miR-193a-3p inhibition of the Slug activator PAK4 suppresses non-small cell lung cancer aggressiveness via the p53/Slug/L1CAM pathway
miR-193a-3p inhibition of the Slug activator PAK4 suppresses non-small cell lung cancer aggressiveness via the p53/Slug/L1CAM pathway
复制标题
miR-193a-3p 抑制 Slug 激活剂 PAK4 通过 p53/Slug/L1CAM 通路抑制非小细胞肺癌侵袭性
DOI：
10.1016/j.canlet.2019.01.027
复制
发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Wang, Xiaojing
中科院分区：
文献类型：
--
作者：
Liu, Xincheng;Min, Shengping;Wang, Xiaojing
L1细胞黏附分子(L1CAM)促进非小细胞肺癌(NSCLC)细胞的侵袭和转移，并被P53调节的转录因子slug上调。P21激活的蛋白4(PAK4)直接磷酸化鼻涕蛋白，使其趋于稳定。我们假设，基于microRNA的PAK4负调控将通过不稳定的鼻塞降低L1CAM诱导的非小细胞肺癌侵袭性。我们发现，L1CAM表达升高与P53功能丧失和NSCLC患者生存期降低密切相关。抑制L1CAM抑制NSCLC细胞在体外的迁移和侵袭力，以及体内肿瘤的形成和远端转移。在机制上，P53通过β-连环素/Slug途径限制L1CAM的表达，在NSCLC肿瘤中，β-连环素和Slug的水平与L1CAM的表达呈正相关。MicroRNA miR-193a-3p直接靶向PAK4，抑制下游p-slug和L1CAM的表达。沉默PAK4、Slug和L1CAM反映了miR-193a-3p对NSCLC细胞体外迁移和侵袭能力的影响。在NSCLC肿瘤中，miR-193a-3p水平降低与PAK4、p-slug和L1CAM水平升高相关。我们的发现支持miR-193a-3p通过调节P53/slug/L1CAM通路抑制非小细胞肺癌转移疾病进展的模型。
L1 cell adhesion molecule (L1CAM) promotes invasiveness and metastasis in non-small cell lung cancer (NSCLC) cells and is upregulated by the p53-regulated transcription factor Slug. p21-activated kinase 4 (PAK4) directly phosphorylates Slug, resulting in pro-malignant Slug stabilization. We hypothesized that microRNA-based negative regulation of PAK4 would reduce L1CAM-induced NSCLC aggressiveness via destabilizing Slug. We found that elevated L1CAM expression was tightly correlated with p53 loss-of-function and reduced NSCLC patient survival. L1CAM suppression reduced NSCLC cell migration and invasiveness in vitro as well as tumor formation and distal metastasis in vivo. Mechanistically, p53 restricts L1CAM expression through the beta-catenin/Slug pathway, with levels of beta-catenin and Slug positively correlating with L1CAM expression in NSCLC tumors. The microRNA miR-193a-3p directly targets PAK4 and suppresses downstream p-Slug and L1CAM expression. Silencing PAK4, Slug, and L1 CAM mirrored miR-193a-3p's effects upon the migration and invasiveness of NSCLC cells in vitro. Decreased miR-193a-3p levels correlated with elevated PAK4, p-Slug, and L1CAM levels in NSCLC tumors. Our findings support a model of miR-193a-3p as a suppressor of metastatic disease progression in NSCLC via modulation of the p53/Slug/L1CAM pathway.