Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells
Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells
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DOI：
10.1073/pnas.1806851116
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发表时间：
2019-01-08
影响因子：
11.1
通讯作者：
Gotoh, Noriko
中科院分区：
文献类型：
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作者：
Tominaga, Kana;Minato, Hiroshi;Gotoh, Noriko
癌症干细胞样细胞（CSC）在CSC小生境中通过增加对称细胞分裂的频率以不对称细胞分裂为代价而扩增。CSC的对称分裂对于癌症的恶性性质是重要的;然而，潜在的分子机制在很大程度上仍然难以捉摸。在这里，我们展示了一种细胞因子，脑信号蛋白3（Sema 3），从CSC生态位产生，诱导CSC的对称分裂，以扩大CSC人口。我们的研究结果表明，刺激Sema 3诱导球体形成的乳腺癌细胞通过神经纤毛蛋白1（NP 1）受体，在乳腺CSC（BCSC）中特异性表达。MICAL 3是一种细胞质Sema 3信号转导子，其敲低可大大降低肿瘤球形成和肿瘤起始活性。在机制上，Sema 3诱导MICAL 3、胰蛋白酶反应介导蛋白2（CRMP 2）和Numb之间的相互作用。由Sema 3刺激的MICAL 3单加氧酶（MO）的活性似乎是肿瘤球形成、CRMP 2与Numb之间的相互作用以及Numb蛋白积累所需的。我们发现CRMP 2或Numb的敲低显著减少了肿瘤球的形成。此外，MICAL 3敲低显著降低了NP 1/Numb阳性BCSC中Sema 3诱导的对称分裂，并增加了产生没有干细胞样特性的NP 1/Numb阴性细胞的不对称分裂。此外，具有NP 1阳性癌组织的乳腺癌患者显示不良预后。因此，小生境因子Sema 3刺激的NP 1/MICAL 3/CRMP 2/Numb轴似乎至少部分地通过增加MICAL 3介导的CSC对称分裂的频率来扩增CSC。
Cancer stem-like cells (CSCs) are expanded in the CSC niche by increased frequency of symmetric cell divisions at the expense of asymmetric cell divisions. The symmetric division of CSCs is important for the malignant properties of cancer; however, underlying molecular mechanisms remain largely elusive. Here, we show a cytokine, semaphorin 3 (Sema3), produced from the CSC niche, induces symmetric divisions of CSCs to expand the CSC population. Our findings indicate that stimulation with Sema3 induced sphere formation in breast cancer cells through neuropilin 1 (NP1) receptor that was specifically expressed in breast CSCs (BCSCs). Knockdown of MICAL3, a cytoplasmic Sema3 signal transducer, greatly decreased tumor sphere formation and tumor-initiating activity. Mechanistically, Sema3 induced interaction among MICAL3, collapsin response mediator protein 2 (CRMP2), and Numb. It appears that activity of MICAL3 monooxygenase (MO) stimulated by Sema3 is required for tumor sphere formation, interaction between CRMP2 and Numb, and accumulation of Numb protein. We found that knockdown of CRMP2 or Numb significantly decreased tumor sphere formation. Moreover, MICAL3 knockdown significantly decreased Sema3-induced symmetric divisions in NP1/Numb-positive BCSCs and increased asymmetric division that produces NP1/Numb negative cells without stem-like properties. In addition, breast cancer patients with NP1-positive cancer tissues show poor prognosis. Therefore, the niche factor Sema3-stimulated NP1/MICAL3/CRMP2/Numb axis appears to expand CSCs at least partly through increased frequency of MICAL3-mediated symmetric division of CSCs.