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

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。

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.