Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Am J Physiol Cell Physiol. 2022 May 1;322(5):C814-C824. doi: 10.1152/ajpcell.00463.2021. Epub 2022 Mar 23.
Cachexia is a complex metabolic syndrome that occurs in approximately 50% of patients with cancer. Skeletal muscle atrophy is the primary clinical feature. Interleukin (IL)-17A, a proinflammatory factor, plays an important role in many chronic inflammatory diseases. Here, we describe a novel signaling pathway through which IL-17A induced muscle atrophy. We conducted a retrospective clinical study to investigate the relationship between IL-17A and the skeletal muscle index in patients with lung adenocarcinoma. We also investigated the involvement of JAK2/STAT3 signaling pathway regarding the main features of cachexia by injecting Lewis lung carcinoma (LLC) cells into C57BL/6 mice as a model to replicate cancer-induced cachexia. In vitro, C2C12 myotubes were treated with recombinant IL-17A, anti-IL-17A monoclonal antibody, STAT3 inhibitor AG490, and LLC-conditioned medium. Cell viability and aging were also evaluated. We found that in cancer conditions, increased serum levels of IL-17A were related to muscle wasting. JAK2/STAT3 phosphorylation was observed in the muscle of LLC tumor-bearing mice, accompanied by decreased MHC/Myog levels and increased MuRF1/Atrogin-1 levels. Administration of anti-IL-17A monoclonal antibody and AG490 slowed muscle atrophy development. Consistent with the in vivo findings, C2C12 myotubes treated with IL-17A and LLC-conditioned medium demonstrated phosphorylated JAK2/STAT3 signaling, resulting in MHC loss and myotube atrophy. IL-17A also inhibited C2C12 cell proliferation, cell cycle breaking, and cellular senescence. Our results identify that phosphorylation of IL-17A/JAK2/STAT3 signaling pathway appears to be an important component in the pathogenesis of LLC tumor-induced cachexia. Targeted therapy of IL-17A may be a promising approach to reduce skeletal muscle loss in patients with cancer.
恶病质是一种复杂的代谢综合征，约发生于 50%的癌症患者中。骨骼肌萎缩是其主要的临床特征。白细胞介素（IL）-17A 是一种促炎因子，在许多慢性炎症性疾病中发挥着重要作用。在这里，我们描述了一条新的信号通路，通过该通路，IL-17A 可诱导肌肉萎缩。我们进行了一项回顾性临床研究，以探讨肺癌腺癌患者中 IL-17A 与骨骼肌指数之间的关系。我们还通过向 C57BL/6 小鼠注射 Lewis 肺癌（LLC）细胞作为模型来复制癌症引起的恶病质，以研究 JAK2/STAT3 信号通路在恶病质的主要特征中的参与情况。在体外，用重组 IL-17A、抗 IL-17A 单克隆抗体、STAT3 抑制剂 AG490 和 LLC 条件培养基处理 C2C12 肌管。还评估了细胞活力和衰老情况。我们发现，在癌症情况下，血清中 IL-17A 水平的升高与肌肉消耗有关。在 LLC 荷瘤小鼠的肌肉中观察到 JAK2/STAT3 磷酸化，同时 MHC/Myog 水平降低，MuRF1/Atrogin-1 水平升高。给予抗 IL-17A 单克隆抗体和 AG490 可减缓肌肉萎缩的发展。与体内发现一致，用 IL-17A 和 LLC 条件培养基处理的 C2C12 肌管表现出磷酸化的 JAK2/STAT3 信号，导致 MHC 丢失和肌管萎缩。IL-17A 还抑制 C2C12 细胞增殖、细胞周期阻断和细胞衰老。我们的结果表明，IL-17A/JAK2/STAT3 信号通路的磷酸化似乎是 LLC 肿瘤诱导恶病质发病机制中的一个重要组成部分。针对 IL-17A 的靶向治疗可能是减少癌症患者骨骼肌丢失的一种有前途的方法。
