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

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Abstract

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.

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Abbreviations

CsA:

Cyclosporine A

DEN:

Diethylnitrosamine

HCC:

Hepatocellular carcinoma

HE:

Haematoxylin and eosin

HIF-1alpha:

Hypoxia-inducible factor 1 alpha

mTOR:

Mammalian target of rapamycin

MVD:

Microvessel density

NMOR:

N-nitrosomorpholine

RAPA:

Rapamycin

SD:

Spreque–Dawley

VEGF:

Vascular endothelial growth factor

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Acknowledgments

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.

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Authors and Affiliations

  1. Centre for the Study of Liver Cancer, Anhui Provincial Hospital, Anhui Medical University, 17 Lujiang Road, Hefei, 230001, People’s Republic of China

    Wei Wang, Wei-Dong Jia, Ge-Liang Xu, Jian-Sheng Li, Jin-Liang Ma, Yong-Sheng Ge, Sheng-Xue Xie & Ji-Hai Yu

  2. Department of Hepatic Surgery, Anhui Provincial Hospital, Anhui Medical University, Hefei, 230001, People’s Republic of China

    Wei Wang, Wei-Dong Jia, Ge-Liang Xu, Jian-Sheng Li, Jin-Liang Ma, Yong-Sheng Ge & Ji-Hai Yu

  3. Department of Pathology, Anhui Provincial Hospital, Anhui Medical University, Hefei, 230001, People’s Republic of China

    Zhi-Hua Wang

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  1. Wei Wang
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Correspondence to Ge-Liang Xu.

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Wei Wang and Wei-Dong Jia contributed equally to this work as co–first authors.

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Wang, W., Jia, WD., Xu, GL. et al. Antitumoral Activity of Rapamycin Mediated Through Inhibition of HIF-1alpha and VEGF in Hepatocellular Carcinoma. Dig Dis Sci 54, 2128–2136 (2009). https://doi.org/10.1007/s10620-008-0605-3

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  • DOI: https://doi.org/10.1007/s10620-008-0605-3

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