IL-6 promotes metastasis of non-small-cell lung cancer by up-regulating TIM-4 via NF-κB
IL-6 promotes metastasis of non-small-cell lung cancer by up-regulating TIM-4 via NF-κB
复制标题
IL-6通过NF-κB上调TIM-4促进非小细胞肺癌转移
DOI：
10.1111/cpr.12776
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发表时间：
2020-02-05
影响因子：
8.5
通讯作者：
Gao, Lifen
中科院分区：
文献类型：
--
作者：
Liu, Wen;Wang, Hongxing;Gao, Lifen
目的白细胞介素-6 （IL-6）在非小细胞肺癌（NSCLC）的发展中起着至关重要的作用。最近，我们发现t细胞免疫球蛋白结构域和粘蛋白结构域4 （TIM-4）在NSCLC进展中是一个新的促生长因子。然而，TIM-4在il -6促进的NSCLC迁移、侵袭和上皮-间质转化（EMT）中的作用尚不清楚。材料与方法采用免疫组化染色法检测非小细胞肺癌组织中TIM-4、IL-6的表达。采用实时荧光定量PCR （Real-time quantitative PCR, qPCR）、Western blot、流式细胞术、RT-PCR检测IL-6刺激下NSCLC细胞中TIM-4的表达。transwell法检测TIM-4在IL-6促进NSCLC迁移和侵袭中的作用。采用体外qPCR和Western blot方法分析emt相关标志物，采用体内肺癌转移小鼠模型评估BALB/c裸鼠的转移情况。结果高IL-6表达可作为非小细胞肺癌组织中TIM-4表达的独立预测因子。TIM-4、IL-6双高表达的NSCLC患者预后最差。IL-6通过nf - κ B信号通路促进TIM-4在NSCLC细胞中的表达。TIM-4和IL-6均能促进NSCLC细胞的迁移、侵袭和EMT。有趣的是，TIM-4敲低逆转了IL-6在NSCLC中的作用，IL-6通过NF-kappa b上调TIM-4促进了NSCLC的转移。结论TIM-4参与了IL-6促进NSCLC的迁移、侵袭和EMT。
Objectives Interleukin-6 (IL-6) is critical for the development of non-small-cell lung cancer (NSCLC). Recently, we identified T-cell immunoglobulin domain and mucin domain 4 (TIM-4) as a new pro-growth player in NSCLC progression. However, the role of TIM-4 in IL-6-promoted NSCLC migration, invasion and epithelial-to-mesenchymal transition (EMT) remains unclear.Materials and Methods Expressions of TIM-4 and IL-6 were both evaluated by immunohistochemical staining in NSCLC tissues. Real-time quantitative PCR (qPCR), Western blot, flow cytometry and RT-PCR were performed to detect TIM-4 expression in NSCLC cells with IL-6 stimulation. The roles of TIM-4 in IL-6 promoting migration and invasion of NSCLC were detected by transwell assay. EMT-related markers were analysed by qPCR and Western blot in vitro, and metastasis was evaluated in BALB/c nude mice using lung cancer metastasis mouse model in vivo.Results High IL-6 expression was identified as an independent predictive factor for TIM-4 expression in NSCLC tissues. NSCLC patients with TIM-4 and IL-6 double high expression showed the worst prognosis. IL-6 promoted TIM-4 expression in NSCLC cells depending on NF-kappa B signal pathway. Both TIM-4 and IL-6 promoted migration, invasion and EMT of NSCLC cells. Interestingly, TIM-4 knockdown reversed the role of IL-6 in NSCLC and IL-6 promoted metastasis of NSCLC by up-regulating TIM-4 via NF-kappa B.Conclusions TIM-4 involves in IL-6 promoted migration, invasion and EMT of NSCLC.