Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan City, Taiwan.
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan City, Taiwan.
J Cachexia Sarcopenia Muscle. 2022 Apr;13(2):1314-1328. doi: 10.1002/jcsm.12943. Epub 2022 Feb 15.
Interferon-induced protein with tetratricopeptide repeat 2 (IFIT2) is a reported metastasis suppressor in oral squamous cell carcinoma (OSCC). Metastases and cachexia may coexist. The effect of cancer metastasis on cancer cachexia is largely unknown. We aimed to address this gap in knowledge by characterizing the cachectic phenotype of an IFIT2-depleted metastatic OSCC mouse model.
Genetically engineered and xenograft tumour models were used to explore the effect of IFIT2-depleted metastatic OSCC on cancer cachexia. Muscle and organ weight changes, tumour burden, inflammatory cytokine profiles, body composition, food intake, serum albumin and C-reactive protein (CRP) levels, and survival were assessed. The activation of the IL6/p38 pathway in atrophied muscle was measured.
IFIT2-depleted metastatic tumours caused marked body weight loss (-18.2% vs. initial body weight, P < 0.001) and a poor survival rate (P < 0.01). Skeletal muscles were markedly smaller in IFIT2-depleted metastatic tumour-bearing mice (quadriceps: -28.7%, gastrocnemius: -29.4%, and tibialis: -24.3%, all P < 0.001). Tumour-derived circulating granulocyte-macrophage colony-stimulating factor (+772.2-fold, P < 0.05), GROα (+1283.7-fold, P < 0.05), IL6 (+245.8-fold, P < 0.001), IL8 (+616.9-fold, P < 0.001), IL18 (+24-fold, P < 0.05), IP10 (+18.8-fold, P < 0.001), CCL2 (+439.2-fold, P < 0.001), CCL22 (+9.1-fold, P < 0.01) and tumour necrosis factor α (+196.8-fold, P < 0.05) were elevated in IFIT2-depleted metastatic tumour-bearing mice. Murine granulocyte colony-stimulating factor (+61.4-fold, P < 0.001) and IL6 (+110.9-fold, P < 0.01) levels were significantly increased in IFIT2-depleted metastatic tumour-bearing mice. Serum CRP level (+82.1%, P < 0.05) was significantly increased in cachectic shIFIT2 mice. Serum albumin level (-26.7%, P < 0.01) was significantly decreased in cachectic shIFIT2 mice. An assessment of body composition revealed decreased fat (-81%, P < 0.001) and lean tissue (-21.7%, P < 0.01), which was consistent with the reduced food intake (-19.3%, P < 0.05). Muscle loss was accompanied by a smaller muscle cross-sectional area (-23.3%, P < 0.05). Muscle atrophy of cachectic IFIT2-depleted metastatic tumour-bearing mice (i.v.-shIFIT2 group) was associated with elevated IL6 (+2.7-fold, P < 0.05), phospho-p38 (+2.8-fold, P < 0.05), and atrogin-1 levels (+2.3-fold, P < 0.05) in the skeletal muscle. Neutralization of IL6 rescued shIFIT2 conditioned medium-induced myotube atrophy (+24.6%, P < 0.01).
Our results suggest that the development of shIFIT2 metastatic OSCC lesions promotes IL6 production and is accompanied by the loss of fat and lean tissue, anorexia, and muscle atrophy. This model is appropriate for the study of OSCC cachexia, especially in linking metastasis with cachexia.
干扰素诱导蛋白具有四肽重复结构域 2（IFIT2）是口腔鳞状细胞癌（OSCC）中报道的转移抑制因子。转移和恶病质可能同时存在。癌症转移对癌症恶病质的影响在很大程度上尚不清楚。我们旨在通过描述 IFIT2 耗尽的转移性 OSCC 小鼠模型的恶病质表型来填补这一知识空白。
使用基因工程和异种移植肿瘤模型来研究 IFIT2 耗尽的转移性 OSCC 对癌症恶病质的影响。评估肌肉和器官重量变化、肿瘤负担、炎症细胞因子谱、身体成分、食物摄入、血清白蛋白和 C 反应蛋白（CRP）水平以及存活情况。测量萎缩肌肉中 IL6/p38 通路的激活情况。
IFIT2 耗尽的转移性肿瘤导致体重明显下降（与初始体重相比，-18.2%，P < 0.001）和存活率降低（P < 0.01）。IFIT2 耗尽的转移性肿瘤荷瘤小鼠的骨骼肌明显变小（股四头肌：-28.7%，比目鱼肌：-29.4%，胫骨前肌：-24.3%，均 P < 0.001）。肿瘤衍生的循环粒细胞-巨噬细胞集落刺激因子（+772.2 倍，P < 0.05）、GROα（+1283.7 倍，P < 0.05）、IL6（+245.8 倍，P < 0.001）、IL8（+616.9 倍，P < 0.001）、IL18（+24 倍，P < 0.05）、IP10（+18.8 倍，P < 0.001）、CCL2（+439.2 倍，P < 0.001）、CCL22（+9.1 倍，P < 0.01）和肿瘤坏死因子α（+196.8 倍，P < 0.05）在 IFIT2 耗尽的转移性肿瘤荷瘤小鼠中升高。IFIT2 耗尽的转移性肿瘤荷瘤小鼠的鼠粒细胞集落刺激因子（+61.4 倍，P < 0.001）和 IL6（+110.9 倍，P < 0.01）水平显著增加。IFIT2 耗尽的转移性肿瘤荷瘤小鼠的血清 CRP 水平（+82.1%，P < 0.05）显著升高。血清白蛋白水平（-26.7%，P < 0.01）在恶病质 shIFIT2 小鼠中显著降低。身体成分评估显示，脂肪减少（-81%，P < 0.001）和瘦组织减少（-21.7%，P < 0.01），这与减少的食物摄入（-19.3%，P < 0.05）一致。肌肉减少伴有肌肉横截面积减小（-23.3%，P < 0.05）。IFIT2 耗尽的转移性肿瘤荷瘤小鼠（静脉注射-shIFIT2 组）的肌肉萎缩与 IL6（+2.7 倍，P < 0.05）、磷酸化 p38（+2.8 倍，P < 0.05）和 atrogin-1 水平（+2.3 倍，P < 0.05）升高有关。IL6 的中和挽救了 shIFIT2 条件培养基诱导的肌管萎缩（+24.6%，P < 0.01）。
我们的结果表明，shIFIT2 转移性 OSCC 病变的发展促进了 IL6 的产生，并伴有脂肪和瘦组织、厌食和肌肉萎缩的丢失。该模型适合研究 OSCC 恶病质，特别是在将转移与恶病质联系起来。
