Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila
Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila
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DOI：
10.1016/j.cub.2006.04.042
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发表时间：
2006-06-06
期刊：
影响因子：
9.2
通讯作者：
Xu, Tian
中科院分区：
文献类型：
--
作者：
Igaki, Tatsushi;Pagliarini, Raymond A.;Xu, Tian
细胞极性的明显缺陷通常见于人类癌症[1，2]。然而，细胞极性破坏如何促进肿瘤进展的潜在机制尚不清楚。在这里，使用果蝇基因模型Ras诱导的肿瘤进展，我们显示了细胞极性丧失和肿瘤恶性之间的分子联系。不同顶基极性基因的突变激活c-Jun N-末端激酶（JNK）信号传导并下调E-钙粘蛋白/β-连环蛋白粘附复合物，这两者都是必要的，足以导致致癌Ras（V12）诱导的良性肿瘤在发育中的眼睛表现出转移行为。此外，激活的JNK和Ras信号传导在促进肿瘤细胞自主生长中合作，因为JNK信号传导在致癌Ras的存在下将其促凋亡作用转换为促生长作用。我们的发现，这种背景依赖性改变促进肿瘤生长和转移行为表明，转移促进突变可能主要是基于其生长促进能力。通过这些进化上保守的信号通路介导的类似致癌合作可能有助于人类癌症的进展。
Apparent defects in cell polarity are often seen in human cancer [1, 2]. However, the underlying mechanisms of how cell polarity disruption contributes to tumor progression are unknown. Here, using a Drosophila genetic model for Ras-induced tumor progression, we show a molecular link between loss of cell polarity and tumor malignancy. Mutation of different apicobasal polarity genes activates c-Jun N-terminal kinase (JNK) signaling and downregulates the E-cadherin/beta-catenin adhesion complex, both of which are necessary and sufficient to cause oncogenic Ras(V12)-induced benign tumors in the developing eye to exhibit metastatic behavior. Furthermore, activated JNK and Ras signaling cooperate in promoting tumor growth cell autonomously, as JNK signaling switches its proapoptotic role to a progrowth effect in the presence of oncogenic Ras. Our finding that such context-dependent alterations promote both tumor growth and metastatic behavior suggests that metastasis-promoting mutations may be selected for based primarily on their growth-promoting capabilities. Similar oncogenic cooperation mediated through these evolutionarily conserved signaling pathways could contribute to human cancer progression.