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Cinobufacini Inhibits Colon Cancer Invasion and Metastasis via Suppressing Wnt/β-Catenin Signaling Pathway and EMT

Jie Wang

Department Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P. R. China

These authors contributed equally to this work.

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Han Cai

Department Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P. R. China

These authors contributed equally to this work.

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Qiaoli Liu

Clinical Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P. R. China

These authors contributed equally to this work.

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Yue Xia

Department Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P. R. China

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LiKai Xing

Department Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P. R. China

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Qingsong Zuo

Department Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P. R. China

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Yong Zhang

Department Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P. R. China

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Cao Chen

Department Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P. R. China

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Ke Xu

Department Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P. R. China

Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P. R. China

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Peihao Yin

Department Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P. R. China

Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P. R. China

Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, Anhui 230022, P. R. China

E-mail Address: yinpeihao1975@hotmail.com

Correspondence to: Prof. Peihao Yin, Department Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P. R. China. Tel: (+86) 21-2223-3189, Fax: (+86) 21-5266-5957.

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, and

Teng Chen

Department Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P. R. China

Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, Anhui 230022, P. R. China

E-mail Address: 13801842406@163.com

Correspondence to: Prof. Teng Chen, Department Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P. R. China. Tel: (+86) 21-2223-3189, Fax: (+86) 21-5266-5957.

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https://doi.org/10.1142/S0192415X20500354Cited by:95 (Source: Crossref)

Abstract

Cinobufacini is a well-known Chinese medicine extracted from Venenum Bufonis, also called Chan Su. It has been used clinically for various cancers, including colon cancer. However, the function of Cinobufacini on colon cancer invasion and metastasis, and its underlying molecular mechanism, is still not clear. In this study, we investigated the function and mechanism of Cinobufacini on colon cancer invasion and metastasis both in vitro and in vivo studies. Human colon cancer cells were cultured. CCK assay was used to detect the effect of Cinobufacini on colon cancer cells proliferation. The invasion and migration abilities were observed by transwell assays, and the expression of invasion and migration related genes MMP2, MMP9, and epithelial-to-mesenchymal transition (EMT) relate genes were observed by Western blot assays. An orthotopic xenograft model in nude mice was established using colon cancer HCT116 cells, and the function of Cinobufacini on colon cancer invasion and metastasis were observed in vivo. We found Cinobufacini significantly inhibited colon cancer cell proliferation in a dose/time-dependent manner; the invasion and migration abilities of colon cancer were decreased after treated with Cinobufacini. The metastasis and EMT related genes MMP9, MMP2, N-cadherin and Snail were obviously down-regulated, while the expression of E-cadherin was up-regulated after treatment with Cinobufacini. The Wnt/ $β$ -catenin signaling pathway related genes were observed using WB,and results show that the expression of $β$ -catenin, wnt3a, c-myc, cyclin D1, and MMP7 were all down-regulated after being treated with cinobufacini, while the expression of APC was up-regulated. In vivo studies of the volume and weight of orthotopic xenograft tumors showed significantly shrinkage in the Cinobufacini group compared to the control group. The enterocoelia and liver metastasis tumors were significantly decreased, and the expression of MMP9, MMP2, and $β$ -catenin were also down-regulated, while E-cadherin was up-regulated in vivo after the treatment with Cinobufacini. Our data proves that Cinobufacini can inhibit colon cancer invasion and metastasis both in vitro and in vivo; the mechanism is related by suppressing the Wnt/ $β$ -catenin signaling pathway and then inhibiting the EMT of CRC.

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References

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