黄栌提取物Fisetin调控lncRNA-HCP5/miR-186-5p/PRKCA轴逆转肺腺癌EGFR-TKI耐药的机制

Tyrosine kinase inhibitor (TKI) is currently the most widely used target drug in non-small cell lung cancer, but its acquired drug resistance has become a serious problem. Based on bioinformatics analysis and preliminary experiments, PRKCA has been suggested to play a key role in TKI resistance. Long-chain non-coding RNA-HCP5 may act as ceRNA to regulate PRKCA expression by sponging miR-186-5p, which may affect TKI resistance of lung cancer. Furthermore, Fisetin, an extract of Quercus platyphylla, may reverse cell TKI resistance. Therefore, we aim to establish cell and animal models to verify that activation of the HCP5/miR-186-5p/PRKCA axis leads to activation of the downstream survival signaling pathway of EGFR, which may be an important mechanism of TKI resistance in lung adenocarcinoma and a new target for its treatment. Fisetin may reverse cell TKI resistance through this axis. This study can help explore new mechanisms of TKI resistance in lung adenocarcinoma, provide new ideas and experimental data for TKI resistance therapy and drug development, and develop new therapeutic strategies for lung adenocarcinoma.

酪氨酸激酶抑制剂（TKI）是非小细胞肺癌中目前应用最广的靶向药物，但其获得性耐药已成治疗难题。基于生物信息学分析和预实验发现：“枢纽基因”PRKCA可能在TKI耐药中起关键作用；长链非编码RNA-HCP5可能作为ceRNA通过吸附miR-186-5p调节PRKCA表达而影响肺癌TKI耐药；此外，中药黄栌提取物Fisetin可能逆转细胞耐药。因此，我们拟采用细胞和动物模型验证：HCP5/miR-186-5p/PRKCA轴活化导致EGFR下游的生存信号通路激活，可能是肺腺癌TKI耐药的重要机制，还可能是肺癌治疗的新靶点，Fisetin可能通过该机制逆转细胞耐药。本研究旨在探索肺腺癌的TKI耐药新机制，为肺癌TKI耐药治疗和新药研制提供新的思路及实验数据，对开发新的肺癌治疗策略具有重要的理论意义。

酪氨酸激酶抑制剂（TKI）是目前治疗非小细胞肺癌应用最广的靶向药物，其获得性耐药已成治疗难题，且耐药分子机制至今仍不清楚。本研究基于生物信息学分析筛选肺腺癌细胞TKI耐药过程中的关键分子、预测可能逆转该过程的小分子药物，并经过实验验证药物对关键分子的作用和细胞耐药表型的影响。本研究完成的工作有：（1）生物大数据筛选发现HCP5/miR-186-5p/PRKCA轴活化导致EGFR下游的生存信号通路激活，可能是肺腺癌TKI耐药的重要机制；（2）细胞实验提示HCP5可能通过吸附miR-186-5p而调控PRKCA的表达；（3）中药黄栌提取物Fisetin可能影响HCP5/miR-186-5p/PRKCA轴而逆转肺癌细胞的TKI耐药；（4）PRKCA可能通过激活下游MAPK、AKT和STAT通路而促进肺癌细胞的TKI耐药表型，而Fisetin可抑制耐药细胞中PRKCA表达，抑制这些通路激活，从而增加细胞对TKI的敏感性；（5）动物实验采用耐药细胞构建裸鼠移植瘤模型，Fisetin联合TKI使用可以显著减小移植瘤体积、降低移植瘤重量。

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