2. Academic Validation
  3. Cancer associated fibroblast-derived CCL5 promotes hepatocellular carcinoma metastasis through activating HIF1α/ZEB1 axis

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

  • Cell Death Dis. 2022 May 20;13(5):478. doi: 10.1038/s41419-022-04935-1.
Haixu Xu  # 1,  Jie Zhao  # 1,  Jinping Li 1 2,  Zhifeng Zhu 1 2,  Zhaohai Cui 1,  Ran Liu 1,  Rong Lu 3,  Zhi Yao 4,  Qiong Xu 5 6
Affiliations

Affiliations

  • 1 Department of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China.
  • 2 Tianjin Kangzhe Pharmaceutical Technology Development Company, Ltd, 300042, Tianjin, China.
  • 3 Tianjin Kangzhe Pharmaceutical Technology Development Company, Ltd, 300042, Tianjin, China. lu_rong@vip.sina.com.
  • 4 Department of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China. yaozhi@tmu.edu.cn.
  • 5 Department of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China. xvqiong1980@vip.sina.com.
  • 6 Tianjin Kangzhe Pharmaceutical Technology Development Company, Ltd, 300042, Tianjin, China. xvqiong1980@vip.sina.com.
  • # Contributed equally.
PMID: 35589690 DOI: 10.1038/s41419-022-04935-1
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.

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