Wingless modulates activator protein-1-mediated tumor invasion.
Wingless modulates activator protein-1-mediated tumor invasion.
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Wingless 调节激活蛋白 1 介导的肿瘤侵袭。
DOI：
10.1038/s41388-018-0629-x
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发表时间：
2019
期刊：
影响因子：
8
通讯作者：
Xue Lei
中科院分区：
文献类型：
--
作者：
Zhang Shiping;Guo Xiaowei;Wu Honggui;Sun Ying;Ma Xianjue;Li Jikai;Xu Qian;Wu Chenxi;Li Qiwen;Jiang Cizhong;Li Wenzhe;Ho Margaret S;Lv Zhongwei;Xue Lei
转移开始于局部肿瘤细胞亚群获得侵入周围组织的潜力，并且仍然是癌症治疗的主要障碍。超过90%的癌症患者死于肿瘤转移，而不是原发肿瘤生长。典型的Wnt/β-catenin通路在促进肿瘤形成中发挥重要作用，但其调控肿瘤转移的功能及其机制仍存在争议。本研究采用成熟的果蝇肿瘤模型，探讨无翼通路（Wingless pathway, Wg）在肿瘤侵袭中的调控机制。我们的研究结果表明，Wg信号对于细胞极性破坏诱导的细胞迁移和类似上皮-间质转化（EMT）的分子变化是必要和充分的。此外，减少Wg信号可以抑制lgl−/−/ rasv12诱导的肿瘤侵袭，而Arm和rasv12的协同作用足以诱导肿瘤侵袭。在机制上，我们发现细胞极性破坏激活JNK信号，进而通过转录因子激活蛋白1 （AP-1）上调wg的表达。我们发现了一个一致的AP-1结合位点，位于wg的第2位，并证实了它在体外和体内都是AP-1诱导的wg转录所必需的。最后，我们证实了AP-1对wntby的转录激活在人类癌细胞中是保守的。这些证据揭示了Wnt/β-catenin通路在肿瘤侵袭中的积极作用，并提供了JNK和Wnt信号连接调控肿瘤进展的保守机制。
Metastasis begins with a subset of local tumor cells acquiring the potential to invade into surrounding tissues, and remains to be a major obstacle for cancer treatments. More than 90% of cancer patients died from tumor metastasis, instead of primary tumor growth. The canonical Wnt/β-catenin pathway plays essential roles in promoting tumor formation, yet its function in regulating tumor metastasis and the underlying mechanisms remain controversial. Here we employed well-establishedDrosophilatumor models to investigate the regulating mechanism of Wingless (Wg) pathway in tumor invasion. Our results showed that Wg signaling is necessary and sufficient for cell polarity disruption-induced cell migration and molecular changes reminiscent of epithelial-mesenchymal transition (EMT). Moreover, reducing Wg signaling suppressedlgl−/−/RasV12-induced tumor invasion, and cooperation between Arm and RasV12is sufficient to induce tumor invasion. Mechanistically, we found that cell polarity disruption activates JNK signaling, which in turn upregulatewgexpression through transcription factor activator protein-1 (AP-1). We identified a consensus AP-1 binding site located in the 2ndintron ofwg, and confirmed that it is essential for AP-1 inducedwgtranscription both in vitro and in vivo. Lastly, we confirmed that the transcriptional activation ofWNTby AP-1 is conserved in human cancer cells. These evidences reveal a positive role of Wnt/β-catenin pathway in tumor invasion, and provide a conserved mechanism that connects JNK and Wnt signaling in regulating tumor progression.