular Carcinoma

  • Wei Wang
  • Wei-Dong Jia
  • Ge-Liang XuEmail author
  • Zhi-Hua Wang
  • Jian-Sheng Li
  • Jin-Liang Ma
  • Yong-Sheng Ge
  • Sheng-Xue Xie
  • Ji-Hai Yu
Original Article


Rapamycin (RAPA) inhibits tumor growth and angiogenesis in hepatocellular carcinoma (HCC). The molecular mechanism underlying the antitumoral effects of RAPA remains unclear. Here we established a chemical-induced rat HCC model to investigate the signaling pathways mediating RAPA’s antitumor activity. We found that RAPA exposure significantly diminished tumor growth, angiogenesis, and metastasis of HCC. Meanwhile, the antitumor drug dramatically decreased expression of HIF-1alpha and VEGF, either at mRNA or protein levels. Moreover, the low-dose of RAPA (1.5 mg/kg/day) was effective enough to markedly inhibit tumor progression of HCC. The preliminary results suggested that the antitumoral effects of RAPA might be at least partially mediated through downregulation of HIF-1alpha and VEGF, and low-dose RAPA-based regimens exhibited a promising future in treatment of HCC.


Rapamycin Hepatocellular carcinoma HIF-1alpha VEGF Angiogenesis 



Cyclosporine A




Hepatocellular carcinoma


Haematoxylin and eosin


Hypoxia-inducible factor 1 alpha


Mammalian target of rapamycin


Microvessel density








Vascular endothelial growth factor



This research was supported by the National Natural Science Foundation of China (30772097), Anhui Provincial Natural Science Foundation (070413073), the Science and Technological Fund of Anhui Province for Outstanding Youth (08040106818), the Science and Technology Key Project of Anhui Province (07010302193), and the Anhui Provincial “115” Industrial Innovation Program. The authors declare no competing financial interests.


  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.PubMedCrossRefGoogle Scholar
  2. 2.
    Yu MC, Yuan JM. Environmental factors and risk for hepatocellular carcinoma. Gastroenterology. 2004;127:S72–S78. doi: 10.1016/j.gastro.2004.09.018.PubMedCrossRefGoogle Scholar
  3. 3.
    Wang Z, Zhou J, Fan J, et al. Effect of rapamycin alone and in combination with sorafenib in an orthotopic model of human hepatocellular carcinoma. Clin Cancer Res. 2008;14:5124–5130. doi: 10.1158/1078-0432.CCR-07-4774.PubMedCrossRefGoogle Scholar
  4. 4.
    Huynh H, Chow PK, Palanisamy N, et al. Bevacizumab and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma. J Hepatol. 2008;49:52–60. doi: 10.1016/j.jhep.2008.02.022.PubMedCrossRefGoogle Scholar
  5. 5.
    Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007;12:9–22. doi: 10.1016/j.ccr.2007.05.008.PubMedCrossRefGoogle Scholar
  6. 6.
    Vignot S, Faivre S, Aguirre D, Raymond E. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol. 2005;16:525–537. doi: 10.1093/annonc/mdi113.PubMedCrossRefGoogle Scholar
  7. 7.
    Bu X, Le C, Jia F, et al. Synergistic effect of mTOR inhibitor rapamycin and fluorouracil in inducing apoptosis and cell senescence in hepatocarcinoma cells. Cancer Biol Ther. 2008;7:392–396.PubMedCrossRefGoogle Scholar
  8. 8.
    Semela D, Piguet AC, Kolev M, et al. Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma. J Hepatol. 2007;46:840–848. doi: 10.1016/j.jhep.2006.11.021.PubMedCrossRefGoogle Scholar
  9. 9.
    Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002;8:128–135. doi: 10.1038/nm0202-128.PubMedCrossRefGoogle Scholar
  10. 10.
    Basu A, Contreras AG, Datta D, et al. Overexpression of vascular endothelial growth factor and the development of post-transplantation cancer. Cancer Res. 2008;68:5689–5698. doi: 10.1158/0008-5472.CAN-07-6603.PubMedCrossRefGoogle Scholar
  11. 11.
    von Marschall Z, Cramer T. Höcker M, Finkenzeller G, Wiedenmann B, Rosewicz S: Dual mechanism of vascular endothelial growth factor upregulation by hypoxia in human hepatocellular carcinoma. Gut. 2001;48:87–96. doi: 10.1136/gut.48.1.87.CrossRefGoogle Scholar
  12. 12.
    Lee TK, Poon RT, Yuen AP, et al. Regulation of angiogenesis by Id-1 through hypoxia-inducible factor-1alpha-mediated vascular endothelial growth factor up-regulation in hepatocellular carcinoma. Clin Cancer Res. 2006;12:6910–6919. doi: 10.1158/1078-0432.CCR-06-0489.PubMedCrossRefGoogle Scholar
  13. 13.
    Yoshino H, Futakuchi M, Cho YM, et al. Modification of an in vivo lung metastasis model of hepatocellular carcinoma by low dose N-nitrosomorpholine and diethylnitrosamine. Clin Exp Metastasis. 2005;22:441–447. doi: 10.1007/s10585-005-2807-9.PubMedCrossRefGoogle Scholar
  14. 14.
    Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis–correlation in invasive breast carcinoma. N Engl J Med. 1991;324:1–8.PubMedGoogle Scholar
  15. 15.
    Zimmerman MA, Trotter JF, Wachs M, et al. Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma. Liver Transpl. 2008;14:633–638. doi: 10.1002/lt.21420.PubMedCrossRefGoogle Scholar
  16. 16.
    Mizukami Y, Kohgo Y, Chung DC. Hypoxia Inducible Factor-1 Independent Pathways in Tumor Angiogenesis. Clin Cancer Res. 2007;13:5670–5674. doi: 10.1158/1078-0432.CCR-07-0111.PubMedCrossRefGoogle Scholar
  17. 17.
    Mizukami Y, Fujiki K, Duerr EM, et al. Hypoxic regulation of vascular endothelial growth factor through the induction of phosphatidylinositol 3-kinase/Rho/ROCK and c-Myc. J Biol Chem. 2006;281:13957–13963. doi: 10.1074/jbc.M511763200.PubMedCrossRefGoogle Scholar
  18. 18.
    Cao Y, Li CY, Moeller BJ, et al. Observation of incipient tumor angiogenesis that is independent of hypoxia and hypoxia inducible factor-1 activation. Cancer Res. 2005;65:5498–5505. doi: 10.1158/0008-5472.CAN-04-4553.PubMedCrossRefGoogle Scholar
  19. 19.
    Mizukami Y, Li J, Zhang X, Zimmer MA, Iliopoulos O, Chung DC. Hypoxia-inducible factor-1-independent regulation of vascular endothelial growth factor by hypoxia in colon cancer. Cancer Res. 2004;64:1765–1772. doi: 10.1158/0008-5472.CAN-03-3017.PubMedCrossRefGoogle Scholar
  20. 20.
    Tanaka H, Yamamoto M, Hashimoto N, et al. Hypoxia-independent overexpression of hypoxia-inducible factor 1alpha as an early change in mouse hepatocarcinogenesis. Cancer Res. 2006;66:11263–11270. doi: 10.1158/0008-5472.CAN-06-1699.PubMedCrossRefGoogle Scholar
  21. 21.
    Yasuda S, Arii S, Mori A, et al. Hexokinase II and VEGF expression in liver tumors: correlation with hypoxia-inducible factor 1 alpha and its significance. J Hepatol. 2004;40:117–123. doi: 10.1016/S0168-8278(03)00503-8.PubMedCrossRefGoogle Scholar
  22. 22.
    Hojo M, Morimoto T, Maluccio M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature. 1999;397:530–534. doi: 10.1038/17401.PubMedCrossRefGoogle Scholar
  23. 23.
    Iurlaro M, Vacca A, Minischetti M, et al. Antiangiogenesis by cyclosporine. Exp Hematol. 1998;26:1215–1222.PubMedGoogle Scholar
  24. 24.
    Aeder SE, Martin PM, Soh JW, Hussaini IM. PKC-eta mediates glioblastoma cell proliferation through the Akt and mTOR signaling pathways. Oncogene. 2004;23:9062–9069. doi: 10.1038/sj.onc.1208093.PubMedCrossRefGoogle Scholar
  25. 25.
    Leseux L, Laurent G, Laurent C, et al. PKC zeta mTOR pathway: a new target for rituximab therapy in follicular lymphoma. Blood. 2008;111:285–291. doi: 10.1182/blood-2007-04-085092.PubMedCrossRefGoogle Scholar
  26. 26.
    Moschella PC, Rao VU, McDermott PJ, Kuppuswamy D. Regulation of mTOR and S6K1 activation by the nPKC isoforms, PKCepsilon and PKCdelta, in adult cardiac muscle cells. J Mol Cell Cardiol. 2007;43:754–766. doi: 10.1016/j.yjmcc.2007.09.015.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Wei Wang
    • 1
    • 2
  • Wei-Dong Jia
    • 1
    • 2
  • Ge-Liang Xu
    • 1
    • 2
    Email author
  • Zhi-Hua Wang
    • 3
  • Jian-Sheng Li
    • 1
    • 2
  • Jin-Liang Ma
    • 1
    • 2
  • Yong-Sheng Ge
    • 1
    • 2
  • Sheng-Xue Xie
    • 1
  • Ji-Hai Yu
    • 1
    • 2
  1. 1.Centre for the Study of Liver Cancer, Anhui Provincial HospitalAnhui Medical UniversityHefeiPeople’s Republic of China
  2. 2.Department of Hepatic Surgery, Anhui Provincial HospitalAnhui Medical UniversityHefeiPeople’s Republic of China
  3. 3.Department of Pathology, Anhui Provincial HospitalAnhui Medical UniversityHefeiPeople’s Republic of China

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