Berberine inhibits epithelial-mesenchymal transition and promotes apoptosis of tumour-associated fibroblast-induced colonic epithelial cells through regulation of TGF-β signalling

Abstract

Tumour-associated fibroblasts (TAFs) mediate the differentiation of adjacent stromal cells. Berberine (BBR), a monomer of traditional Chinese herbs, exhibits a potent therapeutic effect against cancer. However, the effects of BBR on the differentiation of normal colonic epithelial cells induced by TAFs have not been determined. In the present study, we selected the TAF-like myofibroblast cell line CCD-18Co. CCD-18Co-derived conditioned medium (CM) and co-culture induced epithelial-mesenchymal transition (EMT) changes in colonic epithelial HCoEpiC cells with decreased E-cadherin and increased vimentin and α-SMA expression. In addition, CCD-18Co stimulated the expression of ZEB1 and Snail and promoted motility. We used LY364947, a TGF-β receptor kinase type I (TβRI) inhibitor, and BBR. Our results showed that LY364947 and BBR inhibited these phenomena. BBR decreased the expression of ZEB1 and Snail, and this effect was concentration dependent. BBR also downregulated the expression of TβRI, TβRII, Smad2/p-Smad2 and Smad3/p-Smad3. In addition, BBR induced apoptosis in EMT-like HCoEpiC cells in a concentration-dependent manner with upregulation of Bax and downregulation of Bcl-2. However, VX-702, an inhibitor of p38 MAPK, significantly suppressed the apoptosis rate. BBR promoted the expression of p38 MAPK and phosphorylated p38 MAPK. In conclusion, berberine inhibits EMT and promotes apoptosis in TAF-induced colonic epithelial cells through mediation of the Smad-dependent and SMAD-independent TGF-β signalling pathways.

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Acknowledgments

This work was supported by Natural Science Foundation of Guangdong Province (2018A030310060), China Postdoctoral Foundation (2018 M643353).

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C.H wrote the main manuscript text, F.Q and L. W prepared Figs. 15, and L. P examined all the manuscript. All authors reviewed the manuscript.

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Correspondence to Chao Huang or Zuo-liang Pang.

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Huang, C., Wang, X., Qi, F. et al. Berberine inhibits epithelial-mesenchymal transition and promotes apoptosis of tumour-associated fibroblast-induced colonic epithelial cells through regulation of TGF-β signalling. J. Cell Commun. Signal. 14, 53–66 (2020). https://doi.org/10.1007/s12079-019-00525-7

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Keywords

  • Tumor microenvironment
  • Tumor-associated fibroblasts
  • Epithelial-mesenchymal transition
  • Transforming growth factor-β
  • Berberine