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.
Highlights
Tumor-secreted protein that increases vascular permeability[6]
The results indicated that VEGF165 increased the capillary bed area of the chorioallantois in the CAMs more so than did the non-treatment control and that recombinant LECT2 (rLECT2) protein suppressed the Human umbilical vein endothelial cells (HUVECs). (a) HUVECs were seeded in a 24-well plate, treated with VEGF165 (50 ng/mL), platelet-derived growth factor (PDGF) (50 ng/mL), basic fibroblast growth factor (bFGF) (50 ng/mL), epidermal growth factor (EGF) (50 ng/mL), or hepatocyte growth factor (HGF) (40 ng/mL) alone or combined with rLECT2 protein (5 nM) as indicated for 14 h, and subjected to Migration assay. (b) HUVECs were seeded onto a Matrigel layer in a 24-well plate, treated with different angiogenic factors as indicated for 6 h, and subjected to tube formation assay
We found that treatment with leukocyte cell-derived chemotaxin 2 (LECT2) inhibited tumor growth but not cancer cell proliferation in a xenograft mice model of Hepatocellular carcinoma (HCC)
Summary
Tumor-secreted protein that increases vascular permeability[6]. VEGF family members exert their activities by binding to VEGF receptors (VEGFRs) 1, 2, and 3. We previously identified the hepatocyte growth factor (HGF) receptor MET as an important target of LECT2 in HCC cells using liquid chromatography tandem-mass spectrometry and a receptor tyrosine kinase (RTK) array. Clinical and mechanistic findings from our own and other studies suggest that LECT2 is an important regulator of tumor growth during HCC development and progression. We found that LECT2 suppressed tumor growth in vivo without affecting cancer cell proliferation in vitro. On the basis of these findings, we hypothesized that LECT2 suppresses vascular invasion and metastasis of HCC cells and inhibits tumor growth by targeting stromal cells. We first demonstrated that LECT2 suppressed HCC growth by inhibiting tumor angiogenesis in vivo. We evaluated the correlation of LECT2 expression with tumor angiogenesis in HCC patients
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