Igaki Tatsushi, Pagliarini Raymond A, Xu Tian
Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, Connecticut 06536, USA.
Curr Biol. 2006 Jun 6;16(11):1139-46. doi: 10.1016/j.cub.2006.04.042.
Apparent defects in cell polarity are often seen in human cancer. 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.
细胞极性的明显缺陷在人类癌症中经常可见。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，我们使用果蝇遗传模型来研究Ras诱导的肿瘤进展，揭示了细胞极性丧失与肿瘤恶性之间的分子联系。不同顶基极性基因的突变激活了c-Jun氨基末端激酶（JNK）信号通路，并下调了E-钙黏蛋白/β-连环蛋白黏附复合体，这两者对于导致发育中的眼睛中致癌性Ras（V12）诱导的良性肿瘤表现出转移行为都是必要且充分的。此外，激活的JNK和Ras信号通路在促进肿瘤生长方面存在细胞自主协同作用，因为在致癌性Ras存在的情况下，JNK信号通路将其促凋亡作用转变为促生长作用。我们的发现表明，这种依赖于背景的改变既促进肿瘤生长又促进转移行为，这表明促进转移的突变可能主要是基于其促进生长的能力而被选择的。通过这些进化上保守的信号通路介导的类似致癌协同作用可能会促进人类癌症的进展。
