Myo9b is a key player in SLIT/ROBO-mediated lung tumor suppression
Myo9b is a key player in SLIT/ROBO-mediated lung tumor suppression
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Myo9b 是 SLIT/ROBO 介导的肺肿瘤抑制的关键参与者。
DOI：
10.1172/jci81673
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发表时间：
2015-12-01
影响因子：
15.9
通讯作者：
Wu, Jane Y.
中科院分区：
文献类型：
--
作者：
Kong, Ruirui;Yi, Fengshuang;Wu, Jane Y.
新的证据表明，神经元引导分子 SLIT 在肿瘤抑制中发挥着作用，因为 SLIT 编码基因在包括肺癌在内的多种癌症中失活；然而，目前尚不清楚 SLIT 在肺癌中如何发挥作用。在这里，我们的数据表明，SLIT 通过激活 RhoA 来抑制癌细胞迁移，而肌球蛋白 9b (Myo9b) 是一种 ROBO 相互作用蛋白，可抑制肺癌细胞中的 RhoA 活性。结构分析表明，Myo9b 的 RhoGAP 结构域包含一个专门识别 RhoA 的独特补丁。我们还确定 ROBO 胞内结构域与 Myo9b RhoGAP 结构域相互作用并抑制其活性；因此，RhoA 的 SLIT 依赖性激活是通过 ROBO 对 Myo9b 的抑制介导的。在小鼠模型中，与对照肺癌细胞相比，表达 SLIT 的细胞肿瘤形成和肺转移的能力降低。对人类肺癌和邻近非肿瘤组织的评估表明，Myo9b 在癌组织中表达上调。此外，Myo9b 表达升高与肺癌进展和不良预后相关。总之，我们的数据表明 Myo9b 是肺癌的关键参与者，并且是一种 ROBO 相互作用蛋白，据我们所知，这是一个新定义的 SLIT/ROBO/Myo9b/RhoA 信号通路，可限制肺癌的进展和转移。此外，我们的工作表明，靶向 SLIT/ROBO/Myo9b/RhoA 通路具有作为肺癌诊断和治疗策略的潜力。
Emerging evidence indicates that the neuronal guidance molecule SLIT plays a role in tumor suppression, as SLIT-encoding genes are inactivated in several types of cancer, including lung cancer; however, it is not clear how SLIT functions in lung cancer. Here, our data show that SLIT inhibits cancer cell migration by activating RhoA and that myosin 9b (Myo9b) is a ROBO-interacting protein that suppresses RhoA activity in lung cancer cells. Structural analyses revealed that the RhoGAP domain of Myo9b contains a unique patch that specifically recognizes RhoA. We also determined that the ROBO intracellular domain interacts with the Myo9b RhoGAP domain and inhibits its activity; therefore, SLIT-dependent activation of RhoA is mediated by ROBO inhibition of Myo9b. In a murine model, compared with control lung cancer cells, SLIT-expressing cells had a decreased capacity for tumor formation and lung metastasis. Evaluation of human lung cancer and adjacent nontumor tissues revealed that Myo9b is upregulated in the cancer tissue. Moreover, elevated Myo9b expression was associated with lung cancer progression and poor prognosis. Together, our data identify Myo9b as a key player in lung cancer and as a ROBO-interacting protein in what is, to the best of our knowledge, a newly defined SLIT/ROBO/Myo9b/RhoA signaling pathway that restricts lung cancer progression and metastasis. Additionally, our work suggests that targeting the SLIT/ROBO/Myo9b/RhoA pathway has potential as a diagnostic and therapeutic strategy for lung cancer.