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

背景与目的：ER as是ras家族的新成员，仅在ES细胞中表达。ERas是组成型活性的，没有任何突变，并且在移植时在ES细胞向畸胎瘤的转化中起关键作用，并且当ES细胞被诱导分化时，ERas的表达水平逐渐降低。本研究探讨了ER α_1在人胃癌细胞中的表达及其作用。ERas在人胃癌及几乎所有胃癌细胞系中均有表达。2. ERas的过表达不诱导MEK的磷酸化。然而，ERas的过表达诱导Akt的磷酸化。3. ERas转染子对CPT-11的抗性显著高于亲本系（存活率：对照23.0%，ERas转染子67.4%，p <0.001），但对5-氟尿嘧啶、顺铂和紫杉醇的抗性不显著。ERas的过表达显著降低CPT-11诱导的细胞凋亡（p <0.01）。4.给予雷帕霉素显著诱导了对ERas转染子的细胞毒性（存活率：对照93.9%，ERas转染子68.5%，p <0.01）。5. ERas在胃癌组织中的表达率约为30%。ERas的过表达不诱导MEK的磷酸化，但诱导Akt的磷酸化。6.基因芯片分析显示，ERas诱导E-cadherin下调和ABCG 2上调，ABCG 2能够从细胞中挤出CTPT-11。基因芯片分析结果显示ER α诱导NF-κB B活化。E-cadherin抑制也证实了在蛋白水平上的westernblot和ERas显着促进在软琼脂中的集落形成，与约4倍的菌落数相比，contradiction.Conclusion：ERas表达在人胃癌和胃细胞株，并发挥重要作用，通过Akt的磷酸化抗凋亡。ERas可能通过抑制E-cadherin和激活NFκB参与胃癌的增殖和转移。

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.