The incidence of cutaneous melanoma(CM)has been increasing annually worldwide.In this study,we identify that MrgprF,a MAS related GPR family member,is decreased in cutaneous melanoma tissues and cell lines due to hype...The incidence of cutaneous melanoma(CM)has been increasing annually worldwide.In this study,we identify that MrgprF,a MAS related GPR family member,is decreased in cutaneous melanoma tissues and cell lines due to hypermethylation of its promoter region,and show that patients with CM expressing high levels of MrgprF exhibit an improved clinical outcome.We demonstrate that MrgprF forced expression inhibits tumor cell proliferation,migration,xenograft tumor growth,and metastasis.On the contrary,MrgprF knockdown promotes tumor cell proliferation and transformation of immortalized human keratinocyte-HaCaT cells,supporting the inhibitory role of MrgprF during tumor progression.Mechanistic studies reveal that MrgprF reduces the phosphoinositol‑3‑kinase(PI3K)complex formation between p101 and p110γsubunits,the critical step for phosphatidylinositol-(3,4)-P2(PIP2)conversion to phosphatidylinositol-(3,4,5)-P3(PIP3),and then reduces the activation of PI3K/Akt signaling.This effect can be reversed by Akt specific agonist SC79.In addition,AMG 706,a previously documented inhibitor for endothelial cell proliferation,is identified as a potential agonist for MrgprF,and can impede tumor growth both in vitro and in vivo.Taken together,our findings suggest that MrgprF,a novel tumor suppressor in cutaneous melanoma,may be useful as a therapeutic target in the future.展开更多
基金This study was supported by National Key Research and Development Program of China(2021YFF1000602)National Nature Science Foundation of China(U2102206,U1902216,81772996,82173110,82002439,81972181,82060515)+6 种基金Yunnan Applied Basic Research Projects(2019FJ009,202001AS070037,2019HB076,202001AY070001-068,2019FE001-042)C.P.Y was supported by Youth Innovation Promotion Association,CASY.B.C was supported by grant from the Strategic Priority Research Program of the Chinese Academy of Sciences XDPB17,and YJKYYQ20190048Science&Technology Department of Sichuan Province Research Program(2020YFSY0009)Q.S.S was also supported by China Postdoctoral Science Foundation(2019M662547)the Fellowship of China National Postdoctoral Program for Innovative Talents(BX20190299)S.Z was also supported by Key Scientific Research Projects of Colleges and Universities in Henan Province(21A320024).
文摘The incidence of cutaneous melanoma(CM)has been increasing annually worldwide.In this study,we identify that MrgprF,a MAS related GPR family member,is decreased in cutaneous melanoma tissues and cell lines due to hypermethylation of its promoter region,and show that patients with CM expressing high levels of MrgprF exhibit an improved clinical outcome.We demonstrate that MrgprF forced expression inhibits tumor cell proliferation,migration,xenograft tumor growth,and metastasis.On the contrary,MrgprF knockdown promotes tumor cell proliferation and transformation of immortalized human keratinocyte-HaCaT cells,supporting the inhibitory role of MrgprF during tumor progression.Mechanistic studies reveal that MrgprF reduces the phosphoinositol‑3‑kinase(PI3K)complex formation between p101 and p110γsubunits,the critical step for phosphatidylinositol-(3,4)-P2(PIP2)conversion to phosphatidylinositol-(3,4,5)-P3(PIP3),and then reduces the activation of PI3K/Akt signaling.This effect can be reversed by Akt specific agonist SC79.In addition,AMG 706,a previously documented inhibitor for endothelial cell proliferation,is identified as a potential agonist for MrgprF,and can impede tumor growth both in vitro and in vivo.Taken together,our findings suggest that MrgprF,a novel tumor suppressor in cutaneous melanoma,may be useful as a therapeutic target in the future.
