同济大学生科院揭示肿瘤发生与细胞迁移新机制

　　

   2015年5月11日，自然出版社旗下杂志《Oncogene》在线发表了同济大学生命学院薛雷教授课题组题为“Rho1-Wnd signaling regulates loss-of-cell polarity-induced cell invasion in Drosophila”的研究论文。
 
       细胞极性(cell polarity)对于体内稳态的维持有着重要的作用，其异常与癌症发生发展密切相关。薛雷课题组利用果蝇作为模式动物，在翅成虫盘 (wing disc)特异性下调细胞极性调控基因scribble (scrib) 的表达，建立了体内细胞侵袭模型。利用该模型，课题组进行了遗传筛选，发现Rho1和Wnd相互结合，构成一个关键的信号传导复合物，在细胞极性丢失，JNK通路激活及细胞侵袭之间起重要的调控作用。Wnd属于MAPKKK家族成员，下调其表达能够抑制scrib缺失或Rho1上调引起的JNK激活及细胞侵袭；反之，表达Wnd则能够促进细胞侵袭和EMT转化(epithelial–mesenchymal transition)。表达Wnd的同时抑制细胞凋亡能激活Wnt信号通路，诱导细胞增殖。

       此外，Wnd能够与癌基因Ras协同作用，促进细胞增殖、肿瘤生长和侵袭。鉴于Scrib和JNK通路成员从果蝇到人类高度保守，该研究不仅揭示了缺失细胞极性诱发细胞侵袭的分子机制，同时也凸显了果蝇这一模式动物对于癌症生物学机制研究的重要性。
 
       薛雷研究组的马仙珏博士为该论文第一作者。该项目得到了科技部、自然科学基金委、国家教委和上海市科委的经费支持。
 

原文摘要：

Rho1–Wnd signaling regulates loss-of-cell polarity-induced cell invasion in Drosophila

Both cell polarity and c-Jun N-terminal kinase (JNK) activity are essential to the maintenance of tissue homeostasis, and disruption of either is commonly seen in cancer progression. Despite the established connection between loss-of-cell polarity and JNK activation, much less is known about the molecular mechanism by which aberrant cell polarity induces JNK-mediated cell migration and tumor invasion. Here we show results from a genetic screen using an in vivo invasion model via knocking down cell polarity gene in Drosophila wing discs, and identify Rho1–Wnd signaling as an important molecular link that mediates loss-of-cell polarity-triggered JNK activation and cell invasion. We show that Wallenda (Wnd), a protein kinase of the mitogen-activated protein kinase kinase kinase family, by forming a complex with the GTPase Rho1, is both necessary and sufficient for Rho1-induced JNK-dependent cell invasion, MMP1 activation and epithelial–mesenchymal transition. Furthermore, Wnd promotes cell proliferation and tissue growth through wingless production when apoptosis is inhibited by p35. Finally, Wnd shows oncogenic cooperation with RasV12 to trigger tumor growth in eye discs and causes invasion into the ventral nerve cord. Together, our data not only provides a novel mechanistic insight on how cell polarity loss contributes to cell invasion, but also highlights the value of the Drosophila model system to explore human cancer biology.