a Department of Thoracic Surgery and Oncology, The Second Department of Thoracic Surgery , Cancer Center , The First Affiliated Hospital of Xi'an Jiaotong University , Xi'an, Shaanxi Province , China.
b Department of Surgery Oncology , The First People's Hospital of Xianyang City , Xianyang, Shaanxi Province , China.
Cell Cycle. 2017;16(24):2374-2385. doi: 10.1080/15384101.2017.1380136. Epub 2017 Nov 14.
Lung carcinoma tops the categories of cancer related motility, and has been treated as the main threat to human health. The functions and related mechanism of FBXW7 controlled lung cancer stem cells' signatures is barely unknown, and the miR-367 regulations of FBXW7 via Wnt signaling have not been explored. Cancer stem cells of either ALDH1+ or CD133+ phenotype were found to be referred to advanced stages in patients with NSCLC (non-small cell lung carcinoma). To study the roles of miR-367, we found greater miR-367 level or FBXW7 level was reserved in NSCLC than that of paired adjacent normal tissues, and their upregulations were positively correlated with Wnt signaling activation. On the contrary, increased miR-367 was correlated with Let-7 repression. MiR-367 was related to stronger sphere forming ability in stem cells of NSCLC. We then explored the functions of the endogenous miR-367 in stem-like cells isolated from NSCLC cell lines. In HEK-293 cells, we identified FBXW7 as the direct downstream gene of miR-367, which consequently released the LIN-28 dependent inhibition of suppressive Let-7. Through informatics analysis, miR-367 was predicated to function through Wnt signaling, and decreased Let-7 played the pivotal role to maintain TCF-4/Wnt pathway activity. The reintroduction of FBXW7 abolished the oncogenic stimulation of miR-367 on TCF-4 activity, with Wnt signaling factors depression. In conclusion, our findings demonstrated the oncogenic roles of miR-367 exerting on the self-renewal ability of cancer stem-like cells through degrading the suppressive FBXW7, eventually helping to maintain Wnt signaling activation through a LIN28B/Let-7 dependent manner.
肺癌是癌症相关运动性的首要类别，一直被视为人类健康的主要威胁。FBXW7 控制肺癌干细胞特征的功能和相关机制知之甚少，miR-367 通过 Wnt 信号对 FBXW7 的调节也尚未得到探索。ALDH1+或 CD133+表型的癌症干细胞被认为与 NSCLC（非小细胞肺癌）患者的晚期有关。为了研究 miR-367 的作用，我们发现 NSCLC 中的 miR-367 水平或 FBXW7 水平高于配对的相邻正常组织，它们的上调与 Wnt 信号激活呈正相关。相反，miR-367 的增加与 Let-7 的抑制有关。miR-367 与 NSCLC 干细胞更强的球体形成能力有关。然后，我们研究了内源性 miR-367 在 NSCLC 细胞系中分离的干细胞样细胞中的功能。在 HEK-293 细胞中，我们鉴定出 FBXW7 是 miR-367 的直接下游基因，这导致 LIN-28 依赖性抑制物 Let-7 的释放。通过信息学分析，miR-367 被预测通过 Wnt 信号发挥作用，并且下调的 Let-7 发挥关键作用来维持 TCF-4/Wnt 通路的活性。FBXW7 的再引入消除了 miR-367 对 TCF-4 活性的致癌刺激，同时抑制了 Wnt 信号因子。总之，我们的研究结果表明，miR-367 通过降解抑制性 FBXW7 发挥其致癌作用，从而增强癌症干细胞样细胞的自我更新能力，最终通过 LIN28B/Let-7 依赖性方式帮助维持 Wnt 信号激活。
