title: Role of ES cell-expressed Ras (ERas) in tumorigenicity of gastric cancer.
abstract: ERas, a unique member of the Ras family, was initially found only in embryonic stem (ES) cells, where it plays a crucial role in the transformation of transplanted ES cells to teratomas. ERas is involved in ES cell survival, and unlike other Ras family members, is constitutively active without any mutations. The aim of this study was to investigate the expression and role of ERas in human gastric cancer. To test whether ERas played a significant role in human cancer cells, we examined its expression and function in gastric cancer. ERas was expressed in gastric cancer cell lines at different levels. Induction of ERas expression activated the phosphatidylinositol 3 kinase (PI3K)/Akt axis and then enhanced anchorage-independent growth and ERas knockdown by siRNA suppressed cell invasion. Immunohistochemical analyses revealed that ERas was expressed in 38.7% (55/142) of human gastric carcinoma tissues, and its expression was significantly associated with metastasis to the liver (P < 0.0001) and lymph nodes (P < 0.05). ERas up-regulated transcription regulatory factors including ZFHX1A, ZFHX1B, and TCF3, which repress E-cadherin. These data suggest that ERas is activated in a significant population of gastric cancer, where it may play a crucial role in gastric cancer cell survival and metastases to liver via down-regulation of E-cadherin.
authors.affiliation: Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kubota
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kataoka
authors.forename: Mineyoshi
authors.initials: M
authors.lastname: Aoyama
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Mizoshita
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Mori
authors.forename: Takaya
authors.initials: T
authors.lastname: Shimura
authors.forename: Mamoru
authors.initials: M
authors.lastname: Tanaka
authors.forename: Makoto
authors.initials: M
authors.lastname: Sasaki
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Asai
authors.forename: Takashi
authors.initials: T
authors.lastname: Joh
mesh_terms: D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D053595:Embryonic Stem Cells / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D046228:Microarray Analysis; D009362:Neoplasm Metastasis; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D013724:Teratoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D015820:Cadherins; C474774:ERas protein, human; D034741:RNA, Small Interfering; D058539:Phosphatidylinositol 3-Kinase; D015689:Oncogene Protein p21(ras)