核受体Nur77及其下游lncRNA调控糖酵解抑制肝癌的机制研究

Nuclear receptor Nur77 (also known as TR3) possesses diverse biological functions, and contributes to the regulation of tumor development and metabolic homeostasis through protein-protein interaction or inducing downstream target genes’ expression. However, whether Nur77 regulates the expressions and functions of lncRNA is still unknown. In our preliminary experiments, we found that the transcriptional activity of Nur77 is required for its inhibitory effect on hepatocellular carcinoma (HCC) cell proliferation. Through an lncRNA microarray analysis, we found a new Nur77-regulated lncRNA named NILA1, which is lower expressed in HCC tissues than in para-carcinoma tissues, and the expression of NILA1 in HCC samples is positive correlated with Nur77. Further studies showed that NILA1 not only bound to two rate-limiting enzymes in glycolysis, but also inhibited glycolysis and HCC development. In this project, we will further study the regulatory effect of Nur77 on NILA1 expression, the underlining mechanism of NILA1 on glycolysis regulation and the inhibitory function of Nur77 and NILA1 on HCC development. Together, our study will not only clarify the regulatory role of Nur77 and NILA1 on the glucose metabolic reprogramming, but also provide new ideas and potential targets for HCC therapy.

核受体Nur77（也被称为TR3）具有复杂多样的生物学功能，可通过蛋白质相互作用或直接诱导下游基因表达参与肿瘤发生发展以及机体代谢稳态的调控，但Nur77是否调控lncRNA来发挥作用还不清楚。预实验中，我们发现Nur77的转录激活活性对其抑制肝癌细胞生长至关重要。通过lncRNA芯片分析，我们筛选到一个表达受Nur77调控的新的lncRNA—NILA1，它在肝癌中的表达与Nur77呈正相关，并且显著低于癌旁组织。进一步研究发现NILA1可与两个糖酵解限速酶结合，并抑制肝癌细胞糖酵解和肝癌细胞生长。本项目将据此进一步研究Nur77调控NILA1表达的作用与机制；分析NILA1调控糖酵解的机制及其对肝癌细胞生长的抑制作用；探讨Nur77通过调控NILA1对肝癌发生发展的影响。通过研究，有望阐明Nur77及NILA1对肝癌细胞葡萄糖代谢重编程的调控作用，为肝癌的防治提供新思路与新靶点。

代谢重编程是肿瘤的重要特征。肿瘤细胞面临的内外界因素共同调控着细胞的代谢模式，协同促进肿瘤发生发展。在本项目中，我们围绕核受体Nur77等关键因子调控肝癌等肿瘤代谢重编程的机制和作用开展研究，取得了如下研究成果：.1. 在肝癌细胞中，Nur77通过结合lncRNA-WFDC21P启动子上调其表达。WFDC21P能够与糖酵解限速酶PFKP和PKM2结合，进而抑制肝癌细胞糖酵解，抑制肝癌的生长与转移。在临床标本中，Nur77和WFDC21P的表达呈正相关，且均与肿瘤的恶性程度负相关（Oncogene， 2020）。.2. 在肝纤维化向肝癌转化的过程中，TGFβ信号通路激活肝星状细胞，促进糖酵解限速酶HK1的棕榈酰化修饰，使其以胞外囊泡形式向微环境释放。肝癌细胞摄取肝星状细胞来源的HK1后发生代谢重塑，提高糖酵解水平，从而促进肝癌进程。小分子PDNPA通过提高肝星状细胞中的Nur77的表达促进去棕榈酰化酶ABHD17B的转录，从而抑制HK1的棕榈酰化和外泌，抑制肝癌进程（Nature Metabolism，2022）。受邀就胞外囊泡在肿瘤中的作用在Cancer Letters发表一篇综述。.3. 在酸性环境下，三羧酸循环的代谢中间产物α酮戊二酸可被还原为L2HG。L2HG能够提高ROS水平，促进DR6的氧化多聚并发生内吞。内吞后的DR6 receptorsome募集Caspase-8和GSDMC，从而促进GSDMC的剪切激活，最终诱导细胞发生GSDMC依赖的细胞焦亡（Cell Research，2020）。.综上，本项目经过4年的研究，阐明了Nur77等关键蛋白调控代谢重编程促进肿瘤发生发展的机制与作用，为靶向代谢干预肿瘤提供了理论基础。