Grb2介导α-硫辛酸抑制肺癌细胞增殖的机制研究

Our previous study showed that α- lipoic acid (α-LA) signifitly inhibited cell growth and colony information in non-small cell lung cancer (NSCLC) cells. The transcriptional difference analyses and immunoblotting result showed the expression of growth factor receptor-bound protein 2 (Grb2) was decreased signifitly after cell treated with α-LA. While the overexpression of Grb2 diminished the effect of α-LA on NSCLC cells growth. Moreover, in EGFR mutated cell line NCI-1975, it was found the expression of phosph-EGFR decreased with downregulation of Grb2 expression. Which suggested Grb2-EGFR signal plays an important role in mediating the effect of α-LA on lung cancer cells. However, the specific mechanisms are still unclear. Based our previous results, by the regular molecular biology and cell biology methods , RNA sequence and bioinformation analyses, we will further explore the molecular mechanism of α-LA mediated inhibition of NSCLC cell growth in this project, which will provide new evidence for the potential application of α-LA in NSCLC treatment.

课题组前期研究发现α-硫辛酸（α- lipoic acid，α-LA）能显著抑制非小细胞肺癌（Non-Small Cell Lung Cancer，NSCLC）细胞的增殖和克隆形成。α-LA处理前后转录差异分析和免疫印迹结果A549细胞内Grb2蛋白（growth factor receptor-bound protein 2)表达显著下调。过表达Grb2，α-LA对NSCLC细胞增殖的抑制作用减弱。在EGFR突变细胞株NCI-1975中还发现，随着Grb2表达下调，p-EGFR的表达水平也逐渐下降。提示Grb2-EGFR信号在α-LA抑制NSCLC细胞增殖的过程中扮演重要角色，但具体机制尚不明确。本项目拟在前期研究基础上，深入探讨Grb2介导α-LA抑制NSCLC细胞增殖的分子作用机制，为α-LA在肺癌中的潜在应用提供新的科学依据。

项目背景： 前期研究发现，α-硫辛酸（α- lipoic acid，α-LA）抑制非小细胞肺癌细胞（Non-Small Cell Lung Cancer cell，NSCLC）增殖。α-LA显著下调肿瘤细胞内Grb2蛋白（growth factor receptor-bound protein 2)表达。主要研究内容： 通过常规分子生物学、细胞生物学明确α-LA抑制NSCLC增殖的生物学作用；α-LA下调Grb2分子表达，Grb2介导α-LA 抑制肿瘤细胞增殖；转录组学和生物信息学分析Grb2下游 EGFR及MAPK分子通路，导致α-LA 抑制 NSCLC 细胞增殖的分子机制；芯片数据验证EGFR与Grb2 表达水平，α-LA抑制肿瘤细胞恶性行为与肿瘤细胞内Grb2表达水平；α-LA 治疗临床肿瘤可能性和详实理论依据。 重要结果：1. α-LA具有抑制肿瘤细胞增殖的生物学作用; 2. α-LA显著下调Grb2分子在肿瘤细胞系中的表达; 3.Grb2分子介导 α-LA抑制肿瘤细胞增殖的作用；4. α-LA抑制NSCLC细胞中EGFR-MAPK/ERK 分子信号通路活性。该研究表明Grb2抑制 EGFR-MAPK/ERK 分子信号通路活性介导 α-LA抑制通过肿瘤细胞增殖，为α-LA 用于临床肿瘤治疗提供了重要证据。