LncRNA SFTA1P介导TGF-β/DDR通路抑制非小细胞肺癌顺铂耐药的 作用及机制研究

Cisplatin is a first-line treatment for non-small cell lung cancer (NSCLC), but the drug resistance is a major problem for the treatment of NSCLC. Our previous studies found that LncRNA SFTA1P (SFTA1P) was a lung-specific high expression gene，and it could increase cisplatin-induced apoptosis by inhibiting the activity of DNA damage repair (DDR) pathway. Further experiments showed that TGF-β significantly down-regulated the expression of SFTA1P and increased the activity of the DDR pathway, then promoted cisplatin resistance in NSCLC. However, its mechanism remains unclear. Based on previous study, we propose the hypothesis that SFTA1P is a key mediator of the TGF-β/DDR pathway, which can inhibit the activity of DDR pathway and then reverse NSCLC cisplatin resistance ultimately. In the present study, we will first use cellular and animal models to determine the role of SFTA1P in TGF-β/DDR pathway mediated NSCLC cisplatin resistance. Secondly, we will further explore the target gene and target protein of SFTA1P and elucidate its regulatory mechanism. Finally, the clinical significance of this study will be verified in NSCLC clinical samples. This project will provide new theoretical basis and potential specific molecular target for prediction and precise intervention NSCLC cisplatin resistance.

顺铂是非小细胞肺癌（NSCLC）一线治疗药物，其耐药性的产生是临床亟待解决的重大难题。我们前期发现LncRNA SFTA1P（SFTA1P）具肺组织特异性，其可通过抑制DNA损伤修复（DDR）通路活性，增敏顺铂诱导细胞凋亡。进一步预实验显示TGF-β可显著下调SFTA1P表达，进而使DDR通路活性增加，促进NSCLC顺铂耐药，但作用机制尚不清楚。我们推测SFTA1P可能为TGF-β/DDR通路关键介导因子，通过调控DDR通路基因表达下调其活性，实现逆转NSCLC顺铂耐药。本课题拟：①体内外实验进一步研究SFTA1P经TGF-β/DDR途径介导NSCLC顺铂耐药的作用；②明确SFTA1P靶基因和靶蛋白并阐明其调控机制；③通过临床样本验证TGF-β/SFTA1P/DDR通路与顺铂耐药的相关性，探讨其临床意义。本课题完成将为NSCLC顺铂耐药预测及精准干预提供新依据和潜在特异性靶标。

铂类药物为非小细胞肺癌（NSCLC）治疗的基石，其耐药性导致临床疗效不佳仍是临床面临的主要问题之一。本项目通过体内外实验探索了肺组织特异性LncRNA SFTA1P通过TGFB1和DNA损伤修复通路（DDR）调控NSCLC顺铂耐药的潜在机制，为寻找NSCLC顺铂耐药预测及治疗特异性靶标提供了实验基础。同时，我们系统分析了DDR基因表达谱改变与NSCLC预后的关系，并基于预后相关DDR基因的表达成功建立了NSCLC预后模型，为NSCLC患者的分级管理和个性化临床治疗提供了依据和潜在治疗靶点。此外，本项目采用生物信息大数据挖掘手段，充分整合了TCGA和GEO中临床大样本数据（n=1633），基于REO算法构建了铂类药物治疗响应预测模型，性能分析显示所构建的46-GPS模型与其他同类模型相比具有更佳的准确性和敏感性。同时在NSCLC不同的分子亚型中探索了NSCLC铂类耐药潜在机制，研究发现铂类耐药组NSCLC患者显示出高度的基因组稳定和高免疫浸润性，这为临床结合分子分型选择治疗药物提供了参考。综合本项目所有研究内容，均致力于寻找NSCLC患者铂类药物耐药预测和治疗的药物基因组学新靶标，为NSCLC的个性化治疗提供理论依据。