靶向干预胰腺癌干细胞（PCSCs）生长已成为胰腺癌治疗的重要策略之一。研究表明突变的K-RAS可以维持PCSCs的干性和驱动其自我更新，且多能性基因Lin28B可调控K-RAS的翻译过程。然而，K-RAS/Lin28B间相互调控的分子机制及其在PCSCs生长中的作用尚需进一步阐明。基于本课题组前期研究结果和生物信息学的分析，我们推测K-RAS的下游节点激酶PKC可能介导了Lin28B磷酸化，促进了其核转位，核内Lin28B抑制let-7的成熟，从而提高其下游靶分子TET3翻译水平，维持干性基因OCT4、NANOG等启动子区CpG 岛的低甲基化状态，形成一个正反馈调节环路促进胰腺癌干细胞的生长。本项目拟通过体内、外实验验证上述假说，旨在揭示K-RAS/lin28B/TET3通路调控的分子机制及其在胰腺癌干细胞生长中的作用，研究结果将为靶向胰腺癌干细胞的治疗策略提供理论依据。

It is a promising therapeutic strategy for anti-pancreatic cancer to target pancreatic cancer stem cells (PCSCs). Recent studies indicate that mutant K-RAS can maintain PCSCs stemness and promote self-renewal, and is regulated at translational level by Lin28B, a key pluripotent protein. However, the molecular mechanism of regulation between K-RAS and Lin2B and their roles in the growth of PCSCs remains to be clarified. Based on previous studies and analysis of bioinformatics, we proposed that PKC, a downstream node kinase of K-RAS signaling, might mediate phosphorylation of Lin28B, and thus promote Lin28B nuclear translocation. Nuclear Lin28B binds pre-let-7 and inhibits its maturation, and subsequently might result in upregulation TET3, a putative downstream target of let-7 at translational level, which maintains lower CpG methylation in promoters of stemness genes such as OCT4 and NANOG. The above pathway might form a probable feedback loop in promoting the growth of PCSCs. We will confirm the above hypothesis using experiments in vitro and in vivo to explore the regulation mechanism of K-RAS/lin28B/TET3 pathway and examine its roles in growth of PCSCs，which might provide the evidence for therapeutic strategy targeting anti-PSCSs.