论文标题
通过查找网络控制枢纽将癌症保存基因鉴定为治疗靶标
Identification of cancer-keeping genes as therapeutic targets by finding network control hubs
论文作者
论文摘要
寻找癌症驱动基因一直是癌症研究和临床研究的焦点主题。最近的方法之一是基于网络结构可控性，该结构可控性着重于找到控制方案和驱动基因，该基因可以将细胞从任意状态转移到指定状态。尽管从理论上讲是正确的，但由于许多原因，这种方法是不切实际的，例如，控制方案通常不是唯一的，一半的节点可能是细胞的驱动基因。我们开发了一种超越结构可控性的新型方法。我们不考虑一个控制方案的驱动基因，而是考虑了位于每个控制方案的控制路径中间的控制枢纽基因。控制轮毂是控制细胞和外源刺激的最脆弱的斑点，可能会使细胞无法控制。我们采用了控制枢纽作为癌症保存基因（CKG），并将其应用于膀胱癌（BLCA）的基因调节网络。 BLCA中细胞周期和p53单途径上的所有基因都是CKG，证实了这些基因的重要性以及癌症中的两种途径。通过删除网络链接来识别一组较小的35个敏感CKGS（SCKG）。在四个细胞系中，将六个SCKGS（RPS6KA3，FGFR3，N-钙粘蛋白（CDH2），EP300，caspase-1和FN1）在四个细胞系中进行小型Interterencing-RNA敲低，以验证其对癌细胞增殖或迁移的影响。在BLCA的小鼠模型中敲低RPS6KA3可显着抑制小鼠模型中肿瘤异种移植物的生长。结合在一起，我们的结果证明了CKG作为癌症治疗的治疗靶标的价值，以及CKGs作为研究和表征癌症病因的有效手段的潜力。
Finding cancer driver genes has been a focal theme of cancer research and clinical studies. One of the recent approaches is based on network structural controllability that focuses on finding a control scheme and driver genes that can steer the cell from an arbitrary state to a designated state. While theoretically sound, this approach is impractical for many reasons, e.g., the control scheme is often not unique and half of the nodes may be driver genes for the cell. We developed a novel approach that transcends structural controllability. Instead of considering driver genes for one control scheme, we considered control hub genes that reside in the middle of a control path of every control scheme. Control hubs are the most vulnerable spots for controlling the cell and exogenous stimuli on them may render the cell uncontrollable. We adopted control hubs as cancer-keep genes (CKGs) and applied them to a gene regulatory network of bladder cancer (BLCA). All the genes on the cell cycle and p53 singling pathways in BLCA are CKGs, confirming the importance of these genes and the two pathways in cancer. A smaller set of 35 sensitive CKGs (sCKGs) for BLCA was identified by removing network links. Six sCKGs (RPS6KA3, FGFR3, N-cadherin (CDH2), EP300, caspase-1, and FN1) were subjected to small-interferencing-RNA knockdown in four cell lines to validate their effects on the proliferation or migration of cancer cells. Knocking down RPS6KA3 in a mouse model of BLCA significantly inhibited the growth of tumor xenografts in the mouse model. Combined, our results demonstrated the value of CKGs as therapeutic targets for cancer therapy and the potential of CKGs as an effective means for studying and characterizing cancer etiology.
