Wu Linwei, Nguyen Liem H, Zhou Kejin, de Soysa T Yvanka, Li Lin, Miller Jason B, Tian Jianmin, Locker Joseph, Zhang Shuyuan, Shinoda Gen, Seligson Marc T, Zeitels Lauren R, Acharya Asha, Wang Sam C, Mendell Joshua T, He Xiaoshun, Nishino Jinsuke, Morrison Sean J, Siegwart Daniel J, Daley George Q, Shyh-Chang Ng, Zhu Hao
Children's Research Institute, Departments of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States.
Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Elife. 2015 Oct 7;4:e09431. doi: 10.7554/eLife.09431.
The in vivo roles for even the most intensely studied microRNAs remain poorly defined. Here, analysis of mouse models revealed that let-7, a large and ancient microRNA family, performs tumor suppressive roles at the expense of regeneration. Too little or too much let-7 resulted in compromised protection against cancer or tissue damage, respectively. Modest let-7 overexpression abrogated MYC-driven liver cancer by antagonizing multiple let-7 sensitive oncogenes. However, the same level of overexpression blocked liver regeneration, while let-7 deletion enhanced it, demonstrating that distinct let-7 levels can mediate desirable phenotypes. let-7 dependent regeneration phenotypes resulted from influences on the insulin-PI3K-mTOR pathway. We found that chronic high-dose let-7 overexpression caused liver damage and degeneration, paradoxically leading to tumorigenesis. These dose-dependent roles for let-7 in tissue repair and tumorigenesis rationalize the tight regulation of this microRNA in development, and have important implications for let-7 based therapeutics.
即使是研究最深入的微小RNA，其在体内的作用仍未完全明确。在这里，对小鼠模型的分析表明，let-7是一个庞大且古老的微小RNA家族，它以牺牲再生为代价发挥肿瘤抑制作用。let-7过少或过多分别导致对癌症的保护受损或组织损伤。适度的let-7过表达通过拮抗多个对let-7敏感的癌基因，消除了MYC驱动的肝癌。然而，相同水平的过表达会阻碍肝脏再生，而let-7缺失则会增强肝脏再生，这表明不同水平的let-7可以介导理想的表型。let-7依赖的再生表型是由对胰岛素-PI3K-mTOR通路的影响导致的。我们发现，慢性高剂量let-7过表达会导致肝脏损伤和退化，反常地导致肿瘤发生。let-7在组织修复和肿瘤发生中的这些剂量依赖性作用，解释了这种微小RNA在发育过程中的严格调控，并对基于let-7的治疗具有重要意义。
