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  3. Direct interaction of platelet with tumor cell aggravates hepatocellular carcinoma metastasis by activating TLR4/ADAM10/CX3cl1 axis

Direct interaction of platelet with tumor cell aggravates hepatocellular carcinoma metastasis by activating TLR4/ADAM10/CX3cl1 axis

  • Cancer Lett. 2024 Jan 25:216674. doi: 10.1016/j.canlet.2024.216674.
Jia-Hui Gao 1,  Ao-Di He 2,  Lu-Man Liu 1,  Ya-Jun Zhou 3,  Ya-Wei Guo 1,  Meng Lu 1,  Xiang-Bin Zeng 1,  Xue Gong 1,  Yong-Jie Lu 4,  Hui-Fang Liang 5,  Bi-Xiang Zhang 5,  Rong Ma 1,  Ru-Yi Zhang 6,  Zhang-Yin Ming 7
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, 430030, Hubei, China.
  • 2 Department of Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, China.
  • 3 Department of Pharmacy, Hubei Provincial Hospital of Traditional Chinese Medicine, Hubei Province Academy of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, China.
  • 4 Centre for Biomarkers and Therapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
  • 5 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 6 Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China.
  • 7 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, 430030, Hubei, 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: 38280480 DOI: 10.1016/j.canlet.2024.216674
Abstract

Metastasis is the main culprit of cancer-related death and account for the poor prognosis of hepatocellular carcinoma. Although platelets have been shown to accelerate tumor cell metastasis, the exact mechanism remained to be fully understood. Here, we found that high blood platelet counts and increased tumor tissue ADAM10 expression indicated the poor prognosis of HCC patients. Meanwhile, blood platelet count has positive correlation with tumor tissue ADAM10 expression. In vitro, we revealed that platelet increased ADAM10 expression in tumor cell through TLR4/NF-κB signaling pathway. ADAM10 catalyzed the shedding of CX3CL1 which bound to CX3CR1 receptor, followed by inducing epithelial to mesenchymal transition and activating RhoA signaling in Cancer cell. Moreover, knockdown HCC cell TLR4 (TLR4) or inhibition of ADAM10 prevented platelet-increased tumor cell migration, invasion and endothelial permeability. In vivo, we further verified in mice lung metastatic model that platelet accelerated tumor metastasis via Cancer cell TLR4/ADAM10/CX3CL1 axis. Overall, our study provides new insights into the underlying mechanism of platelet-induced HCC metastasis. Therefore, targeting the TLR4/ADAM10/CX3CL1 axis in Cancer cells hold promise for the inhibition of platelet-promoted lung metastasis of HCC.

Keywords

ADAM10; CX3CL1; HCC; Metastasis; Platelet; TLR4.

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