title: Inhibition of VEGF165/VEGFR2-dependent signaling by LECT2 suppresses hepatocellular carcinoma angiogenesis.
abstract: Hepatocellular carcinoma (HCC) relies on angiogenesis for growth and metastasis. Leukocyte cell-derived chemotaxin 2 (LECT2) is a cytokine and preferentially expressed in the liver. Previous studies have found that LECT2 targets to both immune and tumor cells to suppress HCC development and vascular invasion. Although LECT2 did not affect HCC cells growth in vitro, it still suppressed HCC xenografts growth in immune-deficient mice, suggesting other cells such as stroma cells may also be targeted by LECT2. Here, we sought to determine the role of LECT2 in tumor angiogenesis in HCC patients. We found that LECT2 expression inhibited tumor growth via angiogenesis in the HCC xenograft model. Specifically, we demonstrated that recombinant human LECT2 protein selectively suppressed vascular endothelial growth factor (VEGF)165-induced endothelial cell proliferation, migration, and tube formation in vitro and in vivo. Mechanistically, LECT2 reduced VEGF receptor 2 tyrosine phosphorylation and its downstream extracellular signal-regulated kinase and AKT phosphorylation. Furthermore, LECT2 gene expression correlated negatively with angiogenesis in HCC patients. Taken together, our findings demonstrate that LECT2 inhibits VEGF165-induced HCC angiogenesis through directly binding to VEGFR2 and has broad applications in treating VEGF-mediated solid tumors.
authors: Genomics Research Center, Academia Sinica, Taipei, Taiwan.|Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Chi-Kuan
authors: CK
authors: Chen
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston TX, USA.|Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.
authors: Wen-Hsuan
authors: WH
authors: Yu
authors: Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors: Tsu-Yao
authors: TY
authors: Cheng
authors: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors: Min-Wei
authors: MW
authors: Chen
authors: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors: Chia-Yi
authors: CY
authors: Su
authors: Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Yi-Chieh
authors: YC
authors: Yang
authors: Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan.
authors: Tsang-Chih
authors: TC
authors: Kuo
authors: Department of Surgery, National Taiwan University Hospital, and National Taiwan University College of Medicine, Taipei, Taiwan.|Department of Primary Care Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors: Ming-Tsan
authors: MT
authors: Lin
authors: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Ya-Chi
authors: YC
authors: Huang
authors: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors: Michael
authors: M
authors: Hsiao
authors: Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Kuo-Tai
authors: KT
authors: Hua
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston TX, USA.|Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.
authors: Mien-Chie
authors: MC
authors: Hung
authors: Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan.
authors: Min-Liang
authors: ML
authors: Kuo
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage* / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; C103468:LECT2 protein, human; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2