Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, USA.
Cancer Res. 2011 Dec 15;71(24):7537-46. doi: 10.1158/0008-5472.CAN-11-2170. Epub 2011 Oct 28.
Dysfunctional autophagy is associated with tumorigenesis; however, the relationship between the two processes remains unclear. In the present study, we showed that MAP1S levels immediately become elevated in response to diethylnitrosamine-induced or genome instability-driven metabolic stress in a murine model of hepatocarcinoma. Upregulation of MAP1S enhanced autophagy to remove aggresomes and dysfunctional organelles that trigger DNA double-strand breaks and genome instability. The early accumulation of an unstable genome before signs of tumorigenesis indicated that genome instability caused tumorigenesis. After tumorigenesis, tumor development triggered the activation of autophagy to reduce genome instability in tumor foci. We, therefore, conclude that an increase in MAP1S levels triggers autophagy to suppress genome instability such that both the incidence of diethylnitrosamine-induced hepatocarcinogenesis and malignant progression are suppressed. Taken together, the data establish a link between MAP1S-enhanced autophagy and suppression of genomic instability and tumorigenesis.
功能失调的自噬与肿瘤发生有关；然而，这两个过程之间的关系尚不清楚。在本研究中，我们显示 MAP1S 水平在二乙基亚硝胺诱导的或基因组不稳定性驱动的代谢应激后立即升高，在肝癌的小鼠模型中。MAP1S 的上调增强了自噬，以清除引发 DNA 双链断裂和基因组不稳定性的聚集物和功能失调的细胞器。在出现肿瘤发生迹象之前，不稳定基因组的早期积累表明基因组不稳定性导致了肿瘤发生。肿瘤发生后，肿瘤的发展触发了自噬的激活，以减少肿瘤灶中的基因组不稳定性。因此，我们得出结论，MAP1S 水平的增加引发自噬以抑制基因组不稳定性，从而抑制二乙基亚硝胺诱导的肝癌发生和恶性进展的发生率。总之，这些数据建立了 MAP1S 增强的自噬与抑制基因组不稳定性和肿瘤发生之间的联系。
