Epac1 increases migration of endothelial cells and melanoma cells via FGF2-mediated paracrine signaling
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Epac1 increases migration of endothelial cells and melanoma cells via FGF2-mediated paracrine signaling. / Baljinnyam, Erdene; Umemura, Masanari; Chuang, Christine; De Lorenzo, Mariana S; Iwatsubo, Mizuka; Chen, Suzie; Goydos, James S; Ishikawa, Yoshihiro; Whitelock, John M; Iwatsubo, Kousaku.
In: Pigment Cell & Melanoma Research, Vol. 27, No. 4, 07.2014, p. 611-20.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Epac1 increases migration of endothelial cells and melanoma cells via FGF2-mediated paracrine signaling
AU - Baljinnyam, Erdene
AU - Umemura, Masanari
AU - Chuang, Christine
AU - De Lorenzo, Mariana S
AU - Iwatsubo, Mizuka
AU - Chen, Suzie
AU - Goydos, James S
AU - Ishikawa, Yoshihiro
AU - Whitelock, John M
AU - Iwatsubo, Kousaku
N1 - © 2014 The Authors. Pigment Cell & Melanoma Research Published by John Wiley & Sons Ltd.
PY - 2014/7
Y1 - 2014/7
N2 - Fibroblast growth factor (FGF2) regulates endothelial and melanoma cell migration. The binding of FGF2 to its receptor requires N-sulfated heparan sulfate (HS) glycosamine. We have previously reported that Epac1, an exchange protein activated by cAMP, increases N-sulfation of HS in melanoma. Therefore, we examined whether Epac1 regulates FGF2-mediated cell-cell communication. Conditioned medium (CM) of melanoma cells with abundant expression of Epac1 increased migration of human umbilical endothelial cells (HUVEC) and melanoma cells with poor expression of Epac1. CM-induced increase in migration was inhibited by antagonizing FGF2, by the removal of HS and by the knockdown of Epac1. In addition, knockdown of Epac1 suppressed the binding of FGF2 to FGF receptor in HUVEC, and in vivo angiogenesis in melanoma. Furthermore, knockdown of Epac1 reduced N-sulfation of HS chains attached to perlecan, a major secreted type of HS proteoglycan that mediates the binding of FGF2 to FGF receptor. These data suggested that Epac1 in melanoma cells regulates melanoma progression via the HS-FGF2-mediated cell-cell communication.
AB - Fibroblast growth factor (FGF2) regulates endothelial and melanoma cell migration. The binding of FGF2 to its receptor requires N-sulfated heparan sulfate (HS) glycosamine. We have previously reported that Epac1, an exchange protein activated by cAMP, increases N-sulfation of HS in melanoma. Therefore, we examined whether Epac1 regulates FGF2-mediated cell-cell communication. Conditioned medium (CM) of melanoma cells with abundant expression of Epac1 increased migration of human umbilical endothelial cells (HUVEC) and melanoma cells with poor expression of Epac1. CM-induced increase in migration was inhibited by antagonizing FGF2, by the removal of HS and by the knockdown of Epac1. In addition, knockdown of Epac1 suppressed the binding of FGF2 to FGF receptor in HUVEC, and in vivo angiogenesis in melanoma. Furthermore, knockdown of Epac1 reduced N-sulfation of HS chains attached to perlecan, a major secreted type of HS proteoglycan that mediates the binding of FGF2 to FGF receptor. These data suggested that Epac1 in melanoma cells regulates melanoma progression via the HS-FGF2-mediated cell-cell communication.
KW - Cell Line, Tumor
KW - Cell Movement
KW - Fibroblast Growth Factor 2
KW - Gene Expression Regulation, Neoplastic
KW - Gene Knockdown Techniques
KW - Guanine Nucleotide Exchange Factors
KW - Human Umbilical Vein Endothelial Cells
KW - Humans
KW - Melanoma
KW - Neoplasm Proteins
KW - Neovascularization, Pathologic
KW - Paracrine Communication
U2 - 10.1111/pcmr.12250
DO - 10.1111/pcmr.12250
M3 - Journal article
C2 - 24725364
VL - 27
SP - 611
EP - 620
JO - Pigment Cell & Melanoma Research
JF - Pigment Cell & Melanoma Research
SN - 1755-1471
IS - 4
ER -
ID: 162757671