Bufalin inhibits gastric cancer invasion and metastasis by down-regulating Wnt/ASCL2 expression
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Jie Wang1,*, Han Cai1,*, Yue Xia1,*, Shiying Wang2, Likai Xing1, Chao Chen1, Yong Zhang1, Jie Xu1, Peihao Yin1, Yiming Jiang1, Ronghua Zhao3, Qingshong Zuo1 and Teng Chen1,4
1Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
2Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
3Department of Medical, Virogin Biotech Ltd., Vancouver, British Columbia V6S 2L9, Canada
4Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, Shanghai 200062, China
*These authors have contributed equally to this work
Teng Chen, email: [email protected]
Qingshong Zuo, email: [email protected]
Keywords: bufalin; gastric cancer; invasion and metastasis; Wnt/ASCL2 signaling; EMT
Received: September 28, 2017 Accepted: January 02, 2018 Epub: January 11, 2018 Published: May 04, 2018
Achaete-scute-like 2 (ASCL2) is a transcription factor containing a basic helix-loop-helix (bHLH) domain and is a downstream target of Wnt signaling in intestinal stem cells. Bufalin is the primary active ingredient in Chan Su, a traditional Chinese medicine obtained from the skin and parotid venom glands of toads. The purpose of this study was to research the anti-invasion and anti-metastasis activity of bufalin in gastric cancer and to identify the potential mechanism. Bufalin inhibited gastric cancer cell invasion and metastasis, suppressed cancer cell colony formation, and inhibited the growth of subcutaneous xenografted tumors in nude mice. Furthermore, bufalin inhibited ASCL2 expression and down-regulated the expression of invasion-related genes such as MMP2, MMP9, and vimentin, thereby suppressing epithelial-mesenchymal transition (EMT) in gastric cancer. A Wnt signaling inhibitor (XAV939) down-regulated invasion and the expression of ASCL2, β-catenin, and vimentin but up-regulated E-cadherin expression. In nude mice, bufalin inhibited the tumorigenic behavior of gastric cancer cells, induced cancer cell apoptosis, and regulated invasion-related gene expression. Together, our results suggest that bufalin arrests invasion and metastasis and that its mechanism of action may involve down-regulating Wnt/ASCL2 expression.
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