title: Activated platelets inhibit hepatocellular carcinoma cell differentiation and promote tumor progression via platelet-tumor cell binding.
abstract: Lack of differentiation in hepatocellular carcinoma (HCC) is associated with increased circulating platelet size. We measured platelet activation and plasma adenosine diphosphate (ADP) levels in HCC patients based on differentiation status. Local platelet accumulation and platelet-hepatoma cell binding were measured using immunohistochemistry (IHC) or flow cytometry. Using a xenograft assay in NON/SCID mice, we tested the effects of the anti-platelet drug clopidogrel on platelet activation, platelet infiltration, platelet-tumor cell binding and tumor cell differentiation. HCC patients with poor differentiation status displayed elevated platelet activation and higher ADP levels. Platelets accumulated within poorly differentiated tissues and localized at hepatoma cell membranes. Platelet-tumor cell binding was existed in carcinoma tissues, largely mediated by P-selectin on platelets. NOD/SCID mice with xenograft tumors also exhibited increased platelet activation and platelet-tumor cell binding. Clopidogrel therapy triggered hepatoma cell differentiation by attenuating platelet activation and platelet-tumor cell binding. TCF4 knockdown promoted HepG-2 cell differentiation and inhibited tumor formation, and TCF4 could be the potential downstream target for clopidogrel therapy.
authors.affiliation: Institute of Heart and Vascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Rongfeng
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Central Laboratory, First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Huishu
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Jingchao
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Clinical Laboratory, First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Central Laboratory, First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Yue-Jian
authors.initials: YJ
authors.lastname: Liu
authors.affiliation: Translational Research on Neurological Diseases Center, First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Clinical Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Yongfu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Institute of Heart and Vascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000368:Aged; D000818:Animals; D001792:Blood Platelets / Q000276:immunology*; D063646:Carcinogenesis; D006528:Carcinoma, Hepatocellular / Q000276:immunology*; D002454:Cell Differentiation; D000077144:Clopidogrel; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D007365:Intercellular Junctions / Q000276:immunology*; D008113:Liver Neoplasms / Q000276:immunology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000073940:Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D019007:P-Selectin; D034741:RNA, Small Interfering; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D013988:Ticlopidine
keywords: TCF4; clopidogrel; hepatocellular carcinoma; platelet; tumor differentiation