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Inhibition of TGFBIp expression reduces lymphangiogenesis and tumor metastasis

Oncogene volume 35, pages 196–205 (2016)Cite this article

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Abstract

Transforming growth factor-β-induced protein (TGFBIp) is an extracellular matrix protein that has a role in a wide range of pathological conditions. However, the role of TGFBIp signaling in lymphangiogenesis is poorly understood. The purpose of this study was therefore to analyze the effects of TGFBIp on lymphangiogenesis and determine whether TGFBIp-related lymphangiogenesis is important for the metastasis of tumor cells. TGFBIp increased adhesion, migration, and morphologic differentiation of human lymphatic endothelial cells (LECs), consistent with an increase in lymphatic vessel sprouting in a three-dimensional lymphatic ring assay. TGFBIp also induced phosphorylation of intracellular signaling molecules SRC, FAK, AKT, JNK and ERK. TGFBIp-induced lymphatic vessel sprouting was inhibited by addition of anti-integrin β3 antibody and pharmacologic inhibitors of FAK, AKT, JNK or ERK. TGFBIp increased both CCL21 expression in LECs, a chemokine that actively recruits tumor cells expressing the cognate chemokine receptors to lymphatic vessels and LEC permeability by inducing the dissociation of VE-cadherin junctions between LECs via the activation of SRC signaling. In vivo, inhibition of TGFBIp expression in SW620 cancer cells dramatically reduced tumor lymphangiogenesis and metastasis. Collectively, our findings demonstrate that TGFBIp is a lymphangiogenic factor contributing to tumor dissemination and represents a potential target to inhibit metastasis.

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2011-0028699).

Author Contributions

Conceived and designed the experiments: YSM, BA, SIC. Performed the experiments: YSM, SIC. Analyzed the data: YSM, SIC, EKK. Contributed reagents/materials/analysis tools: YSM, SIC, EKK. Wrote the manuscript: YSM, BA, EKK.

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Authors and Affiliations

  1. Department of Ophthalmology, Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Korea

    Y-S Maeng, S-I Choi & E K Kim

  2. Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, CA, USA

    B Aguilar

  3. Severance Biomedical Science Institute, Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea

    E K Kim

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  1. Y-S Maeng
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  2. B Aguilar
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  3. S-I Choi
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  4. E K Kim
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Correspondence to E K Kim.

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Maeng, YS., Aguilar, B., Choi, SI. et al. Inhibition of TGFBIp expression reduces lymphangiogenesis and tumor metastasis. Oncogene 35, 196–205 (2016). https://doi.org/10.1038/onc.2015.73

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