Precise let-7 expression levels balance organ regeneration against tumor suppression.
Precise let-7 expression levels balance organ regeneration against tumor suppression.
复制标题
精确的Let-7表达水平平衡器官再生与肿瘤抑制。
作者：
Wu L;Nguyen LH;Zhou K;de Soysa TY;Li L;Miller JB;Tian J;Locker J;Zhang S;Shinoda G;Seligson MT;Zeitels LR;Acharya A;Wang SC;Mendell JT;He X;Nishino J;Morrison SJ;Siegwart DJ;Daley GQ;Shyh-Chang N;Zhu H
即使是研究最深入的microRNA在体内的作用仍然很难确定。在这里，对小鼠模型的分析表明，let-7是一个庞大而古老的microRNA家族，以再生为代价发挥肿瘤抑制作用。太少或太多的let-7分别导致对癌症或组织损伤的保护作用受损。适度的let-7过表达通过拮抗多种let-7敏感癌基因来消除MYC驱动的肝癌。然而，相同水平的过表达阻断了肝再生，而let-7缺失增强了肝再生，表明不同的let-7水平可以介导理想的表型。let-7依赖性再生表型是由对胰岛素-PI3 K-mTOR途径的影响引起的。我们发现，长期高剂量let-7过度表达导致肝损伤和变性，矛盾的是导致肿瘤发生。let-7在组织修复和肿瘤发生中的这些剂量依赖性作用使这种microRNA在发育中的严格调控合理化，并且对基于let-7的治疗具有重要意义。DOI：www.example.com动物的发育是由某些基因在关键时刻的表达所引导的。许多不同的机制控制着发育;其中之一，基因的表达可以被称为microRNA的分子降低。特别是，被称为let-7的microRNA组已在蛔虫和果蝇中进行了深入研究。虽然哺乳动物有非常相似的let-7 microRNA，但它们在成年期似乎更重要。先前使用实验室中生长的细胞进行的研究表明，哺乳动物let-7 microRNAs会降低细胞增殖和细胞生长。此外，在各种癌症的小鼠模型中，let-7 microRNA在提供给成年小鼠时通常会减少肿瘤生长。因此，总的来说，let-7基因组被归类为抑制肿瘤的基因，从而保护小鼠（也很可能是人类）免受癌症的侵害。然而，let-7 microRNA的深入分析仍然缺失。Wu和Nguyen等人现在已经使用能够调节let-7水平的菌株研究了肝癌小鼠。这些小鼠在肝脏中过度产生了一种强烈的致癌基因;一半被用作对照，另一半被进一步改造成具有适度升高的let-7表达水平。大多数对照组小鼠都有大的癌性肿瘤，但另一组中只有少数小鼠患上了癌症，而且肿瘤较小。这证实let-7阻碍肿瘤形成。Wu和Nguyen等人还观察到，受保护的小鼠再生肝组织的能力较低。进一步的实验表明，删除10个let-7 microRNA中的2个可以增强小鼠在损伤后再生肝组织的能力。这些发现表明let-7 microRNA减缓了癌细胞和正常细胞的生长。最后，当let-7水平长时间升高到非常高的水平时，这实际上会导致肝损伤和随后的肿瘤形成。这最后一个观察结果可能对可能的癌症治疗产生重要影响。一些科学家已经证明，提供额外的let-7可以减缓甚至逆转肿瘤的生长，但这里的研究结果清楚地指出，过多的let-7实际上会使情况恶化。由于let-7家族由哺乳动物中的少数microRNA组成，因此在未来，找出这些分子在多大程度上发挥重叠作用以及它们之间的差异也将非常重要。DOI：www.example.com网站
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. DOI: http://dx.doi.org/10.7554/eLife.09431.001 The development of animals is guided by the expression of certain genes at critical moments. Many different mechanisms control development; in one of them, the expression of genes can be decreased by molecules called microRNAs. In particular, the group of microRNAs called let-7 has been intensively studied in roundworms and fruit flies. Although mammals have extremely similar let-7 microRNAs they seem to be more important during adulthood. Previous studies using cells grown in the laboratory have shown that mammalian let-7 microRNAs decrease cell proliferation and cell growth. Furthermore, in mouse models of various cancers, let-7 microRNAs often reduce tumour growth when they are supplied to adult mice. Therefore, overall the let-7 group has been classified as genes that act to suppress tumors, and thus protect mice (and most likely humans too) from cancers. However, in-depth analysis of let-7 microRNAs was still missing. Wu and Nguyen et al. have now studied mice with liver cancer using strains where they were able to regulate the levels of let-7. These mice overproduce a strong cancer-inducing gene in the liver; half were used as controls and the other half were further engineered to have moderately elevated levels of let-7 expression. Most of the control mice got large cancerous tumors, but only a few mice in the other group developed cancers and the tumors were smaller. This confirmed that let-7 hinders tumor formation. Wu and Nguyen et al. also observed that the protected mice were less able to regenerate their liver tissues. Further experiments showed that deleting just two out of ten let-7 microRNAs enhanced the mice’s ability to regenerate liver tissue after injury. These findings indicate that let-7 microRNAs slow down the growth of both cancerous and normal cells. Lastly, when let-7 levels were raised to very high levels for a prolonged amount of time this actually led to liver damage and subsequent tumor formation. This last observation may have important consequences for possible cancer therapies. Some scientists have shown that providing extra let-7 can slow or even reverse tumour growth, but the findings here clearly point out that too much let-7 could actually worsen the situation. Since the let-7 family comprises a handful of microRNAs in mammals, in the future it will also be important to find out to what extent these molecules play overlapping roles and how much they differ. DOI: http://dx.doi.org/10.7554/eLife.09431.002