Cancer associated fibroblast-derived CCL5 promotes hepatocellular carcinoma metastasis through activating HIF1?/ZEB1 axis.

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 HIF1?/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 (HIF1?) by binding to specific receptors, maintained HIF1? 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 HIF1?/ZEB1 cascade possibly propose a new therapeutic route for HCC.
Mesh Terms:
Animals, Cancer-Associated Fibroblasts, Carcinoma, Hepatocellular, Cell Line, Tumor, Cell Movement, Chemokine CCL5, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Liver Neoplasms, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Metastasis, Tumor Microenvironment
Cell Death Dis
Date: May. 20, 2022
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