miR-23a～27a簇调控TET2和Wnt/β-catenin通路促进肺腺癌转移的机制研究

Lung adenocarcinoma (LC) treatment often fails due to development of metastasis, but the mechanism is unclear. Previous results show that miR-23a~27a cluster and β-catenin were overexpressed, but TET2 was decreased in metastatic tumors than primary tumors in LC patients. Overexpression of miR-23a~27a cluster stimulated lung cancer cell invasion and increased expression of nuclear β-catenin. Also, overexpression of miR-23a~27a cluster inhibited TET2 and Wnt/β-catenin signal inhibitors, such as NLK, GSK3β and CTNNBIP1. In addition, we found that 3`-UTR region of TET2, NLK, GSK3β and CTNNBIP1 have the binding sites with miR-23a, miR-24 and miR-27a. Taken together, these results suggest that overexpression miR-23a~27a cluster stimulates LC metastasis by targeting TET2 and activating Wnt/β-catenin signaling pathway. In this study, we will use in vitro and in vivo experiments to investigate the mechanism of miR-23a~27a cluster how to stimulate LC metastasis, and evaluate the possibility of miR-23a~27a cluster as a therapeutic target of LC metastasis. In addition, we will analysis clinical samples to evaluate the possibility of miR-23a~27a cluster as a predictor of LC prognosis.

转移是肺腺癌治疗失败的重要原因，但其机制尚不明确。我们前期研究发现肺腺癌患者的转移瘤组织中miR-23a～27a簇和β-catenin高表达，TET2低表达。过表达miR-23a～27a簇促进肺癌细胞侵袭性，增加细胞核内β-catenin，抑制TET2和Wnt/β-catenin通路负调控因子NLK、GSK3β和CTNNBIP1。TET2、NLK、GSK3β和CTNNBIP1基因3`UTR区有miR-23a～27a结合位点。据此推测，miR-23a～27a簇可能通过抑制TET2和激活Wnt/β-catenin通路促进肺腺癌转移。本课题拟通过细胞和动物实验重点研究miR-23a～27a簇促进肺腺癌转移的分子机制，评价其作为肺腺癌转移治疗靶点的可能性。进一步，通过临床样本分析评价miR-23a～27a簇作为肺腺癌患者预后标志物的可能性，为miR-23a～27a簇的临床应用提供理论依据。

即使采用最佳的手术方式，许多早期非小细胞肺癌患者也会因复发而死亡。然而，早期非小细胞肺癌术后复发尚无预测指标，而且其复发机制尚不清楚。本研究主要探讨了miR-23a/27a/24-2簇在早期非小细胞肺癌术后复发中的作用及机制和临床意义。通过研究我们发现 miR-23a/27a/24-2簇中所有miRNAs同时过表达与早期NSCLC患者术后复发和不良预后相关。miR-23a/27a/24-2簇中所有miRNA的过表达或抑制分别协同刺激或抑制细胞的干性、致瘤性和转移。miR-23a/27a/24-2簇中的miRNAs通过靶向Wnt/β-catenin信号通路激活其信号传导，并通过影响DNA甲基化相关基因表达来刺激启动子DNA甲基化而诱导肿瘤抑制基因（TSG）沉默。我们还发现β-catenin沉默和去甲基化联合治疗更有效地抑制了miR-23a/27a/24-2簇的NSCLC的促癌作用。这些研究结果提示miR-23a/27a/24-2簇中所有miRNAs的同时高表达可作为早期NSCLC术后复发和不良预后的预测指标。此外，抑制miR-23a/27a/24-2簇中的所有miRNAs可能是一个诊治NSCLC的有效策略。