Yu Yan Xia, Wu Hai Jian, Tan Bing Xu, Qiu Chen, Liu Hui Zhong
Cancer Treatment Research Center, Qilu Hospital of Shandong UniversityNo.107, Wenhua West Road, Jinan, China.
Am J Cancer Res. 2017 Nov 1;7(11):2144-2156. eCollection 2017.
Therapeutic antibodies targeting colony stimulating factor 1 receptor (CSF-1R) to block colony stimulating factor-1/colony stimulating factor 1 receptor (CSF-1/CSF-R) signaling axis have exhibit remarkable efficacy in the treatment of malignant tumor. Yet, little is known about the effects of intrinsic CSF-1R in human non-small-cell carcinoma (NSCLC). Here we demonstrated that NSCLC cell-intrinsic CSF-1R promoted cells growth and metastasis both in vitro and in vivo. CSF-1R knocked-down by transfecting with shRNA target CSF-1R suppressed NSCLC cells proliferation and tumor growth in nude mice. Conversely, ectopic expression of CSF-1R promoted cells proliferation and accelerated tumor growth. Mechanistically, the NSCLC CSF-1R modulated downstream effectors of phosphatidylinositol 3-kinase (PI3K) signaling. In addition, CSF-1R overexpression significantly enhanced NSCLC cells mobility, invasion and epithelial-mesenchymal transition (EMT) process, whereas silencing CSF-1R inhibits these phenotypes. Microarray analysis suggested that Wnt family member 3a (Wnt3a) function as a downstream factor of CSF-1R. On account of this, we future identified CSF-1R/Wnt3a a signaling pathway sustained NSCLC cells metastasis. Finally, in patients, CSF-1R and Wnt3a expression positively correlated with the of NSCLC patients. Our results identify NSCLC cell intrinsic functions of CSF-1R/Wnt3a axis in dissemination of NSCLC.
靶向集落刺激因子1受体（CSF-1R）以阻断集落刺激因子-1/集落刺激因子1受体（CSF-1/CSF-R）信号轴的治疗性抗体在恶性肿瘤治疗中已显示出显著疗效。然而，关于内源性CSF-1R在人类非小细胞肺癌（NSCLC）中的作用知之甚少。在此，我们证明NSCLC细胞内源性CSF-1R在体外和体内均促进细胞生长和转移。通过转染靶向CSF-1R的短发夹RNA（shRNA）敲低CSF-1R可抑制NSCLC细胞增殖和裸鼠体内肿瘤生长。相反，CSF-1R的异位表达促进细胞增殖并加速肿瘤生长。机制上，NSCLC的CSF-1R调节磷脂酰肌醇3-激酶（PI3K）信号的下游效应器。此外，CSF-1R的过表达显著增强NSCLC细胞迁移、侵袭和上皮-间质转化（EMT）过程，而沉默CSF-1R则抑制这些表型。基因芯片分析表明，Wnt家族成员3a（Wnt3a）作为CSF-1R的下游因子发挥作用。基于此，我们进一步确定CSF-1R/Wnt3a是维持NSCLC细胞转移的信号通路。最后，在患者中，CSF-1R和Wnt3a的表达与NSCLC患者的[此处原文缺失相关内容]呈正相关。我们的结果确定了NSCLC细胞内CSF-1R/Wnt3a轴在NSCLC扩散中的功能。
