消癌平注射液调控HDGF改善肺癌gefitinib耐药的活性成分及分子机制研究

Resistance has become a major problem that restraining the efficacy of gefitinib for cancer treatment. Identifying the molecular mechanisms of drug resistance and exploring new methods to overcome resistance are the key scientific issues to be solved. Our previous work has shown that traditional Chinese medicine, Xiaoaiping injection, could restore gefitinib sensitivity in the resistant non-small cell lung cancer. Proteomics study found that Xiaoaiping injection combined with gefitinib significantly reduced the hepatoma-derived growth factor (HDGF) expression in gefitinib resistant non-small cell lung cancer, knockdown or overexpression of HDGF gene influenced the expressions of p-Akt and p-ERK which related to gefitinib resistant, suggesting HDGF may be one of the underlying mechanisms for Xiaoaiping injection overcoming gefitinib resistance. Based on the previous work, our present proposal intends to perform a systematic research involving the targets and molecular mechanisms elucidation for Xiaoaiping injection overcoming gefitinib resistance in non-small cell lung cancer. Upon this, it will offer further scientific evidence for clarifying the mechanisms of Xiaoaiping injection restored gefitinib efficacy in the resistant non-small cell lung cancer, and provide experimental and theoretical foundation for the clinical application. Therefore, it is of important scientific value and clinical significance to undertake the proposed project.

肿瘤耐药已成为制约吉非替尼 (gefitinib) 疗效的主要临床问题，寻找其耐药的分子机制和克服耐药的新方法是本领域亟待解决的关键科学问题。我们前期工作表明中药消癌平注射液具有克服非小细胞肺癌对gefitinib耐药的作用。蛋白组学研究发现消癌平联合gefitinib能显著降低耐药非小细胞肺癌中肝癌衍生生长因子(HDGF) 的表达，敲降/过表达HDGF能影响gefitinib耐药相关蛋白p-Akt和p-ERK的表达，提示HDGF可能是消癌平注射液改善gefitinib耐药机制之一。本项目拟在前期工作基础上，系统研究消癌平注射液克服肺癌对gefitinib耐药的作用靶点和分子机制，为进一步揭示消癌平注射液克服gefitinib耐药的机制提供科学依据；为消癌平注射液改善gefitinib耐药的临床应用提供实验基础和理论依据，具有重要的学术价值和临床意义。

酪氨酸激酶抑制剂 (TKI) 对具有表皮生长因子 (EGFR) 敏感突变的晚期非小细胞肺癌疗效较好，但终会发生耐药出现疾病进展。肿瘤耐药已成为制约吉非替尼 (gefitinib) 等TKI疗效的主要临床问题，寻找其耐药的分子机制和克服耐药的新方法是本领域亟待解决的关键科学问题。前期工作表明中药消癌平注射液具有克服非小细胞肺癌对gefitinib耐药的作用。本研究发现肝癌衍生生长因子 (HDGF) 的高表达不仅与非小细胞肺癌的恶性表型相关，而且与gefitinib的耐药相关。通过敲低或过表达非小细胞肺癌细胞中HDGF水平，比较表达不同水平HDGF的细胞对gefitinib的响应，从细胞和动物试验明确了HDGF是参与gefitinib耐药的机制之一。通过筛选对HDGF具有调控作用的miRNA并进行验证，明确了miR-129和miR-139具有靶向HDGF的作用。消癌平注射液联合gefitinib能抑制HDGF在耐药非小细胞肺癌的表达，并能降低耐药相关蛋白p-Akt和p-ERK的表达。明确了消癌平注射液通过上调靶向HDGF的miRNA-129和miRNA-139改善gefitinib耐药的分子机制。上述研究首次明确了HDGF是非小细胞肺癌gefitinib耐药的机制之一，消癌平注射液通过调控靶向HDGF的miRNA发挥了改善gefitinib耐药的作用机制，为进一步揭示消癌平注射液克服gefitinib耐药的机制提供科学依据；为消癌平注射液改善gefitinib耐药的临床应用提供实验基础和理论依据，具有重要的学术价值和临床意义。