长非编码RNA在肿瘤细胞代谢中的功能与机制研究

发布时间：2018-08-20 19:20

【摘要】：癌基因c-Myc是常氧条件下调控糖酵解的主要因子,在肿瘤细胞中也是如此,而低氧响应因子HIF1a通常是低氧条件下调控糖酵解的主要因子。有不少研究发现,即便是在常氧条件下HIF1a也有着较高的表达水平。这两个瓦博格效应的核心调控因子之间有着怎样的联系,到目前仍然没被研究清楚。本研究发现,在常氧条件下,c-Myc通过调控一个长非编码RNA IDH1-AS1来协同HIF1a调控瓦博格效应。IDH1-AS1能结合IDH1并提高其酶活,c-Myc通过转录抑制IDH1-AS1的表达来降低IDH1的活性,从而减少IDH1的催化产物α-KG的含量。α-KG是HIF1a羟基化的底物,减少的α-KG会削弱HIF1a羟基化从而稳定HIF1a,使其表达水平升高。通过上面的机制,在常氧条件下c-Myc能够增加HIF1a的表达,从而共同调控瓦博格效应。这其中的关键纽带是IDH1-AS1,通过敲低和过表达实验,进一步表明IDH1-AS1能够抑制细胞的增殖和裸鼠成瘤能力,这意味着IDH1-AS1具有潜在的抑癌效应,可能会成为一个有潜力的肿瘤代谢治疗因子。在应激压力条件下,著名肿瘤抑制因子p53会被激活来抑制细胞增殖或促进细胞凋亡以阻止细胞恶性转化。近年来也有越来越多的研究表明在压力条件下p53也能发挥保护作用而促进肿瘤细胞生存。那么p53所调控的长片段非编码RNA是否也参与其中发挥作用,目前报道还很少。在本研究中,我们发现在葡萄糖饥饿的条件下,p53直接转录上调长非编码RNA-TRINGS(Tp5 3-regulated inhibitor of necrosis under glucose starvation)来发挥保护肿瘤细胞的作用。该长非编码RNA能与STRAP蛋白结合并抑制其表达,而STRAP能结合GSK3β并增加其活性,所以TRINGS具有抑制GSK3β活性的作用。减弱的GSK3β活性会增加NFκB的活性从而促进细胞存活。所以我们的研究建立了 TRINGS-STRAP-GSK3β-NFκB这条通路,TRINS通过该通路发挥着促进肿瘤细胞在葡萄糖饥饿条件下生存的作用。并且,TRINGS只特异的响应葡萄糖饥饿条件,而不响应血清饥饿、丝氨酸饥饿和谷氨酰胺饥饿刺激。总结起来,我们的研究揭示了一条p53诱导上调的长非编码RNA-TRINGS,在葡萄糖饥饿条件下保护p53野生型的肿瘤细胞免于坏死的功能。
[Abstract]:The oncogene c-Myc is the main factor regulating glycolysis under normoxic condition, and it is also true in tumor cells, while hypoxia response factor (HIF1a) is usually the main factor regulating glycolysis in hypoxic condition. Many studies have found that HIF1a has a high level of expression even under normoxic conditions. The relationship between these two core regulators of the Wabog effect remains unclear. In this study, it was found that c-Myc could inhibit the activity of IDH1 by regulating a long non-coding RNA IDH1-AS1 in coordination with HIF1a to regulate the Vaboger effect. IDH1-AS1 could bind to IDH1 and increase its enzyme activity, c-Myc, by transcription inhibiting the expression of IDH1-AS1. 伪 -KG is the substrate of HIF1a hydroxylation, and the reduced 伪 -KG will weaken the hydroxylation of HIF1a and stabilize HIF1a and increase its expression level. Through the above mechanism, c-Myc can increase the expression of HIF1a under normoxic conditions, thus regulating the Waborg effect. The key link is IDH1-AS1, which further shows that IDH1-AS1 can inhibit cell proliferation and tumorigenesis through knockdown and overexpression experiments, which means that IDH1-AS1 has a potential anti-cancer effect. May become a potential tumor metabolic therapy factor. Under stress, the famous tumor suppressor p53 is activated to inhibit cell proliferation or promote cell apoptosis to prevent cell malignant transformation. In recent years, more and more studies have shown that p53 can also play a protective role in promoting tumor cell survival under stress. There are few reports on whether long-length RNA regulated by p53 plays a role. In this study, we found that p53 directly up-regulates long noncoding RNA-TRINGS (Tp5 3-regulated inhibitor of necrosis under glucose starvation) to protect tumor cells from glucose starvation. The long noncoding RNA could bind to STRAP protein and inhibit its expression, while STRAP could bind to GSK3 尾 and increase its activity, so TRINGS could inhibit GSK3 尾 activity. Decreased GSK3 尾 activity increased NF 魏 B activity and promoted cell survival. Therefore, we have established the TRINGS-STRAP-GSK3 尾 -NF 魏 B pathway through which TRINS plays a role in promoting the survival of tumor cells under glucose starvation. TRINGS only responded specifically to glucose starvation, but not to serum starvation, serine starvation and glutamine starvation. In conclusion, our study revealed the function of a long non-coding RNA-TRINGS induced by p53 to protect p53 wild-type tumor cells from necrosis under glucose starvation.
【学位授予单位】：中国科学技术大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R730.2

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