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FGFR3 promotes angiogenesis-dependent metastasis of hepatocellular carcinoma via facilitating MCP-1-mediated vascular formation

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Abstract

The biological role of fibroblast growth factor receptor 3 (FGFR3) in tumor angiogenesis of hepatocellular carcinoma (HCC) has not been discussed before. Our previous work had indicated FGFR3 was overexpressed in HCC, and silencing FGFR3 in Hu7 cells could regulate tumorigenesis via down-regulating the phosphorylation level of key members of classic signaling pathways including ERK and AKT. In the present work, we explored the role of FGFR3 in angiogenesis-dependent metastasis by using SMMC-7721 and QGY-7703 stable cell lines. Our results indicated FGFR3 could regulate in vitro cell migration ability and in vivo lung metastasis ability of HCC, which was in accordance with increased angiogenesis ability in vitro and in vivo. Using the supernatant from SMMC-7721/FGFR3 cells, we conducted a human angiogenesis protein microarray including 43 angiogenesis factors and found that FGFR3 modulated angiogenesis and metastasis of HCC mainly by promoting the protein level of monocyte chemotactic protein 1 (MCP-1). Silencing FGFR3 by short hairpin RNA (shRNA) could reduce MCP-1 level in lysates and supernatant of QGY-7703 cells and SMMC-7721 cells. Silencing MCP-1 in QGY-7703 or SMMC-7721 cells could induce similar phenotypes compared with silencing FGFR3. Our results suggested FGFR3 promoted metastasis potential of HCC, at least partially if not all, via facilitating MCP-1-mediated angiogenesis, in addition to previously found cell growth and metastasis. MCP-1, a key medium between HCC cells and HUVECs, might be a novel anti-vascular target in HCC.

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Acknowledgments

This study was supported by Nature Science Foundation of China (30872511) and Shanghai Charity Foundation for Cancer Research.

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    Authors and Affiliations

    1. Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Er Rd, Shanghai, 200025, China

      Xinyu Liu, Xiaoqian Jing, Xi Cheng, Ding Ma, Zhijian Jin, Weiping Yang & Weihua Qiu

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    1. Xinyu Liu
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    2. Xiaoqian Jing
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    3. Xi Cheng
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    Correspondence to Weiping Yang or Weihua Qiu.

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    Xinyu Liu, Xiaoqian Jing and Xi Cheng contributed equally to this work.

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    Fig S1

    FGFR3 regulated in vitro proliferation of HCC. a The silencing effect of FGFR3 in SMMC-7721 and QGY-7703 cells was confirmed by western blot with 40 ug total protein per well. b The overexpression effect of FGFR3 in SMMC-7721 and QGY-7703 cells was confirmed by western blot with 15 ug total protein per well. *p<0.05 and **p<0.01 (TIFF 2097 kb)

    Fig S2

    FGFR3 regulated in vivo proliferation of HCC. a Knockdown of FGFR3 inhibited tumor growth in vivo. b The volume of xenografts tumors was measured every 5 days. c Tumor weight was measured after the xenografts tumors were removed. *p<0.05 and **p<0.01 (TIFF 1874 kb)

    Fig S3

    The effect of FGFR3 overexpression on the proliferation of HUVEC cells. a FGFR3 overexpression in SMMC-7721 cells could significantly increase the proliferation ability of HUVECs while silencing FGFR3 had no significant effect on the proliferation ability of HUVECs. b FGFR3 overexpression in QGY-7703 cells could significantly increase the proliferation ability of HUVECs and silencing FGFR3 impaired the proliferation ability of HUVECs. *p<0.05 and **p<0.01 (TIFF 1327 kb)

    Fig S4

    Human angiogenesis array. Molecules shown in red were up-regulated in SMMC-7721/FGFR3 group compared with SMMC-7721/NC group. Pos, positive control; Neg, negative control (TIFF 4157 kb)

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    Liu, X., Jing, X., Cheng, X. et al. FGFR3 promotes angiogenesis-dependent metastasis of hepatocellular carcinoma via facilitating MCP-1-mediated vascular formation. Med Oncol 33, 46 (2016). https://doi.org/10.1007/s12032-016-0761-9

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    • DOI: https://doi.org/10.1007/s12032-016-0761-9

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