Role of ES cell-expressed Ras (ERas) in tumorigenicity of gastric cancer.
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.
Kubota
Eiji
E
Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Kataoka
Hiromi
H
Aoyama
Mineyoshi
M
Mizoshita
Tsutomu
T
Mori
Yoshinori
Y
Shimura
Takaya
T
Tanaka
Mamoru
M
Sasaki
Makoto
M
Takahashi
Satoru
S
Asai
Kiyofumi
K
Joh
Takashi
T
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
D015820:Cadherins; C474774:ERas protein, human; D034741:RNA, Small Interfering; D058539:Phosphatidylinositol 3-Kinase; D015689:Oncogene Protein p21(ras)