JNK与Hippo信号通路在体内的交互作用及机制研究

The crosstalk between different signaling pathways within a cell plays essential roles in maintaining tissue homeostasis and normal development. Both Hippo and JNK signaling have well-established roles in regulating many physiological processes, including cell proliferation, growth, survival, and migration. An increasing body of evidence shows that dysregulation of either Hippo or JNK pathway would lead to tumorigenesis, and studies coupled Hippo with JNK pathway in intestine stem cell proliferation and cell competition. However, it remains unclear how these two pathways crosstalk with each other in the process of tumorigenesis and cell invasion. By using Drosophila as a major model organism, we are going to investigate the following two questions based on tremendous preliminary data we got. 1) Mechanistically, how Hippo signaling regulates JNK-mediated cell migration and invasion? 2) Is Hippo’s role in modulating JNK-dependent cell growth and proliferation conserved in mammal? This study is expected to provide new insights and possible drug targets and therapeutic strategies for Hippo and JNK related cancer treatment.

在生物体正常生长发育过程中，不同的信号通路通过彼此间的通讯，精密调控着细胞内各种重要生理活动，从而维持机体稳态并保证各个细胞、组织及器官正常功能的行使。其中，c-Jun 氨基末端激酶 (c-Jun N-terminal kinase, JNK) 和Hippo信号通路在细胞增殖、生长、存活及迁移过程中有着重要的调控作用。尽管已有研究表明Hippo与JNK通路失活均与肿瘤的发生发展密切相关，但对两者在体内如何相互通讯、作用进而调控肿瘤生长及迁移的分子机制仍不明了。本项目将利用果蝇为主要研究模式生物，在我们已获得的大量前期实验数据的基础上，深入研究回答以下两个问题：1）Hippo信号通路的失活是如何通过bantam调控了JNK通路介导的细胞迁移及侵袭？2）Hippo调控JNK信号通路介导的细胞增殖与生长机制是否保守？本项目将为Hippo及JNK相关的癌症预防及治疗提供新的思路及可能的药物靶点。

果蝇强大的遗传学工具使得Hippo信号通路的许多重要成员得以被发现并进一步在哺乳动物及人类中得到了验证，鉴于Hippo通路与器官大小与肿瘤发生密切相关，阐明其体内调控机理将有助于我们进一步治疗相关疾病。本课题利用黑腹果蝇为主要研究模式生物，通过遗传学等手段首次揭示了Hippo信号通路调控JNK通路介导的细胞迁移及侵袭的新机制，为Hippo及JNK相关的癌症预防及治疗提供新的思路。此外，我们利用果蝇遗传学的优势进行了大规模的遗传筛选，成功鉴定出POSH为Hippo信号通路的新成员，并阐明了其分子机制。鉴于Hippo信号通路的高度保守性与肿瘤发生密切相关，鉴定出POSH这一Hippo信号通路的新成员将有助于我们进一步理解Hippo通路介导的癌症的发生机制。