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  3. Platelets promote primary hepatocellular carcinoma metastasis through TGF-β1-mediated cancer cell autophagy

Platelets promote primary hepatocellular carcinoma metastasis through TGF-β1-mediated cancer cell autophagy

  • Cancer Lett. 2024 Sep 28:600:217161. doi: 10.1016/j.canlet.2024.217161.
Meng Lu 1,  Xue Gong 1,  Yu-Min Zhang 1,  Ya-Wei Guo 1,  Ying Zhu 2,  Xiang-Bin Zeng 1,  Jia-Hui Gao 1,  Lu-Man Liu 1,  Dan Shu 3,  Rong Ma 1,  Hui-Fang Liang 4,  Ru-Yi Zhang 5,  Yun Xu 6,  Bi-Xiang Zhang 4,  Yong-Jie Lu 7,  Zhang-Yin Ming 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Wuhan, China.
  • 2 Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Wuhan, China; Department of Pharmacy, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Wuhan, China; Department of Pharmacy, School of Medicine, Wuhan University of Science and Technology, Wuhan, China.
  • 4 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China.
  • 6 Center for Medical Device Evaluation, National Medical Products Administration, Beijing, China.
  • 7 Center for Biomarkers and Therapeutics, Bart's Cancer Institute, Queen Mary University London, London, EC1M 6BQ, UK.
  • 8 Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Wuhan, China; Tongji-Rongcheng Center for Biomedicine, Huazhong University of Science and Technology, Wuhan, China. Electronic address: zyming@hust.edu.cn.
PMID: 39117067 DOI: 10.1016/j.canlet.2024.217161
Abstract

Previous research has revealed that platelets promote tumor metastasis by binding to circulating tumor cells (CTCs). However, the role of platelets in epithelial-mesenchymal transition (EMT) of Cancer cells at the primary tumor site, the crucial initial step of tumor metastasis, remains to be elucidated. Here, we found that platelet releasate enhanced EMT and motility of hepatocellular carcinoma (HCC) cells via AMPK/mTOR-induced Autophagy. RNA-seq indicated that platelet releasate altered TGF-β signaling pathway of Cancer cells. Inhibiting TGFBR or deleting platelet TGF-β1 suppressed AMPK/mTOR pathway activation and Autophagy induced by platelet releasate. Compared with Pf4cre-; Tgfb1fl/fl mice, HCC orthotopic models established on Pf4cre+; Tgfb1fl/fl mice showed reduced TGF-β1 in primary tumors, which corresponded with decreased Cancer cell EMT, Autophagy, migration ability and tumor metastasis. Inhibition of Autophagy via Atg5 knockdown in Cancer cells negated EMT and metastasis induced by platelet-released TGF-β1. Clinically, higher platelet count correlated with increased TGF-β1, LC3 and N-cad expression in primary tumors of HCC patients, suggesting a link between platelets and HCC progression. Our study indicates that platelets promote Cancer cell EMT in the primary tumor and HCC metastasis through TGF-β1-induced HCC cell Autophagy via the AMPK/mTOR pathway. These findings offer novel insights into the role of platelets in HCC metastasis and the potential therapeutic targets for HCC metastasis.

Keywords

Autophagy; Epithelial-mesenchymal transition; Hepatocellular carcinoma metastasis; Platelets; Primary tumor; TGF-β1.

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