title: ANGPTL4 is a secreted tumor suppressor that inhibits angiogenesis.
abstract: Tumor suppressors with extracellular function are likely to have advantages as targets for cancer therapy, but few are known. Here, we focused on angiopoietin-like 4 (ANGPTL4), which is a secreted glycoprotein involved in lipoprotein metabolism and angiogenesis, is methylation-silenced in human cancers, but has unclear roles in cancer development and progression. We found a deletion mutation in its coiled-coil domain at its N-terminal in human gastric cancers, in addition to hypermethylation of the ANGPTL4 promoter CpG islands. Forced expression of wild-type ANGPTL4, but not ANGPTL4 with the deletion, at physiological levels markedly suppressed in vivo tumorigenicity and tumor angiogenesis, indicating that the latter caused the former. Tumor-derived ANGPTL4 suppressed in vitro vascular tube formation and proliferation of human umbilical vascular endothelial cells, partly due to suppression of ERK signaling. These showed that ANGPTL4 is a genetically and epigenetically inactivated secreted tumor suppressor that inhibits tumor angiogenesis.
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Okochi-Takada
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Hattori
authors.affiliation: Oncological Pathology Division, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tsukamoto
authors.affiliation: Division of Molecular Oncology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kureshi, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Miyamoto
authors.affiliation: 1] Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan [2] Third Department of Internal Medicine, University of Toyama, Toyama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ando
authors.affiliation: Department of Gastroenterological Surgery, Aichi Cancer Center Central Hospital, Nagoya, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of Gastroenterological Surgery, Aichi Cancer Center Central Hospital, Nagoya, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yamamura
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Wakabayashi
authors.affiliation: 1] Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan [2] Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nobeyama
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ushijima
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D016022:Case-Control Studies; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D013274:Stomach Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D025521:Tumor Suppressor Proteins