Analyses of ES specific Ras, ERas function in gastric cancer and development for new chemotherapy

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Background and aims: ERas, a novel member of the ras family, was found to be expressed in ES cells only. ERas is constitutively active without any mutations and plays a crucial role when transplanted in the transformation of ES cells to teratomas and the expression level of ERas gradually decreases when ES cells are induced to differentiate. We investigated the expression and the roles of ERas, in human gastric cancer cells.Results: 1. ERas was expressed in human gastric cancer and almost all gastric cancer cell lines. 2. Overexpression of ERas did not induce the phosphorylation of MEK. However, overexpression of ERas induced phosphorylation of Akt. 3. The ERas transfectants were significantly more resistant to CPT-11 than the parent lines (survival rate: control 23.0%, the ERas transfectants 67.4%, p <0.001), but not to 5-Fluorouracil, Cisplatin, and Paclitaxel. Overexpression of ERas significantly reduced CPT-11-induced apoptosis (p <0.01). 4. Administration of Rapamycin significantly induced cytotoxicity to the ERas transfectants (survival rate: control 93.9%, ERas transfectant 68.5%, p <0.01). 5. ERas was expressed in about 30% in human gastric cancer. Overexpression of ERas did not induce the phosphorylation of MEK but induced phosphorylation of Akt. 6. Microarray analysis revealed that ERas induced down-regulation of E-cadherin and up-regulation of ABCG2 which is capable of extruding CTPT-11 from cells. Gene set analyses of microarray indicated that ERas induced activation of NF-κB. E-cadherin inhibition was also confirmed at protein levels by westernblot and ERas significantly promoted colony-formation in soft agar, with about a 4-fold number of colonies as compared with control.Conclusion: ERas was expressed in human gastric cancer and gastric cell lines, and plays crucial roles for anti-apoptosis via phosphorylation of Akt. ERas may be associated with proliferation and metastasis of gastric cancer through inhibition of E-cadherin and activation of NFκB.