Epigenetic regulation of the embryonic oncogene ERas in gastric cancer cells.
ERas is a recently identified oncogene that supports the tumorigenic growth of embryonic stem cells, it is constitutively active in the absence of mutation. ERas oncogene is expressed only in viviparity phase cells, but not in somatic cells because of epigenetic transcriptional silencing in the somatic phase. The aim of this study was to clarify the ERas expression and its epigenetic regulation in gastric cancer of somatic phase. Fifteen gastric cancer cell lines were used. ERas mRNA expression and its epigenetic regulation were examined by reverse transcription-polymerase chain reaction and bisulfite sequencing analysis. To identify a subset of cancer stem cells, termed 'side population' (SP) cells, flow cytometry analysis was performed. ERas is expressed in 8 of the 15 gastric cancer cell lines, but is silenced in the remaining 7 cancer cell lines and normal cell lines. Six of 7 cancer cell lines without ERas expression had promoter methylation, which correlated with silencing of ERas expression. ERas expression is re-activated following treatment with the DNA methyltransferase inhibitor 5-aza-CdR. The percentage of SP fraction of ERas-positive gastric cancer cells was significantly (p=0.024) higher (3.4+/-1.8%), in comparison to that of ERas-negative cells (1.6+/-0.4%). These findings suggested that the activating ERas oncogene might be associated with tumorigenic growth of somatic cells, and might be a putative molecule responsible for cancer stem cell-like characteristics in gastric cancer. Loss of methylation in the promoter of ERas might be one of mechanisms responsible for the re-expression of an embryonic oncogene in gastric cancer.
Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan. m9312510@med.osaka-cu.ac.jp
Masakazu
M
Yashiro
Koichi
K
Yasuda
Takafumi
T
Nishii
Ryoji
R
Kaizaki
Tetsuji
T
Sawada
Masaichi
M
Ohira
Kosei
K
Hirakawa
D001483:Base Sequence; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015254:DNA Modification Methylases; D053595:Embryonic Stem Cells / Q000502:physiology; D044127:Epigenesis, Genetic; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000502:physiology*; D015689:Oncogene Protein p21(ras) / Q000096:biosynthesis / Q000235:genetics*; D009857:Oncogenes; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D018631:ras Proteins / Q000235:genetics
C474774:ERas protein, human; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D015254:DNA Modification Methylases; D015689:Oncogene Protein p21(ras); D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins