表观修饰异常和代谢重编程是目前肿瘤研究两大热点。转录因子SOX2不仅在胚胎干细胞及部分成体干细胞维持中起重要作用，其基因扩增广泛发生于食道癌和肺癌，并可能通过调控肿瘤干细胞的形成和功能影响肿瘤发生发展、耐药和复发。我们最近的工作发现在食道癌细胞中AKT1通过磷酸化促进SOX2蛋白稳定性，而SOX2促进AKT1基因转录，从而形成SOX2-AKT1相互促进的正反馈循环。在此基础上本项目拟研究SOX2-AKT1正反馈循环：1）是否广泛存在于SOX2基因扩增的食道癌和肺癌；2）对肿瘤细胞基因表达和表观修饰的影响；3）对肿瘤细胞的代谢重编程作用及代谢与表观修饰变化的关系；4）与肿瘤干细胞的关系；5）AKT1抑制剂对治疗SOX2基因扩增肿瘤的可行性。该项目研究将有助于揭示SOX2基因扩增介导肿瘤发生发展的分子机制和对SOX2基因扩增癌症患者的个性化治疗。

In recent years epigenetic alteration and metabolism reprogramming have become two hot topics in cancer research. Transcription factor SOX2 is not only known for its functional importance for maintenance of pluripotency and self-renewal of embryonic stem cells and certain adult stem cells, SOX2 gene amplification has been linked to tumoriogenesis of esophageal and lung cancers. The recent work from our laboratory demonstrated that AKT1 promotes SOX2 protein stability through direct phosphorylation of SOX2 and SOX2 in turn activates AKT1 gene expression at the level of transcription and therefore forms a SOX2-AKT1 positive feedback regulatoryloop. On the basis of these novel findings, in this grant our aims to investigate the following questions: 1) Whether the positive feedback loop of SOX2-AKT1 broadly exists in esophageal and lung cancers with SOX2 gene amplification; 2)The effect of activated SOX2-AKT1 loop on gene expression and epigenetic modifications; 3)The effect of activated SOX2-AKT1 loop on cancer cell metabolism and the relationship between altered metabolism and epigenetic modifications; 4)The relationship between activated SOX2-AKT1 loop and cancer stem cell; 5) in animal models testing AKT1 inhibitors as therapeutic drugs for esophageal and lung cancers with SOX2 gene amplification. We believe this project will not only provide novel insights into the underlying mechanism for SOX2 overexpressed cancers, but also may help the development of personalized therapeutic strategy for cancer patients bearing SOX2 gene amplification.