Cell Death and Disease (May 2022)

Cancer associated fibroblast–derived CCL5 promotes hepatocellular carcinoma metastasis through activating HIF1α/ZEB1 axis

  • Haixu Xu,
  • Jie Zhao,
  • Jinping Li,
  • Zhifeng Zhu,
  • Zhaohai Cui,
  • Ran Liu,
  • Rong Lu,
  • Zhi Yao,
  • Qiong Xu

DOI
https://doi.org/10.1038/s41419-022-04935-1
Journal volume & issue
Vol. 13, no. 5
pp. 1 – 13

Abstract

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Abstract Cancer-associated fibroblasts (CAFs) are one of the most enriched components of Hepatocellular carcinoma (HCC) microenvironment, which are tightly related to the metastasis and invasion of HCC. We identified a mechanism by which CAF-derived chemokine CCL5 enhanced HCC metastasis by triggering the HIF1α/ZEB1 axis. We demonstrated that CAFs derived from HCC tissues promoted the migration and invasion of HCC cells and facilitated metastasis to the lung of NOD/SCID mice. Then the chemokine antibody array elucidated the higher chemokine CCL5 level secreted by CAFs than by paracancerous tissue fibroblasts (PTFs). Mechanistically, we found that CAF-derived CCL5 inhibited the ubiquitination and degradation of hypoxia-inducible factor 1 alpha (HIF1α) by binding to specific receptors, maintained HIF1α under normoxia, thereby up-regulated the downstream gene zinc finger enhancer-binding protein 1 (ZEB1) and induced epithelial-mesenchymal transition (EMT), ultimately validating its ability to promote lung metastasis of HCC. And this novel mechanism may have association with poor prognosis. Taken together, targeting CAF-derived CCL5 mediated HIF1α/ZEB1 cascade possibly propose a new therapeutic route for HCC.