Epac1 increases migration of endothelial cells and melanoma cells via FGF2-mediated paracrine signaling

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 - Summary: 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 - Summary: 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

SN - 1755-1471

VL - 27

SP - 611

EP - 620

JO - Pigment Cell & Melanoma Research

JF - Pigment Cell & Melanoma Research

IS - 4

ER -