Department of Biochemistry and Molecular Biology, The University of Texas M. D. Anderson Cancer Center, Genes & Development Graduate Program, 1515 Holcombe Boulevard-Unit 1000, Houston, TX 77030, USA.
Cell Death Differ. 2013 Feb;20(2):302-11. doi: 10.1038/cdd.2012.126. Epub 2012 Sep 28.
Hedgehog (Hh) signaling is important for development and homeostasis in vertebrates and invertebrates. Ligand-independent, deregulated Hh signaling caused by loss of negative regulators such as Patched causes excessive cell proliferation, leading to overgrowth in Drosophila and tumors in humans, including basal-cell carcinoma and medulloblastoma. We show that in Drosophila deregulated Hh signaling also promotes cell survival by increasing the resistance to apoptosis. Surprisingly, cells with deregulated Hh activity do not protect themselves from apoptosis; instead, they promote cell survival of neighboring wild-type cells. This non-cell autonomous effect is mediated by Hh-induced Notch signaling, which elevates the protein levels of Drosophila inhibitor of apoptosis protein-1 (Diap-1), conferring resistance to apoptosis. In summary, we demonstrate that deregulated Hh signaling not only promotes proliferation but also cell survival of neighboring cells. This non-cell autonomous control of apoptosis highlights an underappreciated function of deregulated Hh signaling, which may help to generate a supportive micro-environment for tumor development.
刺猬（Hh）信号在脊椎动物和无脊椎动物的发育和稳态中起着重要作用。配体非依赖性、由 Patched 等负调节剂缺失引起的失调 Hh 信号导致细胞过度增殖，导致果蝇过度生长和人类肿瘤，包括基底细胞癌和髓母细胞瘤。我们表明，在果蝇中，失调的 Hh 信号通过增加对细胞凋亡的抵抗力来促进细胞存活。令人惊讶的是，具有失调 Hh 活性的细胞不会保护自己免受细胞凋亡；相反，它们促进相邻野生型细胞的存活。这种非细胞自主效应是由 Hh 诱导的 Notch 信号介导的，它提高了果蝇凋亡抑制蛋白-1（Diap-1）的蛋白水平，赋予细胞对细胞凋亡的抗性。总之，我们证明失调的 Hh 信号不仅促进增殖，而且促进相邻细胞的存活。这种对细胞凋亡的非细胞自主控制突出了失调 Hh 信号的一个被低估的功能，它可能有助于为肿瘤发展生成一个支持性的微环境。
