低氧微环境下长片断非编码RNA-HILR1调控肿瘤细胞Warburg效应的作用及机制研究

It has been recognized for a long time that the metabolism of cancer cells is significantly different from that of their normal cell counterparts. Cancer cells exhibit a unique metabolism referred to as the Warburg effect characterized by enhanced glycolysis and reduced oxidative phosphorylation even in the presence of oxygen. The Warburg effect allows cancer cells to metabolize large quantities of glucose in order to generate the biomass required for the rapid cell proliferation, thereby facilitating tumorigenesis. The underlying biochemical and molecular mechanisms of the Warburg effect are multiple, yet one of the most recognized mechanisms is the adaptive response to the unique tumor hypoxic microenvironment. It has been known that under hypoxic conditions, activation of hypoxia inducible factor 1 (HIF-1) contributes to the Warburg effect through co-ordinated upregulation of glycolytic enzymes and downregulation of mitochondrial oxidative phosphorylation. However, whether long non-coding RNA (lncRNA) is involved in the contribution of hypoxia/HIF-1 to the Warburg effect still remains unknown. Our research aims to address this issue. Our preliminary data suggest that hypoxia/HIF-1a-induced lncRNA-HILR1 (Hypoxia-inducible long non-coding RNA 1) could in turn interact with HIF-1a and inhibit its degradation, thus forming a positive feedback loop to promote the Warburg effect. In this study, we will further investigate the molecular mechanism whereby lncRNA-HILR1 regulates the Warburg effect under hypoxic conditions. We will also evaluate the possible role of lncRNA-HILR1 in cancer initiation and progression. This study will generate novel insights into the mechanisms of the Warburg effect. This may also implicate lncRNA-HILR1 as a novel potential therapeutic target for the treatment of cancer.

大量的研究表明，肿瘤细胞的Warburg效应对于肿瘤的发生发展至关重要。肿瘤细胞的Warburg效应被认为是由多种机制共同作用形成，其中一个重要的机制认为Warburg效应是肿瘤细胞对其所处低氧微环境的一种适应，然而其具体的分子基础仍不明确，特别是关于长片断非编码RNA是否以及如何调控低氧微环境下肿瘤细胞的Warburg效应并不清楚。本项目以此为研究切入点，我们前期的研究结果暗示：低氧条件下，被低氧诱导因子HIF-1α激活表达的lncRNA-HILR1可能通过结合HIF-1α并抑制其降解，从而形成一个正反馈循环，最终促进肿瘤细胞的Warburg效应。本项目将在已有的工作基础上，深入研究lncRNA-HILR1调控低氧条件下肿瘤细胞Warburg效应的作用及机制；同时也将研究其在肿瘤发生发展中的作用。这将有助于人们更加深入地理解肿瘤细胞的Warburg效应，并可能为肿瘤治疗提供新的潜在靶点。

大量的研究表明，肿瘤细胞的Warburg效应对于肿瘤的发生和发展至关重要。虽然低氧微环境可以促进肿瘤细胞的Warburg效应这一结论已被人们广泛接受，然而其具体的分子基础仍不明确，特别是关于长片断非编码RNA是否及如何调控低氧微环境下肿瘤细胞的Warburg效应并不清楚。我们的研究表明，一个新的长片断非编码RNA—lincRNA-p21受到低氧/HIF-1α的诱导表达，lincRNA-p21通过分别结合HIF-1α或VHL、阻止HIF-1α-VHL复合物的形成、抑制VHL对HIF-1α的降解，从而提高HIF-1α的蛋白水平，最终形成一个正反馈循环，并促进肿瘤细胞的Warburg效应。更为重要的是，我们运用小鼠肿瘤模型，证明了lincRNA-p21和HIF-1α形成的正反馈循环确实能够促进肿瘤的生长，暗示lincRNA-p21可以作为肿瘤治疗的潜在靶点。我们的研究首次阐明了长片断非编码RNA在调控肿瘤细胞Warburg效应中的重要作用，这从全新的角度揭示了肿瘤细胞Warburg效应形成的分子基础，拓展了人们对长片断非编码RNA功能重要性的认识，并为今后长片断非编码RNA的相关研究提供新的方向。这一研究结果作为通讯作者发表于国际知名杂志“Molecular Cell”杂志上。此研究工作发表之后立刻引起了国际同行的高度关注，被“Science Signaling”杂志以“Editor’s choice”形式对我们的工作进行专门评述；国家自然科学基金委主办的中国科学基金杂志（Science foundation in China）也以封面的形式对我们的这一工作进行了专门报道；目前此论文被他引超过130次。在本项目的大力资助下，项目负责人以通讯作者的身份在Molecular Cell、EMBO Reports和Autophagy等国际主流期刊上发表SCI学术论文4篇。