Fang Lishan, Cai Junchao, Chen Baixue, Wu Shanshan, Li Rong, Xu Xiaonan, Yang Yi, Guan Hongyu, Zhu Xun, Zhang Le, Yuan Jie, Wu Jueheng, Li Mengfeng
Department of Microbiology, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou, Guangdong 510080, China.
Nat Commun. 2015 Oct 15;6:8640. doi: 10.1038/ncomms9640.
Cancer stem cells (CSCs) are involved in tumorigenesis, tumour recurrence and therapy resistance and Wnt signalling is essential for the development of the biological traits of CSCs. In non-small cell lung carcinoma (NSCLC), unlike in colon cancer, mutations in β-catenin and APC genes are uncommon; thus, the mechanism underlying the constitutive activation of Wnt signalling in NSCLC remains unclear. Here we report that miR-582-3p expression correlates with the overall- and recurrence-free-survival of NSCLC patients, and miR-582-3p has an activating effect on Wnt/β-catenin signalling. miR-582-3p overexpression simultaneously targets multiple negative regulators of the Wnt/β-catenin pathway, namely, AXIN2, DKK3 and SFRP1. Consequently, miR-582-3p promotes CSC traits of NSCLC cells in vitro and tumorigenesis and tumour recurrence in vivo. Antagonizing miR-582-3p potently inhibits tumour initiation and progression in xenografted animal models. These findings suggest that miR-582-3p mediates the constitutive activation of Wnt/β-catenin signalling, likely serving as a potential therapeutic target for NSCLC.
癌症干细胞（CSCs）参与肿瘤发生、肿瘤复发和治疗抵抗，而Wnt信号通路对于CSCs生物学特性的发展至关重要。在非小细胞肺癌（NSCLC）中，与结肠癌不同，β-连环蛋白和APC基因的突变并不常见；因此，NSCLC中Wnt信号通路组成性激活的潜在机制仍不清楚。在此我们报告，miR-582-3p的表达与NSCLC患者的总生存期和无复发生存期相关，并且miR-582-3p对Wnt/β-连环蛋白信号通路具有激活作用。miR-582-3p的过表达同时靶向Wnt/β-连环蛋白通路的多个负调节因子，即AXIN2、DKK3和SFRP1。因此，miR-582-3p在体外促进NSCLC细胞的CSC特性，并在体内促进肿瘤发生和肿瘤复发。在异种移植动物模型中，拮抗miR-582-3p可有效抑制肿瘤起始和进展。这些发现表明，miR-582-3p介导Wnt/β-连环蛋白信号通路的组成性激活，可能作为NSCLC的潜在治疗靶点。
