title: RUNX3, a novel tumor suppressor, is frequently inactivated in gastric cancer by protein mislocalization.
abstract: Loss of RUNX3 expression is suggested to be causally related to gastric cancer as 45% to 60% of gastric cancers do not express RUNX3 mainly due to hypermethylation of the RUNX3 promoter. Here, we examined for other defects in the properties of RUNX3 in gastric cancers that express RUNX3. Ninety-seven gastric cancer tumor specimens and 21 gastric cancer cell lines were examined by immunohistochemistry using novel anti-RUNX3 monoclonal antibodies. In normal gastric mucosa, RUNX3 was expressed most strongly in the nuclei of chief cells as well as in surface epithelial cells. In chief cells, a significant portion of the protein was also found in the cytoplasm. RUNX3 was not detectable in 43 of 97 (44%) cases of gastric cancers tested and a further 38% showed exclusive cytoplasmic localization, whereas only 18% showed nuclear localization. Evidence is presented suggesting that transforming growth factor-beta is an inducer of nuclear translocation of RUNX3, and RUNX3 in the cytoplasm of cancer cells is inactive as a tumor suppressor. RUNX3 was found to be inactive in 82% of gastric cancers through either gene silencing or protein mislocalization to the cytoplasm. In addition to the deregulation of mechanisms controlling gene expression, there would also seem to be at least one other mechanism controlling nuclear translocation of RUNX3 that is impaired frequently in gastric cancer.
authors.affiliation: Institute of Molecular and Cell Biology, Proteos, Singapore.
authors.forename: Kosei
authors.initials: K
authors.lastname: Ito
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.forename: Takashi
authors.initials: T
authors.lastname: Yano
authors.forename: Kotaro
authors.initials: K
authors.lastname: Tada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ida
authors.forename: Canhua
authors.initials: C
authors.lastname: Huang
authors.forename: Nilesh
authors.initials: N
authors.lastname: Shah
authors.forename: Masafumi
authors.initials: M
authors.lastname: Inoue
authors.forename: Andrea
authors.initials: A
authors.lastname: Rajnakova
authors.forename: Kum Chew
authors.initials: KC
authors.lastname: Hiong
authors.forename: Bee Keow
authors.initials: BK
authors.lastname: Peh
authors.forename: Hwan Chour
authors.initials: HC
authors.lastname: Han
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ito
authors.forename: Ming
authors.initials: M
authors.lastname: Teh
authors.forename: Khay Guan
authors.initials: KG
authors.lastname: Yeoh
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ito
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000302:isolation & purification; D000918:Antibody Specificity; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D050677:Core Binding Factor Alpha 3 Subunit; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D050677:Core Binding Factor Alpha 3 Subunit; D004268:DNA-Binding Proteins; C493729:Runx3 protein, human; C493730:Runx3 protein, mouse; D014157:Transcription Factors