LINC02421/FOXM1复合体靶向调控eIF4E增加胃癌细胞放射抗拒性的机制研究

Increasing the radiosensitivity of gastric cancer(GC) cells is of great significance for reducing the local recurrence rate of GC. Whether lncRNA is involved in the regulation of GC radiosensitivity remains unclear. Our previous researches indicated that the radiation-induced lncRNA-LINC02421 in GC cells could bind to the transcription factor FOXM1, forming the LINC02421/FOXM1 complex and modulating the transcription of eIF4E, which influenced GC cells radiosensitivity. Based on these clues, we put forward the following scientific hypothesis that LINC02421/FOXM1 complex increases GC cells radioresistance via the targeted regulation of eIF4E. To verify this hypothesis, we intend to further investigate via a variety of molecular biology methods at cellular level and in animal models: ①the influences of “LINC02421/FOXM1-eIF4E” signaling pathway on GC radiosensitivity; ②the molecular mechanism that LINC02421/FOXM1 complex initiates the translation of DNA damage repair related mRNA, enhances DNA double-strand damage repair via the targeted regulation of eIF4E. The study is expected to uncover a new mechanism of GC radioresistance from the perspective of lncRNA, providing new targets and ideas for GC radiosensitization.

增加胃癌细胞的放射敏感性对降低胃癌局部复发率意义重大。长链非编码RNA（lncRNA）是否参与调控胃癌放射敏感性尚不清楚。申请者前期研究发现胃癌细胞中受辐射诱导的lncRNA-LINC02421能与转录因子FOXM1结合，形成LINC02421/FOXM1复合体，调控eIF4E基因转录，影响胃癌细胞放射敏感性。由此提出如下科学假说：LINC02421/FOXM1复合体通过靶向调控eIF4E增加胃癌细胞放射抗拒性。为验证这一假说，我们拟通过多种分子生物学方法在细胞水平和动物模型中进一步研究：①“LINC02421/FOXM1-eIF4E”信号通路对胃癌放射敏感性的影响；②LINC02421/FOXM1复合体靶向调控eIF4E，启动DNA损伤修复相关mRNA翻译，增强DNA双链损伤修复的分子机制。本研究有望从lncRNA角度揭示胃癌放射抗拒性的新机制，为胃癌放射增敏提供新的靶点和思路。

在我国，胃癌患者确诊时大多处于局部进展期，单一手术治疗效果并不理想。放射治疗作为传统的肿瘤物理治疗方法，被认为在胃癌患者中具有一定的疗效。但是如何筛选放疗敏感患者，降低胃癌细胞放射抵抗性是目前的重要问题。长链非编码RNA作为人类基因组的重要组成部分，其在肿瘤的发生发展及治疗抵抗等过程发挥的作用得到日益重视。本研究发现辐射诱导的LINC02421表达上调可促进胃癌细胞放射后细胞存活，抑制细胞凋亡，增强胃癌细胞放射抵抗性。RNA-pull down实验及质谱分析发现LINC02421与FOXM1相互作用，共同促进胃癌细胞放射抵抗性。RNA-seq及启动子活性分析试验等表明LINC02421/FOXM1复合体可转录激活eIF4E表达，增强DNA双链损伤相关蛋白翻译，进而增强胃癌细胞放射抵抗性。综上，本研究阐明了“LINC02421/FOXM1-eIF4E”信号通路促进胃癌放射抵抗的分子机制，提出靶向LINC02421/FOXM1/eIF4E可能是提高胃癌细胞放射敏感性的重要方式。