Ppp-RNA诱导肺癌细胞自噬性死亡的作用及机制研究

ppp-RNA is a multi-functional anti-tumor strategy which was constructed in vitro with a triphosphate group on its 5’ terminus. As a specific ligand of intracytoplasmic retinoic acid inducible gene-I (RIG-I), ppp-RNA could stimulate RIG-I signaling pathway, induces anti-tumor immunity, and promotes endogenous apoptosis in cancer cells. Our group found an interesting phenomenon in a recently research, that ppp-RNA could not only induce apoptosis, it could also stimulate impaired autophagic flux in lung cancer cells. If we pre-inhibited autophagy in lung cancer cells, the cancer killing effects of ppp-RNA could be decreased a lot. Preliminary data just demonstrated that autophagy might play an important role in ppp-RNA related cell death.On this basis, our study will further clarify the function and specific mechanism of ppp-RNA induced impaired autophagic flux in lung cancer cells, after RIG-I activation, it might work from two aspects: stimulate Noxa, and effect lysosomal degradation. ppp-RNA has been considered as a multi-functional anti-tumor strategy, this study could be a comprehensive exploration of its exact mechanism, and might provide experimental and theoretical basis for its clinical application finally.

ppp-RNA是模拟病毒RNA在体外构建的5’端带有三磷酸基团的多功能抗肿瘤小分子，作为胞浆内视磺酸诱导基因-I（RIG-I）的特异性配体，可激活RIG-I信号通路，诱导机体抗肿瘤免疫，促进肿瘤细胞内源性凋亡。本课题组在前期一项研究中意外发现，ppp-RNA不仅能促进凋亡，而且能诱导肺癌细胞产生不完整自噬，若预先抑制细胞自噬，ppp-RNA诱导的细胞死亡明显减少，提示自噬可能在ppp-RNA促进肺癌细胞死亡的过程中发挥重要作用。本研究将在此基础上，进一步验证ppp-RNA是否可诱导肺癌细胞不完整自噬，并从Noxa激活、溶酶体降解功能调节两方面探索其诱导不完整自噬的具体机制。在体内实验中，研究ppp-RNA对于肿瘤组织自噬的影响，以及更改自噬状态后，对ppp-RNA抗肿瘤效率的影响。本研究对于ppp-RNA抗肿瘤功能及机制的全面探索，可为其最终临床应用提供实验基础及理论依据。

ppp-RNA是模拟病毒RNA在体外构建的5’端带有三磷酸基团的多功能抗肿瘤小分子，作为胞浆内视磺酸诱导基因-I（RIG-I）的特异性配体，可激活RIG-I信号通路，诱导机体抗肿瘤免疫，促进肿瘤细胞内源性凋亡。在本课题的研究中，我们阐明了ppp-RNA的具体杀瘤机制：诱导机体抗肿瘤免疫，促进肿瘤细胞程序性死亡；而在肿瘤细胞程序性死亡的研究过程中，我们一方面证实了ppp-RNA能够促进肿瘤细胞凋亡及自噬性死亡；另一方面关注肿瘤细胞的炎性程序性死亡：细胞焦亡，并通过GSDMD探索了细胞凋亡通路和焦亡通路可能存在的交互作用。本研究结果在阐明ppp-RNA杀瘤机制的基础上为其进一步临床转化提供可能性。