Metabolism and Neurophysiology Research Group, Disease Target Structure Research Center, KRIBB, Daejeon, Korea.
Tunneling Nanotube Research Center, Korea University, Seoul, Korea.
Nat Cell Biol. 2021 Feb;23(2):172-183. doi: 10.1038/s41556-020-00628-z. Epub 2021 Feb 8.
In patients with advanced-stage cancer, cancer-associated anorexia affects treatment success and patient survival. However, the underlying mechanism is poorly understood. Here, we show that Dilp8, a Drosophila homologue of mammalian insulin-like 3 peptide (INSL3), is secreted from tumour tissues and induces anorexia through the Lgr3 receptor in the brain. Activated Dilp8-Lgr3 signalling upregulated anorexigenic nucleobinding 1 (NUCB1) and downregulated orexigenic short neuropeptide F (sNPF) and NPF expression in the brain. In the cancer condition, the protein expression of Lgr3 and NUCB1 was significantly upregulated in neurons expressing sNPF and NPF. INSL3 levels were increased in tumour-implanted mice and INSL3-treated mouse hypothalamic cells showed Nucb2 upregulation and Npy downregulation. Food consumption was significantly reduced in intracerebrospinal INSL3-injected mice. In patients with pancreatic cancer, higher serum INSL3 levels increased anorexia. These results indicate that tumour-derived Dilp8/INSL3 induces cancer anorexia by regulating feeding hormones through the Lgr3/Lgr8 receptor in Drosophila and mammals.
在晚期癌症患者中，癌症相关性厌食症会影响治疗效果和患者生存。然而，其潜在机制尚不清楚。在这里，我们表明，Dilp8（果蝇胰岛素样 3 肽（INSL3）的同源物）从肿瘤组织中分泌，并通过大脑中的 Lgr3 受体引起厌食症。激活的 Dilp8-Lgr3 信号通路上调了脑内的厌食性核结合蛋白 1（NUCB1），并下调了食欲刺激肽短神经肽 F（sNPF）和 NPF 的表达。在癌症状态下，表达 sNPF 和 NPF 的神经元中 Lgr3 和 NUCB1 的蛋白表达显著上调。肿瘤植入小鼠的 INSL3 水平升高，INSL3 处理的小鼠下丘脑细胞显示 Nucb2 上调和 Npy 下调。鞘内注射 INSL3 的小鼠的食物摄入量显著减少。在胰腺癌患者中，较高的血清 INSL3 水平增加了厌食症。这些结果表明，肿瘤衍生的 Dilp8/INSL3 通过调节果蝇和哺乳动物中的 Lgr3/Lgr8 受体来调节摄食激素，从而诱导癌症相关性厌食症。
