Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, CA, USA.
J Intern Med. 2014 Jul;276(1):52-60. doi: 10.1111/joim.12237.
The MYC proto-oncogene is an essential regulator of many normal biological programmes. MYC, when activated as an oncogene, has been implicated in the pathogenesis of most types of human cancers. MYC overexpression in normal cells is restrained from causing cancer through multiple genetically and epigenetically controlled checkpoint mechanisms, including proliferative arrest, apoptosis and cellular senescence. When pathologically activated in the correct epigenetic and genetic contexts, MYC bypasses these mechanisms and drives many of the 'hallmark' features of cancer, including uncontrolled tumour growth associated with DNA replication and transcription, cellular proliferation and growth, protein synthesis and altered cellular metabolism. MYC also dictates tumour cell fate by enforcing self-renewal and by abrogating cellular senescence and differentiation programmes. Moreover, MYC influences the tumour microenvironment, including activating angiogenesis and suppressing the host immune response. Provocatively, brief or even partial suppression of MYC back to its physiological levels of activation can lead to the restoration of intrinsic checkpoint mechanisms, resulting in acute and sustained tumour regression associated with tumour cells undergoing proliferative arrest, differentiation, senescence and apoptosis, as well as remodelling of the tumour microenvironment, recruitment of an immune response and shutdown of angiogenesis. Hence, tumours appear to be addicted to the MYC oncogene because of both tumour cell intrinsic and host-dependent mechanisms. MYC is important for the regulation of both the initiation and maintenance of tumorigenesis.
原癌基因 MYC 是许多正常生物学程序的重要调节因子。作为癌基因激活的 MYC，与大多数类型的人类癌症的发病机制有关。MYC 在正常细胞中的过度表达受到多种遗传和表观遗传控制的检查点机制的限制，包括增殖停滞、细胞凋亡和细胞衰老。当在正确的表观遗传和遗传背景下病理性激活时，MYC 绕过这些机制，并驱动许多“标志性”的癌症特征，包括与 DNA 复制和转录、细胞增殖和生长、蛋白质合成和细胞代谢改变相关的不受控制的肿瘤生长。MYC 还通过强制自我更新和废除细胞衰老和分化程序来决定肿瘤细胞的命运。此外，MYC 影响肿瘤微环境，包括激活血管生成和抑制宿主免疫反应。挑衅性的是，即使是短暂的或部分抑制 MYC 使其回到其生理激活水平，也可以导致内在检查点机制的恢复，导致肿瘤的急性和持续消退，与肿瘤细胞经历增殖停滞、分化、衰老和凋亡以及肿瘤微环境的重塑、免疫反应的募集和血管生成的关闭有关。因此，由于肿瘤细胞内在和宿主依赖性机制，肿瘤似乎对 MYC 癌基因上瘾。MYC 对于肿瘤发生的启动和维持的调节都很重要。
