Research Papers:

Bufalin suppresses hepatocellular carcinoma invasion and metastasis by targeting HIF-1α via the PI3K/AKT/mTOR pathway

Haiyong Wang, Chenyue Zhang, Litao Xu, Kun Zang, Zhouyu Ning, Feng Jiang, Huiying Chi, Xiaoyan Zhu and Zhiqiang Meng _

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Oncotarget. 2016; 7:20193-20208. https://doi.org/10.18632/oncotarget.7935

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Haiyong Wang1,2,*, Chenyue Zhang1,3,*, Litao Xu1,3, Kun Zang1,3, Zhouyu Ning1,3, Feng Jiang4, Huiying Chi5, Xiaoyan Zhu1,3, Zhiqiang Meng1,3

1Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China

2Department of Radiation Oncology, Shandong Cancer Hospital & Institute, Jinan, 250117, China

3Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China

4Department of Integrative Oncology, Zhucheng Hospital of TCM, Zhucheng 262200, China

5Shanghai Geriatric Institute of Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200031, China

*These authors contributed equally to this work

Correspondence to:

Xiaoyan Zhu, e-mail: [email protected]

Zhiqiang Meng, e-mail: [email protected]

Keywords: bufalin, metastasis, HIF-1α, hepatocellular carcinoma, PI3K/AKT/mTOR

Received: July 20, 2015     Accepted: January 06, 2016     Published: March 06, 2016


It has been reported that there are multiple mechanisms by which bufalin could exert its antimetastatic effect. HIF-1α has been reported to be involved in tumor migration and invasion by regulating EMT. However, it is not known whether bufalin could exert the antimetastatic effect by modulating HIF-1α expression in hepatocellular carcinoma. In the present study, we aimed to evaluate the antimetastatic potential of bufalin in vivo and in vitro. Our results demonstrated that the liver/lung metastases were significantly reduced in bufalin-treated mice, as tested in the orthotopic transplanted and tail vein injection tumor models. Furthermore, the epithelial-to-mesenchymal transition (EMT) was inhibited in bufalin-treated tumors, as reflected the upregulation of E-cadherin, and downregulation of N-cadherin, vimentin, Snail. Similar results were observed in SMMC7721 cells treated with bufalin. Moreover, the transforming growth factor-β1 (TGF-β1)-induced EMT was also abrogated by bufalin. Mechanistically, our study demonstrated that hypoxia-inducible factor-1α (HIF-1α) played an important role in the antimetastatic effect of bufalin in hepatocellular carcinoma. Importantly, HIF-1α expression may be regulated through the inhibition of the PI3K/AKT/mTOR pathway. Taken together, our results suggest that bufalin suppresses hepatic tumor invasion and metastasis and that this process may be related to the PI3K/AKT/mTOR/ HIF-1α axis.

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