Department of Biological Sciences, National University of Singapore, 117558, Singapore.
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 230002, China.
Dis Model Mech. 2019 Feb 27;12(2):dmm038240. doi: 10.1242/dmm.038240.
Cancer cachexia affects up to 80% of patients with advanced solid cancer and leads to excessive muscle wasting. Here, using an inducible zebrafish hepatocellular carcinoma (HCC) model driven by oncogenic , we observed a progressive muscle-wasting phenotype in adult zebrafish, characterized by significant loss of body weight and muscle fibers. By differential feeding, we observed that overfeeding caused fatty liver, accelerated carcinogenesis and muscle wasting. Interestingly, leptin, an obesity hormone, was upregulated in oncogenic hepatocytes and overfeeding groups. We also found that leptin expression progressively increased during human liver disease progression. By using leptin receptor ()-knockout fish, we found that tumor fish in the mutant background had a higher survival rate and significantly lower muscle-wasting level after tumor induction than the tumor fish in the wild-type background. Chemical inhibitors targeting leptin signaling also alleviated the muscle-wasting phenotype, indicating that leptin signaling may be a new therapeutic target for cancer patients with muscle wasting.
癌症恶病质影响高达 80%的晚期实体瘤患者，并导致过度的肌肉消耗。在这里，我们使用一种诱导的斑马鱼肝细胞癌 (HCC) 模型，该模型由致癌驱动，观察到成年斑马鱼出现进行性肌肉消耗表型，表现为体重和肌肉纤维显著丧失。通过差异喂养，我们观察到过度喂养导致脂肪肝，加速了癌变和肌肉消耗。有趣的是，肥胖激素瘦素在致癌性肝细胞和过度喂养组中上调。我们还发现，瘦素表达在人类肝病进展过程中逐渐增加。通过使用瘦素受体 () 敲除鱼，我们发现肿瘤鱼在突变背景下的存活率高于野生型背景下的肿瘤鱼，并且在肿瘤诱导后肌肉消耗水平显著降低。针对瘦素信号的化学抑制剂也缓解了肌肉消耗表型，表明瘦素信号可能是肌肉消耗的癌症患者的一个新的治疗靶点。
