STAT3调控caveolin-1介导的抗早衰在肿瘤辐射抗性中的作用及机制研究

Induction of premature cell senescence is one of manners of radiation-induced cancer cells death, which has been considered as a novel strategy for cancer therapy and a broad scope in future. However, the mechanisms involved in premature cell senescence are still unclear. Our previous study found that ionizing radiation could activated the signal transducer and activator of transcription 3 (STAT3) in cancer cells, which subsequently attenuated the cell killing effect of radiation to a certain extent and promoted the tumor metastasis, although many of th e tumor cells did be killed by radiation. Under the support of National Science Foundation of China, our preliminary study showed that the functional suppression of STAT3 not only blocked the tumor cell metastasis induced by radiation but also increased the proportion of premature cell senescence in tumor cells. Furthermore, the expression of caveolin-1 involved in the regulation of premature cell senescence increases after ration. These results implied that the activation of STAT3 induced by radiation might partly inhibit the occurrence of premature cell senescence via caveolin-1, which might contribute to the increase in the radioresistance of cancer cells. Based on our previous results of study, the current study will investigate the role caveolin-1 and its downstream pathway, caveolin-1/Sirt1/p53, in STAT3-suppressed premature cell senescence induced by radiation using various methods such as EMSA and CHIP. This study hopes to explore the role of premature cell senescence resistance mediated by STAT3-regulated caveolin-1 and its mechanisms in theory, and provide the experiment evidence for the screen of potential therapeutic targets.

早熟衰老是放疗杀伤肿瘤细胞的方式之一，诱导肿瘤细胞早衰作为新的肿瘤治疗策略具有广阔的研究前景，但其相关机理尚不明确。本课题组发现辐射在杀伤肿瘤细胞的同时，还会激活细胞内STAT3从而对抗辐射的杀伤效应，并促进肿瘤转移。在前期国家自然基金的资助下，我们发现受辐射调控的STAT3表达抑制不但阻断辐射诱导的肿瘤细胞转移，抑制细胞增殖，还增加肿瘤细胞早衰的比例，促进调节早衰的caveolin-1的表达。提示辐射诱导的STAT3活化可能通过caveolin-1抑制了部分细胞早衰的发生，从而增强细胞的辐射抗性。本项目将采用EMSA等方法，体内外水平探索 caveolin-1及下游衰老通路Sirt1/p53在STAT3抑制辐射诱导细胞早衰中的作用机制。本项目的完成可在理论上阐明STAT3调控caveolin-1介导的抗早衰在肿瘤细胞辐射抗性中的作用及其机制，为临床肿瘤放疗寻找潜在的治疗靶点提供实验依据。

大量研究表明电离辐射可诱导肿瘤细胞发生早衰，以细胞衰老为靶标的治疗，虽然在缩小肿瘤体积方面的作用不强，但却可显著提高肿瘤患者的带瘤生存时间，因此，早衰是一个很有潜力的新的肿瘤治疗策略。本项目首先从细胞增殖、细胞形态、早衰产物、细胞迁移能力和细胞溶酶体数量几个角度研究辐射对A549细胞早衰的影响。接着在体外探讨辐射诱导的STAT3 活化对电离辐射诱导的肺腺癌细胞早衰的影响以及caveolin-1/p53 信号通路在此过程中的作用；最后体内验证STAT3 介导的caveolin-1/ p53 信号通路在辐射诱导细胞早衰中的作用。研究结果表明X射线照射可诱导A549细胞出现剂量依赖性早衰（p<0.05）。Western Blot结果表明4 Gy X射线照射可促进磷酸化STAT3（p-STAT3）的表达。加入AG490和Rapamycin（RAPA）抑制STAT3磷酸化后，X射线诱导的A549细胞衰老被显著抑制，而过表达STAT3可模拟X射线照射诱导的A549细胞早衰。最后，体内实验证明辐射可诱导A549细胞发生STAT3/caveolin-1/p53介导的早衰。本课题结果不仅阐明STAT3 调控caveolin-1 介导的早衰在辐射诱导细胞早衰中发挥的作用；还从细胞早衰角度证实肺腺癌放疗的作用机制，在肿瘤放疗基础研究中具有重要价值和意义。最后，我们在辐射诱导的细胞早衰机制方面有新的发现，这为下一步继续研究奠定了工作基础。

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