Autocrine Semaphorin3A signaling is essential for the maintenance of stem-like cells in lung cancer.
Autocrine Semaphorin3A signaling is essential for the maintenance of stem-like cells in lung cancer.
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DOI：
10.1016/j.bbrc.2016.10.057
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发表时间：
2016-11
影响因子：
3.1
通讯作者：
D. Yamada;Kensuke Takahashi;K. Kawahara;T. Maeda
中科院分区：
文献类型：
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作者：
D. Yamada;Kensuke Takahashi;K. Kawahara;T. Maeda
肿瘤干细胞样细胞（Cancer stem-like cell，CSCs）存在于肿瘤组织中，具有自我更新能力和致瘤性。许多研究表明，根除CSC可以防止肿瘤的发展和复发;然而，对CSC维持至关重要的分子尚未完全了解。我们先前报道了Semaphorin 3A（Sema 3a）敲低抑制刘易斯肺癌（LLC）细胞的致瘤性和增殖能力。因此，我们将Sema 3a鉴定为用于建立或维持源自LLC（LLC-干细胞）的CSC的必需因子。将针对Sema 3a的shRNA引入LLC细胞以建立LLC干细胞系，并测试其对肿瘤发生、球体形成和mTORC 1活性的影响。Sema 3a敲除完全消除了LLC干细胞的致瘤性和球体形成和自我更新能力。Sema 3a敲除还与干细胞标志物的mRNA表达降低相关。通过外源性添加重组SEMA 3A不能恢复Sema 3a敲低所消除的自我更新能力。此外，哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）的活性及其底物p70 S6 K1的表达也降低。这些结果表明Sema 3a是根除CSC的潜在治疗靶标。
Cancer stem-like cells (CSCs) exist in tumor tissues composed of heterogeneous cell population and are characterized by their self-renewal capacity and tumorigenicity. Many studies demonstrate that eradication of CSCs prevents development and recurrences of tumor; yet, molecules critical for the maintenance of CSCs have not been completely understood. We previously reported that Semaphorin3A (Sema3a) knockdown suppressed the tumorigenicity and proliferative capacity of Lewis lung carcinoma (LLC) cells. Therefore, we identified Sema3a as an essential factor for the establishment or maintenance of CSCs derived from LLC (LLC-stem cell). shRNA against Sema3a was introduced into LLC cells to establish a LLC-stem cell line and its effects on tumorigenesis, sphere formation, and mTORC1 activity were tested. Sema3a knockdown completely abolished tumorigenicity and the sphere-formation and self-renewal ability of LLC-stem cells. The Sema3a knockdown was also associated with decreased expression of mRNA for stem cell markers. The self-renewal ability abolished by Sema3a knockdown could not be recovered by exogenous addition of recombinant SEMA3A. In addition, the activity of mammalian target of rapamycin complex 1 (mTORC1) and the expression of its substrate p70S6K1 were also decreased. These results demonstrate that Sema3a is a potential therapeutic target in eradication of CSCs.