UCA1/miR-125a-3p轴向调控ErbB3参与NSCLC的EGFR-TKI获得性耐药机制

Acquired drug resistance is the main problem for non-small cell lung cancer (NSCLC) patients with EGFR-TKI targeted therapy. However, the upstream regulation mechanism of acquired resistance to EGFR-TKI caused by ErbB3-PI3K pathway activation is still unclear. Our previous studies have shown that the express level of long non-coding RNA (LncRNA) UCA1 were relatively higher in NSCLC tissues of patients with acquired resistance to EGFR-TKI therapy, and we preliminary confirmed that UCA1 has a negative regulatory role in miR-125a-3p, an inhibitory control factor for ErbB3 expression. Based on our experimental results and previous reports in the literature, we will detect the levels of UCA1, miR-125a-3p and ErbB3 in NSCLC patients with EGFR-TKI resistance causedy by EGFR non-T790M mutation, systematically assess their clinical significance, validate that lncRNA UCA1 negatively regulates the expression level of miR-125a-3p in the form of ceRNA, compete with miR-125a-3p to indirectly raise the level of ErbB3, ErbB3 then combine with amplified C-Met to bypass EGFR regulation and activate downstream PIK3/AKT signaling pathways, promote lung cancer cell proliferation and inhibit apoptosis to obtain the resistance to EGFR-TKI, to seek new resistance molecular markers and provide theoretical basis of targeted therapy for NSCLC patients.

获得性耐药是非小细胞肺癌EGFR-TKI靶向治疗面临的主要问题。其中ErbB3-PI3K通路激活引起耐药的上游调控机制尚不清楚。我们前期发现EGFR-TKI耐药肺癌患者组织中lncRNA UCA1高表达，并初步证实UCA1对ErbB3表达的抑制性调节因子miR-125a-3p具有负调控作用。本研究拟系统地通过体内、外实验，探讨UCA1/miR-125a-3p与EGFR-TKI 非T790M突变耐药的临床相关性，及其与ErbB3之间的级联调控关系，验证“UCA1通过负调控miR-125a-3p，以ceRNA的方式与miR-125a-3p竞争，上调ErbB3，ErbB3 进而通过与扩增的C-Met结合，绕过EGFR，激活下游PIK3/AKT 介导的信号通路，促进肺癌细胞增殖，抑制凋亡，从而获得EGFR-TKI耐药”的分子机制假说，为临床寻求新的耐药分子标志物及靶向治疗提供理论依据。

耐药是非小细胞肺癌（NSCLC）EGFR-TKI靶向治疗面临的主要问题。除EGFR T790M突变外，大约20% 的EGFR-TKI 耐药是由于C-Met扩增，激活ERBB3-PI3K通路引起的。本研究中，我们对EGFR-TKI非T790M突变耐药的肺癌患者组织的RNA、蛋白水平进行研究，通过全基因组测序检测数据和免疫组化结果，发现UCA1和miR-125a-3p与EGFR-TKI非T790M突变耐药肺癌的病理级别和预后存在密切相关性，结合生物信息学和文献报道分析了UCA1/miR-125a-3p可能靶蛋白ErbB3，参与C-Met扩增引起的ERBB3-PI3K通路激活，导致NSCLC EGFR-TKI耐药。我们阐明了UCA1/miR-125a-3p调控EGFR-TKI非T790M突变耐药的分子病理机制及与临床预后的相关性，初步评价了UCA1/miR-125a-3p作为二次治疗靶点及预后判断的可行性。我们发现miRNA-125a-3p在非小细胞肺癌组织显著降低。miR-125a-3p低表达的病人预后较差；同时我们证实miR-125a-3p可能在肺癌发生、发展中起了重要的作用，可以作为一个潜在的肺癌病人预后预测的因子。同时我们发现miR-155可促进肿瘤细胞增殖，而抑制miR-155表达后，肺癌细胞增殖降低，G2/M期细胞减少。我们证实miR-155/FoxO1/ROS通路在调节非小细胞肺癌生长中可能发挥了重要作用。我们发现miR-33在肺癌组织中显著降低。miR-33低表达的病人预后较差，提示了miR-33可能在肺癌发生、发展中起了重要的作用，可以作为一个潜在的肺癌病人预后预测的因子。我们分析了IASLC/ATS/ERS新分类的10个预后相关基因组合与早期肺癌预后预测的相关性，发现其可以提高TNM分期对于肺癌病人的预后预测意义。我们首次证实了E1F2B4-SFN融合和SFN表达增加与NSCLC患者的化疗耐受性和预后不良有关，提示SFN可能作为NSCLC患者预后的肿瘤生物标志物具有潜在的预后价值。相关论文投稿于Thorax杂志（IF8.8分,已修回）。目前已发表肺癌相关论文5篇，影响因子总计24分。其中标注有本基金资助的SCI论文、中科院分区为1区的有两篇，发表于Cancer Lett和Mol Ther，IF分别为7.36和8.986。