title: Lysyl oxidase is a tumor suppressor gene inactivated by methylation and loss of heterozygosity in human gastric cancers.
abstract: Lysyl oxidase (LOX) and HRAS-like suppressor (HRASLS) are silenced in human gastric cancers and are reported to have growth-suppressive activities in ras-transformed mouse/rat fibroblasts. Here, we analyzed whether or not LOX and HRASLS are tumor suppressor genes in human gastric cancers. Loss of heterozygosity and promoter methylation of LOX were detected in 33% (9 of 27) and 27% (26 of 96) of gastric cancers, respectively. Biallelic methylation and loss of heterozygosity with promoter methylation were also demonstrated in gastric cancers. Silencing of LOX was also observed in colon, lung, and ovarian cancer cell lines. As for mutations, only one possible somatic mutation was found by analysis of 96 gastric cancer samples and 58 gastric and other cancer cell lines. When LOX was introduced into a gastric cancer cell line, MKN28, in which LOX and HRASLS were silenced, it reduced the number of anchorage-dependent colonies to 57 to 61%, and the number of anchorage-independent colonies to 11 to 23%. Sizes of tumors formed in nude mice were reduced to 19 to 26%. Growth suppression in soft agar assay was also observed in another gastric cancer cell line, KATOIII. On the other hand, neither loss of heterozygosity nor a somatic mutation was detected in HRASLS, and its introduction into MKN28 did not suppress the growth in vitro or in vivo. These data showed that LOX is a tumor suppressor gene inactivated by methylation and loss of heterozygosity in gastric cancers, and possibly also in other cancers.
authors.affiliation: Carcinogenesis Division, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kaneda
authors.forename: Kuniko
authors.initials: K
authors.lastname: Wakazono
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Naoko
authors.initials: N
authors.lastname: Watanabe
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Yagi
authors.forename: Masae
authors.initials: M
authors.lastname: Tatematsu
authors.forename: Michio
authors.initials: M
authors.lastname: Kaminishi
authors.forename: Takashi
authors.initials: T
authors.lastname: Sugimura
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Ushijima
mesh_terms: D000818:Animals; D002455:Cell Division / Q000235:genetics; D019175:DNA Methylation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D010741:Phospholipases A; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics*; D011506:Proteins / Q000235:genetics; D013274:Stomach Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
chemical_list: D011506:Proteins; D008249:Protein-Lysine 6-Oxidase; C433809:PLAAT1 protein, human; D010741:Phospholipases A