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