Lin28/SREBP1c调控肿瘤细胞脂类合成代谢的机制研究

Dysfunction of lipid metabolism may play an important role in the occurrence of cancer, whereas little is known about the regulatory mechanism. Recently, we have found that Lin28/let-7/PDK1 axis regulates aerobic glycolysis in cancer cells (Nat Communs, 2014). However, by now, the regulatory function of Lin28 in cancer lipid metabolism has not been reported. Our preliminary xenograft experiments in nude mice showed that lipid droplets accumulated more in cancer tissue overexpressing Lin28a or Lin28b than that of control group, which indicates that Lin28 promotes lipid biosynthesis. We further found that SREBP1c, an important transcriptional factor in fatty acid synthesis, was activated by Lin28, but not affected by let-7. Therefore, we will investigate whether Lin28, as an RNA binding protein, can interact with SREBP1c and promote its protein translation. This may further activate multiple fatty acids synthesis genes SREBP1c regulates, enhance lipid biosynthesis, and affect the occurrence and progression of cancers. Our project aims to uncover the relevance between Lin28-regulated lipid biosynthesis and cancer, and explore new mechanisms underlying cancer cell metabolic reprogramming.

脂类代谢的紊乱可能在肿瘤发病中起重要作用，但目前对其调控机制仍然知之甚少。前期研究中，我们发现了Lin28/let-7/PDK1这一调节轴促进肿瘤细胞中的有氧糖酵解(Nat Communs, 2014)，但关于Lin-28是否参与肿瘤细胞中脂类代谢的调控，迄今未见报道。在尚未发表的初步结果中，我们通过小鼠移植瘤模型发现Lin28a/b过表达的肿瘤组织中脂肪滴形成增多，提示Lin28促进脂肪的生成。我们进一步发现脂肪酸合成中重要的转录因子SREBP1c受Lin28a/b激活，但不受let-7影响。因此，本项目将研究Lin28作为一类mRNA结合蛋白，是否和SREBP1c相互作用并促进其蛋白翻译，从而激活其调控的代谢酶的表达，最终促进脂肪的生成并影响肿瘤的发生发展。本项目的研究目标是在揭示Lin28调控脂类合成代谢及其与肿瘤之间的关联的同时，为解析肿瘤细胞中广泛存在的代谢重编程提供新的机制。

脂类代谢的紊乱可能在肿瘤发病中起重要作用，但目前对其调控机制仍然知之甚少。Lin28在促进肿瘤增殖增殖中有重要作用，但是其具体功能和潜在的机制也几乎未知。现在，我们发现Lin28可以通过SREBP-1促进脂肪酸从头合成并调控饱和脂肪酸和不饱和脂肪酸的转换。通过直接与SREBP-1和SCAP的mRNA结合，Lin28可以调控SREBP-1的翻译与成熟，并保护细胞免受脂毒性困扰。Lin28促进的肿瘤增殖会分别被抑制SREBP-1以及Lin28的RNA结合蛋白功能所影响。总之，我们发现了Lin28通过转录后调控SREBP-1影响脂肪酸从头合成过程并影响饱和与不饱和脂肪酸的转换，这种调控对于肿瘤增殖十分重要。在本基金的资助下，我们已经在Nature Communications杂志上发表论文一篇，标注了本基金号。