细胞衰老诱发炎症促进神经胶质瘤发生发展的分子机制

Cellular senescence induced by activation of oncogenes or inactivation of tumor suppressors represent a critical tumor suppressive check point during tumorigenesis. Recent evidence has shown that activation of inflammatory signaling, which is tumor-promoting, is associated with cellular senescence. However, the underlying regulatory mechanism and physiological significance of this phenomenon is largely unknown. Evidence from our preliminary studies has shown that in the process of gliomagenesis, cellular senescence-induced inflammatory signaling could lead to unsolving inflammation when cells bypassed cell cycle arrest, eventually promoting to glioma progression. By employing in situ transformation animal model transcriptome analysis and RNAi library screening, we identified a series of transcripts associated with activation of senescence-induced inflammatory pathways. Furthermore, by employing RNAi library screening, we found that PHF19, TGFB1 and BMP2 were essential for a sustained NF-κB activation after senescence evasion. These factors synergistically enhanced expression of a series of NF-κB activating factors identified in our previous reports. On the other hand, we found that persistent stimulation by inflammatory signaling in tumor cells, particularly IL6 induced-STAT3 activation, was key to establishment of a senescence evasion state before cells acquired mutation in p53 and p16INK4A pathways. In the proposed study, by using RNAi screening strategy, we attempt to identify essential factors that mediate this process. Taking together, we will dissect the regulatory circuits of senescence-induced inflammation signaling and address two important questions, namely, how senescence-induced inflammation becomes unresolving and how such persistent activation of inflammatory pathways in tumor cells promotes senescence evasion. It is hoped that the data derived from the research will not only provide new insight in our current understanding of mechanism governing senescence-associated inflammation but also identify potential new targets for anti-glioma therapy.

近期研究表明，细胞衰老尽管是一重要的肿瘤抑制机制，但同时也伴随着具有促肿瘤潜力的炎症反应，这一现象的病理意义和调控机制尚不清楚。在本项目的前期实验中我们发现，一方面，在神经胶质瘤的发生过程中，衰老诱导的炎症通路激活能够在细胞逃逸衰老诱导的细胞周期阻滞后转化为非可控性炎症，并进一步促进神经胶质瘤的发生发展。利用原位转化的动物胶质瘤模型加以转录组分析以及RNAi文库筛选，我们进一步鉴定了包括PHF19，TGFB1以及BMP2在内的、维持衰老逃逸后炎症通路持续激活的关键因子。另一方面，我们发现持续的炎症信号能够使得细胞在获得p53以及p16INK4A通路失活突变前即形成衰老逃逸。由此在本项目中，我们基于衰老诱导的炎症向非可控炎症转化，以及炎症信号协助衰老逃逸两方面对衰老相关炎症调控网络进行探讨，研究结果将完善衰老相关炎症的调控理论，而且能够为未来的靶向衰老相关炎症的肿瘤治疗手段提供潜在的靶点。

肿瘤发生通常被认为是癌基因激活或抑癌基因失活所驱动的，比如癌基因Ras单个核苷酸突变激活的敲入小鼠直接启动多种肿瘤发生，Ras突变也是肿瘤发生过程中最常见的致癌事件之一，存在于人类三分之一的肿瘤中。有意思的是，在细胞水平，单一突变激活型Ras并不促进正常细胞恶性转化，而是诱导细胞衰老效应。细胞衰老尽管是一重要的肿瘤抑制机制，但同时也伴随着具有大量的炎性因子介导的炎症反应。这些炎症因子一方面维持和加强细胞衰老，另一方面具有促肿瘤效应。因此，癌基因激活或抑癌基因失活所驱动的肿瘤发生过程中如何逃逸细胞衰老，炎症反应在细胞衰老发生和逃逸乃至恶性转化过程中的作用及转变机制等科学问题尚未有较好的阐明。通过完成此项目，我们发现了细胞衰老诱导的炎症因子在衰老逃逸过程中异常激活AKT、β-catenin、IL6/STAT3、TGFβ和NF-κB等一系列炎性通路，从而转化为非可控性炎症，促进肿瘤发生发展。我们发现了IL1β、IL6和TNFα等不同炎症因子在维持细胞衰老和促进恶性转化过程中的信号转换机制，发现了miR-199a、miR-128-3p、miR-582-3p、miR-542-3p 、miR424-503等多个非编码RNA分子可能是调控细胞衰老诱导的炎症向非可控性炎症转化的关键因子。我们也揭示了过度细胞自噬是癌基因Ras诱导细胞衰老后期细胞死亡的重要过程，自噬缺陷则可以促使癌基因Ras诱导恶性转化，并同时发现了在激活型Ras和持续激活型AKT引起的细胞衰老模型中表达下降的PHF19蛋白可以编码两种亚型的蛋白，均能通过重编程干细胞转录模式，维持肿瘤干细胞样特性，逃逸细胞衰老效应。因此，我们的项目基于衰老诱导的炎症向非可控性炎症转化，以及炎症信号协助衰老逃逸两方面对衰老相关炎症调控网络进行探讨，研究结果完善了衰老相关炎症的调控理论，阐明了细胞衰老逃逸和恶性转化的转变过程和机制，为肿瘤的发生发展提供重要的诊断和治疗靶点。