Department of Pathophysiology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, Hubei, China.
TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China.
Nat Commun. 2024 Nov 21;15(1):10106. doi: 10.1038/s41467-024-54480-y.
The Hippo pathway is commonly altered in cancer initiation and progression; however, exactly how this pathway becomes dysregulated to promote human cancer development remains unclear. Here we analyze the Hippo somatic mutations in the human cancer genome and functionally annotate their roles in targeting the Hippo pathway. We identify a total of 85 loss-of-function (LOF) missense mutations for Hippo pathway genes and elucidate their underlying mechanisms. Interestingly, we reveal zinc-finger domain as an integral structure for MOB1 function, whose LOF mutations in head and neck cancer promote tumor growth. Moreover, the schwannoma/meningioma-derived NF2 LOF mutations not only inhibit its tumor suppressive function in the Hippo pathway, but also gain an oncogenic role for NF2 by activating the VANGL-JNK pathway. Collectively, our study not only offers a rich somatic mutation resource for investigating the Hippo pathway in human cancers, but also provides a molecular basis for Hippo-based cancer therapy.
Hippo 通路在癌症的发生和发展中通常会发生改变；然而，这条通路究竟是如何失调从而促进人类癌症的发展仍不清楚。在这里，我们分析了人类癌症基因组中的 Hippo 体细胞突变，并对其在靶向 Hippo 通路中的作用进行了功能注释。我们总共鉴定出 Hippo 通路基因的 85 个失活功能（LOF）错义突变，并阐明了它们的潜在机制。有趣的是，我们揭示了锌指结构域是 MOB1 功能的一个完整结构，其在头颈部癌症中的 LOF 突变会促进肿瘤生长。此外，神经鞘瘤/脑膜瘤衍生的 NF2 LOF 突变不仅抑制了其在 Hippo 通路中的肿瘤抑制功能，而且通过激活 VANGL-JNK 通路获得了 NF2 的致癌作用。总之，我们的研究不仅为研究人类癌症中的 Hippo 通路提供了丰富的体细胞突变资源，还为基于 Hippo 的癌症治疗提供了分子基础。
