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Bufalin reverses cancer-associated fibroblast-mediated colorectal cancer metastasis by inhibiting the STAT3 signaling pathway

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Abstract

At present, recurrence and metastasis are still important factors that lead to a poor prognosis among colorectal cancer (CRC) patients. Cancer-associated fibroblasts (CAFs) can promote tumorigenesis and development. Bufalin is the main active monomer of the clinical drug cinobufacini, which exhibits antitumor activity in various cancers. But few research have investigated the effect of bufalin in inhibiting metastasis from the perspective of the tumor microenvironment. We first isolated CAFs from freshly resected colorectal cancer patient specimens and observed the effect of CAFs on CRC cell invasion through a series of experiments. We explored the effect of bufalin on the physiological activity of CRC mediated by CAFs through experiments. In our study, we found that CAFs could promote CRC cell activity through the STAT3 pathway. Bufalin reversed CAF-mediated CRC invasion and metastasis by inhibiting the STAT3 pathway. Overexpression of STAT3 attenuated the inhibitory function of bufalin on invasion and metastasis. Taken together, bufalin can reverse CAF-mediated colorectal cancer metastasis based on inhibiting the STAT3 signaling pathway.

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Data availability

All data generated or analysed during this study are included in this published article (and its Supplementary Information Files).

Abbreviations

CRC:

Colorectal cancer

CAFs:

Cancer-associated fibroblasts

FBS:

Foetal bovine serum

CCK-8:

Cell Counting Kit-8 assay

IHC:

Immunohistochemistry

OE:

Overexpressing

BU:

Bufalin

WB:

Western blot

CM:

Conditioned medium

TME:

Tumor microenvironment

EMT:

Epithelial-mesenchymal transition

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Acknowledgements

Not applicable.

Funding

This project was sponsored by the Clinical Specialized Disease Construction Project of Shanghai Putuo District Municipal Health Commission (NO. 2020tszb03), the One Hundred Talents Project of Putuo Hospital, Shanghai University of Traditional Chinese Medicine (2022-RCLH-03), the Shanghai Rising-Star Program (Sailing special Project, 22YF1441400), the Natural Science Foundation of Shanghai (20ZR1450500), the Budge Project Shanghai University of Traditional Chinese Medicine (2020LK072), the One Hundred Talents Project of Putuo Hospital, Shanghai University of Traditional Chinese Medicine (2022-RCCY-08) and the research Project of Shanghai Putuo District Central Hospital (2020366 A).

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Author notes

  1. Haijing Wang, Jinbao Chen and Sen Li have contributed equally to this work.

Authors and Affiliations

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

    Haijing Wang, Jinbao Chen, Donghao Tang & Peihao Yin

  2. Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, 164 Lanxi Road, Shanghai, 200062, China

    Sen Li, Jiahua Yang, Wentao Wu, Kun Yu, Yijun Cao, Peihao Yin & Wei Li

  3. Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China

    Ke Xu

  4. Shanghai Putuo Central School of Clinical Medicine, Anhui Medicine University, Anhui, 230032, China

    Peihao Yin & Wei Li

  5. Wenzhou Institute of Shanghai University, Wenzhou, 325000, China

    Ke Xu

  6. Department of Surgery, Minhang Hospital, Fudan University, Shanghai, 201100, China

    Yi Chen

  7. Key laboratory of whole-period monitoring and precise intervention of digestive cancer (SMHC), Minhang Hospital & AHS, Fudan University, Shanghai, 201100, China

    Yi Chen

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  1. Haijing Wang
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Contributions

WL, PY and YC: conceived or designed the study. HW and JC: collected the data, analysed and interpreted the data. HW, JC and SL: drafted the article. DT, WW and KY: did part of experiments and aided in the construction of tumour model. JY, KX and YC: critically revised the article. All authors approved the final version to be published.

Corresponding authors

Correspondence to Peihao Yin, Yi Chen or Wei Li.

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All authors declare no conflict of interest.

Ethical approval

All animal experiments were conducted in accordance with guidelines and protocol approved by the institutional animal care and use committee of Putuo Hospital, Shanghai University of Traditional Chinese Medicine, China.

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Wang, H., Chen, J., Li, S. et al. Bufalin reverses cancer-associated fibroblast-mediated colorectal cancer metastasis by inhibiting the STAT3 signaling pathway. Apoptosis 28, 594–606 (2023). https://doi.org/10.1007/s10495-023-01819-3

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