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

  • Chao HuangEmail author
  • Xiu-lian Wang
  • Fang-fang Qi
  • Zuo-liang PangEmail author
Research Article

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.

Keywords

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

Notes

Acknowledgments

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

Author contributions

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.

Compliance with ethical standards

Conflict of interest

No potential conflicts of interest were disclosed.

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Copyright information

© The International CCN Society 2019

Authors and Affiliations

  1. 1.Department of Traditional Chinese Medicine, Affiliated Bao’an Hospital of ShenzhenSouthern Medical UniversityShenzhenChina
  2. 2.Department of Traditional Chinese Medicine, Affiliated Bao’an Hospital of Traditional Chinese Medicine of ShenzhenTraditional Chinese Medicine University Of GuangzhouShenzhenChina
  3. 3.Elemental Laboratory, Maternal and Child Health Hospital of GanzhouZhangyeChina

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