miR-367 stimulates Wnt cascade activation through degrading FBXW7 in NSCLC stem cells
miR-367 stimulates Wnt cascade activation through degrading FBXW7 in NSCLC stem cells
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miR-367 通过降解 NSCLC 干细胞中的 FBXW7 刺激 Wnt 级联激活
DOI：
10.1080/15384101.2017.1380136
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发表时间：
2017-01-01
期刊：
影响因子：
4.3
通讯作者：
Sun, Xin
中科院分区：
文献类型：
--
作者：
Xiao, Guodong;Zhang, Boxiang;Sun, Xin
肺癌位居癌症相关运动类别之首，已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几乎不为人所知，并且FBXW7通过Wnt信号传导的miR-367调节尚未被探索。发现 ALDH1C 或 CD133C 表型的癌症干细胞在 NSCLC（非小细胞肺癌）患者中处于晚期阶段。为了研究 miR-367 的作用，我们发现 NSCLC 中保留了比配对的相邻正常组织更高的 miR-367 水平或 FBXW7 水平，并且它们的上调与 Wnt 信号激活呈正相关。相反，miR-367 的增加与 Let-7 抑制相关。 MiR-367与NSCLC干细胞较强的成球能力有关。然后，我们探索了从 NSCLC 细胞系中分离的干细胞样细胞中内源性 miR-367 的功能。在 HEK-293 细胞中，我们确定 FBXW7 是 miR-367 的直接下游基因，从而释放抑制性 Let-7 的 LIN-28 依赖性抑制。通过信息学分析，预测 miR-367 通过 Wnt 信号传导发挥作用，而 Let-7 的减少在维持 TCF-4/Wnt 通路活性中发挥着关键作用。重新引入 FBXW7 消除了 miR-367 对 TCF-4 活性的致癌刺激，并抑制了 Wnt 信号因子。总之，我们的研究结果证明了 miR-367 通过降解抑制性 FBXW7 发挥癌症干细胞样细胞自我更新能力的致癌作用，最终通过 LIN28B/Let-7 依赖的方式帮助维持 Wnt 信号激活。
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 ALDH1C or CD133C 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.