Zhao Meng, Liu Yahui, Liu Ran, Qi Jin, Hou Yongwang, Chang Jiao, Ren Li
Department of Clinical Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, National Human Genetic Resources Sharing Service Platform, Tianjin, China.
Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Cell Physiol Biochem. 2018;45(6):2213-2224. doi: 10.1159/000488166. Epub 2018 Mar 10.
BACKGROUND/AIMS: Cytokines are key players in tumorigenesis and are potential targets in cancer treatment. Although IL-6 has attracted considerable attention, interleukin 11 (IL-11), another member of the IL-6 family, has long been overlooked, and little is known regarding its specific function in non-small cell lung cancer (NSCLC). In this study, we explored IL-11's role in NSCLC and the detailed mechanism behind it.
Cell proliferation in response to IL-11 was determined by colony formation, BrdU incorporation and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. Cell motility was measured by Transwell and wound healing assays. NSCLC xenograft models were used to confirm oncogenic function of IL-11 in vivo. Immunohistochemical staining and western blot assay were performed to detect epithelial-mesenchymal transition (EMT) markers and cell signaling pathway alterations. Eighteen NSCLC patients and 5 normal lung samples were collected together with data from an online database to determine the link between IL-11 expression and malignant progression.
We observed that IL-11 was upregulated in NSCLC samples compared with normal tissue samples and correlated with poor prognosis. Data from in vitro and in vivo models indicated that IL-11 promotes cell proliferation and tumorigenesis. Cell migration and invasion were also enhanced by IL-11. Epithelial-mesenchymal transition (EMT) was also observed after IL-11 incubation. Furthermore, IL-11 activated AKT and STAT3 in our experimental models. In addition, we observed that hypoxia induced IL-11 expression in NSCLC cells. Deferoxamine (DFX) or dimethyloxalylglycine (DMOG) induced hypoxia-inducible factor 1-alpha (HIF1α) upregulation, which enhanced IL-11 expression in NSCLC cells.
Taken together, our results indicate that IL-11 is an oncogene in NSCLC, and elucidating the mechanism behind it may provide insights for NSCLC treatment.
背景/目的：细胞因子是肿瘤发生的关键因素，也是癌症治疗的潜在靶点。尽管白细胞介素6（IL-6）已引起广泛关注，但白细胞介素11（IL-11），作为IL-6家族的另一个成员，长期以来一直被忽视，其在非小细胞肺癌（NSCLC）中的具体功能鲜为人知。在本研究中，我们探讨了IL-11在NSCLC中的作用及其背后的详细机制。
通过集落形成、BrdU掺入和MTS（3-(4,5-二甲基噻唑-2-基)-5-(3-羧甲氧基苯基)-2-(4-磺基苯基)-2H-四唑）试验来测定细胞对IL-11的增殖反应。通过Transwell和伤口愈合试验来测量细胞迁移能力。使用NSCLC异种移植模型在体内证实IL-11的致癌功能。进行免疫组织化学染色和蛋白质印迹试验以检测上皮-间质转化（EMT）标志物和细胞信号通路改变。收集18例NSCLC患者和5例正常肺组织样本以及来自在线数据库的数据，以确定IL-11表达与恶性进展之间的联系。
我们观察到，与正常组织样本相比，NSCLC样本中IL-11表达上调，且与预后不良相关。体外和体内模型的数据表明，IL-11促进细胞增殖和肿瘤发生。IL-11还增强了细胞迁移和侵袭能力。IL-11处理后还观察到上皮-间质转化（EMT）。此外，在我们的实验模型中，IL-11激活了AKT和STAT3。另外，我们观察到缺氧诱导NSCLC细胞中IL-11表达。去铁胺（DFX）或二甲基乙二酰甘氨酸（DMOG）诱导缺氧诱导因子1-α（HIF1α）上调，增强了NSCLC细胞中IL-11的表达。
综上所述，我们的结果表明IL-11是NSCLC中的一种癌基因，阐明其背后的机制可能为NSCLC治疗提供思路。
