Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis.
Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis.
复制标题
G 蛋白偶联受体 Gpr161 对 Sonic Hedgehog 通路的基础抑制限制了髓母细胞瘤的发病机制。
DOI：
10.1016/j.celrep.2018.01.018
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发表时间：
2018
期刊：
影响因子：
8.8
通讯作者：
Mukhopadhyay,Saikat
中科院分区：
文献类型：
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作者：
Shimada,IsseiS;Hwang,Sun-Hee;Somatilaka,BandarigodaN;Wang,Xin;Skowron,Patryk;Kim,Jiwoong;Kim,Min;Shelton,JohnM;Rajaram,Veena;Xuan,Zhenyu;Taylor,MichaelD;Mukhopadhyay,Saikat
Sonic hedgehog（Shh）决定小脑颗粒细胞（GC）祖细胞增殖和髓母细胞瘤发病机制。然而，调控GC祖细胞的途径在胚胎发育过程中，由浦肯野神经元产生Shh之前，它们在肿瘤发生中的作用仍然不清楚。纤毛定位的G蛋白偶联受体Gpr161抑制神经管中Shh介导的信号传导。在此，通过在小鼠神经干细胞或GC祖细胞中缺失Gpr161，我们确定Gpr161在Shh亚型髓母细胞瘤中为肿瘤抑制因子。不考虑小脑中Shh的产生，Gpr161缺失通过限制Gli3介导的抑制增加了Shh通路的下游活性，导致GC祖细胞更广泛的产生和增殖。此外，在胚胎发生过程中Gpr161的早期缺失增加了肿瘤的发生率和严重程度。与正常发育不同，Gpr161缺失引起的胚胎发生过程中GC祖细胞的过量产生依赖于纤毛。GPR161低表达与SHH亚型髓母细胞瘤患者的生存率相关。Gpr161通过阻止过早和Shh依赖性途径活性来限制GC祖细胞的产生，突出了基础途径抑制在肿瘤发生中的重要性。
Sonic hedgehog (Shh) determines cerebellar granule cell (GC) progenitor proliferation and medulloblastoma pathogenesis. However, the pathways regulating GC progenitors during embryogenesis before Shh production by Purkinje neurons and their roles in tumorigenesis remain unclear. The cilium-localized G-protein-coupled receptor Gpr161 suppresses Shh-mediated signaling in the neural tube. Here, by deletingGpr161in mouse neural stem cells or GC progenitors, we establish Gpr161 as a tumor suppressor in Shh subtype medulloblastoma. Irrespective of Shh production in the cerebellum,Gpr161deletion increased downstream activity of the Shh pathway by restricting Gli3-mediated repression, causing more extensive generation and proliferation of GC progenitors. Moreover, earlier deletion ofGpr161during embryogenesis increased tumor incidence and severity. GC progenitor overproduction during embryogenesis fromGpr161deletion was cilium dependent, unlike normal development. LowGPR161expression correlated with poor survival of SHH subtype medulloblastoma patients. Gpr161 restricts GC progenitor production by preventing premature and Shh-dependent pathway activity, highlighting the importance of basal pathway suppression in tumorigenesis.