衰老或肿瘤：癌基因诱导的双向性

Senescence or Tumor:The Dual Role of Activated-oncogene Induction

在大部分的肿瘤中都发现有癌基因的活化,癌基因的活化被认为是导致肿瘤发生的重要原因.然而,在野生型细胞内,癌基因的活化可以诱导细胞衰老,称为癌基因诱导的细胞衰老(oncogene-induced senescence,OIS),从而抑制进一步的肿瘤发生.因而,癌基因的活化具有诱导衰老或肿瘤的双向性.DNA损伤调控反应(DNA damage checkpoint response,DDR)是细胞应对DNA损伤时感应损伤,从而延迟或阻滞细胞周期进程的一种分子信号传递通路,是诱导细胞衰老的重要机制.癌基因的活化可以引发DNA损伤信号的产生,从而激活DDR,诱导细胞衰老.在DDR异常时,癌基因的激活可引发DNA的过度复制与细胞的过度增殖,并导致基因组不稳定性的积累,最终导致肿瘤发生.DDR的完整性决定了癌基因诱导的双向性.DDR在癌基因诱导中的重要作用,提示了保持和恢复DDR的完整性可以作为肿瘤预防和治疗的新方向.

The activation of oncogenes occured in most tumors, and is believed to play an important role in tumorigenesis. However, the activation of oncogenes could induce cellular senescence in wild type cells, known as oncogene-induced senescence （OIS）. Thus, the activation of oncogenes has the dual role in inducing cellular senescence or tumorigenesis. DNA damage checkpoint response （DDR） is the molecular signal transduction pathway that delay or arrest cell cycle progression in response to DNA damage and is an important molecular mechanism that induce cellular senescence. Activation of oncogenes could produce DNA damage signals and initiate DDR, which subsequently induce cellular senescence. However, when DDR pathway is deficient, activation of oncogenes could induce unlimited DNA hyper-replication and cellular hyper-proliferation, which results in accumulation of genome instability, and tumorigenesis ultimately. Therefore, the dual role of activated oncogenes is regulated by the integrity of DDR pathway. The key role of DDR in regulating activated oncogenes indicates that maintain or restore the integrity of DDR pathway might provide a new strategy in cancer prevention and therapy.