Liu Ying, Dantas Ezequiel, Ferrer Miriam, Liu Yifang, Comjean Aram, Davidson Emma E, Hu Yanhui, Goncalves Marcus D, Janowitz Tobias, Perrimon Norbert
Department of Genetics, Blavatnik Institute, Harvard Medical School, Harvard University, Boston, MA 02115, USA.
Division of Endocrinology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
bioRxiv. 2023 May 18:2023.05.15.540823. doi: 10.1101/2023.05.15.540823.
A primary cause of death in cancer patients is cachexia, a wasting syndrome attributed to tumor-induced metabolic dysregulation. Despite the major impact of cachexia on the treatment, quality of life, and survival of cancer patients, relatively little is known about the underlying pathogenic mechanisms. Hyperglycemia detected in glucose tolerance test is one of the earliest metabolic abnormalities observed in cancer patients; however, the pathogenesis by which tumors influence blood sugar levels remains poorly understood. Here, utilizing a model, we demonstrate that the tumor secreted interleukin-like cytokine Upd3 induces fat body expression of and , two key regulatory enzymes of gluconeogenesis, contributing to hyperglycemia. Our data further indicate a conserved regulation of these genes by IL-6/JAK-STAT signaling in mouse models. Importantly, in both fly and mouse cancer cachexia models, elevated gluconeogenesis gene levels are associated with poor prognosis. Altogether, our study uncovers a conserved role of Upd3/IL-6/JAK-STAT signaling in inducing tumor-associated hyperglycemia, which provides insights into the pathogenesis of IL-6 signaling in cancer cachexia.
癌症患者死亡的主要原因之一是恶病质，这是一种由肿瘤诱导的代谢失调引起的消耗综合征。尽管恶病质对癌症患者的治疗、生活质量和生存有重大影响，但对其潜在致病机制的了解相对较少。葡萄糖耐量试验中检测到的高血糖是癌症患者最早出现的代谢异常之一；然而，肿瘤影响血糖水平的发病机制仍知之甚少。在这里，利用一个模型，我们证明肿瘤分泌的白细胞介素样细胞因子Upd3诱导脂肪体中糖异生的两个关键调节酶 和 的表达，导致高血糖。我们的数据进一步表明，在小鼠模型中，这些基因受IL-6/JAK-STAT信号通路的保守调控。重要的是，在果蝇和小鼠癌症恶病质模型中，糖异生基因水平升高与预后不良有关。总之，我们的研究揭示了Upd3/IL-6/JAK-STAT信号通路在诱导肿瘤相关高血糖中的保守作用，这为癌症恶病质中IL-6信号通路的发病机制提供了见解。
