ADAMTS1 inhibits lymphangiogenesis by attenuating phosphorylation of the lymphatic endothelial cell-specific VEGF receptor

Junko Inagaki; Katsuyuki Takahashi; Hiroko Ogawa; Keiichi Asano; Omer Faruk Hatipoglu; Mehmet Zeynel Cilek; Masanari Obika; Takashi Ohtsuki; Matthias Hofmann; Shozo Kusachi; Yoshifumi Ninomiya; Satoshi Hirohata

doi:10.1016/j.yexcr.2014.03.002

ADAMTS1 inhibits lymphangiogenesis by attenuating phosphorylation of the lymphatic endothelial cell-specific VEGF receptor

Junko Inagaki, Katsuyuki Takahashi, Hiroko Ogawa, Keiichi Asano, Omer Faruk Hatipoglu, Mehmet Zeynel Cilek, Masanari Obika, Takashi Ohtsuki, Matthias Hofmann, Shozo Kusachi, Yoshifumi Ninomiya, Satoshi Hirohata

Research output: Contribution to journal › Article › peer-review

15 Citations (Scopus)

Abstract

Angiogenesis and lymphangiogenesis play roles in malignant tumor progression, dissemination, and metastasis. ADAMTS1, a member of the matrix metalloproteinase family, is known to inhibit angiogenesis. Recombinant ADAMTS1 was shown to strongly inhibit angiogenesis. We investigated whether ADAMTS1 inhibited lymphangiogenesis in the present study. We examined cell proliferation and cell migration in normal human dermal lymphatic microvascular endothelial cells (HMVEC-dLy) transduced with or without adenoviral human ADAMTS1 gene therapy. We then examined the VEGFC/VEGFR3 signal transduction pathway in ADAMTS1-transduced HMVEC-dLy. Cell proliferation and tube formation in Matrigel were significantly lower with transduced ADAMTS1 than with control (non-transduced HMVEC-dLy). The phosphorylation of VEGFR3 was also attenuated by ADAMTS1 gene therapy in HMVEC-dLy. Immunoprecipitation assays revealed that ADAMTS1 formed a complex with VEGFC. Our results demonstrated that ADAMTS1 inhibited lymphangiogenesis in vitro. The data highlight the new function of ADAMTS1 in the regulation of lymphangiogenesis and the therapeutic potential of ADAMTS1 in cancer therapy.

Original language	English
Pages (from-to)	263-275
Number of pages	13
Journal	Experimental Cell Research
Volume	323
Issue number	2
DOIs	https://doi.org/10.1016/j.yexcr.2014.03.002
Publication status	Published - May 1 2014

Keywords

ADAMTS1
Lymphangiogenesis
Lymphatic endothelial cell
VEGFC
VEGFR-3

ASJC Scopus subject areas

Cell Biology

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Inagaki, J., Takahashi, K., Ogawa, H., Asano, K., Faruk Hatipoglu, O., Zeynel Cilek, M., Obika, M., Ohtsuki, T., Hofmann, M., Kusachi, S., Ninomiya, Y., & Hirohata, S. (2014). ADAMTS1 inhibits lymphangiogenesis by attenuating phosphorylation of the lymphatic endothelial cell-specific VEGF receptor. Experimental Cell Research, 323(2), 263-275. https://doi.org/10.1016/j.yexcr.2014.03.002

ADAMTS1 inhibits lymphangiogenesis by attenuating phosphorylation of the lymphatic endothelial cell-specific VEGF receptor. / Inagaki, Junko; Takahashi, Katsuyuki; Ogawa, Hiroko; Asano, Keiichi; Faruk Hatipoglu, Omer; Zeynel Cilek, Mehmet; Obika, Masanari; Ohtsuki, Takashi; Hofmann, Matthias; Kusachi, Shozo; Ninomiya, Yoshifumi; Hirohata, Satoshi.

In: Experimental Cell Research, Vol. 323, No. 2, 01.05.2014, p. 263-275.

Research output: Contribution to journal › Article › peer-review

Inagaki, J, Takahashi, K, Ogawa, H, Asano, K, Faruk Hatipoglu, O, Zeynel Cilek, M, Obika, M, Ohtsuki, T, Hofmann, M, Kusachi, S, Ninomiya, Y & Hirohata, S 2014, 'ADAMTS1 inhibits lymphangiogenesis by attenuating phosphorylation of the lymphatic endothelial cell-specific VEGF receptor', Experimental Cell Research, vol. 323, no. 2, pp. 263-275. https://doi.org/10.1016/j.yexcr.2014.03.002

Inagaki, Junko ; Takahashi, Katsuyuki ; Ogawa, Hiroko ; Asano, Keiichi ; Faruk Hatipoglu, Omer ; Zeynel Cilek, Mehmet ; Obika, Masanari ; Ohtsuki, Takashi ; Hofmann, Matthias ; Kusachi, Shozo ; Ninomiya, Yoshifumi ; Hirohata, Satoshi. / ADAMTS1 inhibits lymphangiogenesis by attenuating phosphorylation of the lymphatic endothelial cell-specific VEGF receptor. In: Experimental Cell Research. 2014 ; Vol. 323, No. 2. pp. 263-275.

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abstract = "Angiogenesis and lymphangiogenesis play roles in malignant tumor progression, dissemination, and metastasis. ADAMTS1, a member of the matrix metalloproteinase family, is known to inhibit angiogenesis. Recombinant ADAMTS1 was shown to strongly inhibit angiogenesis. We investigated whether ADAMTS1 inhibited lymphangiogenesis in the present study. We examined cell proliferation and cell migration in normal human dermal lymphatic microvascular endothelial cells (HMVEC-dLy) transduced with or without adenoviral human ADAMTS1 gene therapy. We then examined the VEGFC/VEGFR3 signal transduction pathway in ADAMTS1-transduced HMVEC-dLy. Cell proliferation and tube formation in Matrigel were significantly lower with transduced ADAMTS1 than with control (non-transduced HMVEC-dLy). The phosphorylation of VEGFR3 was also attenuated by ADAMTS1 gene therapy in HMVEC-dLy. Immunoprecipitation assays revealed that ADAMTS1 formed a complex with VEGFC. Our results demonstrated that ADAMTS1 inhibited lymphangiogenesis in vitro. The data highlight the new function of ADAMTS1 in the regulation of lymphangiogenesis and the therapeutic potential of ADAMTS1 in cancer therapy.",

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AU - Faruk Hatipoglu, Omer

AU - Zeynel Cilek, Mehmet

AU - Obika, Masanari

AU - Ohtsuki, Takashi

AU - Hofmann, Matthias

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AU - Ninomiya, Yoshifumi

AU - Hirohata, Satoshi

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