Ma Ningqiang, Pang Hailin, Shen Weiwei, Zhang Feng, Cui Zaoxun, Wang Junyan, Wang Jianlin, Liu Lili, Zhang Helong
Department of Oncology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China.
Department of Nuclear Medicine, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China.
Int J Mol Med. 2015 Feb;35(2):425-32. doi: 10.3892/ijmm.2014.2033. Epub 2014 Dec 10.
Metastasis is the principal cause of morbidity and mortality in cancer patients. The master genes that govern organ-selective metastasis remain elusive. We compared the expression levels of C-X-C chemokine receptor type 4 (CXCR4) in the human small cell lung cancer (SCLC) cells, SBC-5 and SBC-3, by flow cytometric analysis and found that CXCR4 was expressed at markedly higher levels in the SBC-5 cells which can produce multiple organ metastasis, particularly bone metastasis compared to the SBC-3 cells. Stromal-derived-factor-1 (SDF-1)-CXCR4 has been shown to regulate cell migration and metastasis in a various types of cancer; however, the roles of SDF-1-CXCR4 in the organ-selective metastasis of SCLC in vivo remain to be elucidated. Thus, in this study, we constructed a phenotype of SBC-5 cells in which CXCR4 was knocked out using the intrakine strategy and found that the downregulation of CXCR4 inhibited cell migration and invasion, but did not affect cell proliferation or apoptosis in vitro. In in vivo experiments, the knockout of CXCR4 suppressed the development of metastastic lesions in the lungs, liver and bone, but did not decrease metastasis to the kidneys. Our data demonstrate that CXCR4 is a candidate gene involved in the development of metastastic lesions in specific organs, such as the lungs, bone and liver, which can secrete high concentrations of SDF-1, the sole ligand of CXCR4. Thus, CXCR4 may prove to be a promising target for the prevention and effective treatment of metastastic lesions due to SCLC.
转移是癌症患者发病和死亡的主要原因。控制器官选择性转移的主控基因仍不清楚。我们通过流式细胞术分析比较了人小细胞肺癌（SCLC）细胞SBC - 5和SBC - 3中C - X - C趋化因子受体4（CXCR4）的表达水平，发现与SBC - 3细胞相比，CXCR4在能够产生多器官转移尤其是骨转移的SBC - 5细胞中表达水平明显更高。基质衍生因子 - 1（SDF - 1）- CXCR4已被证明在多种类型癌症中调节细胞迁移和转移；然而，SDF - 1 - CXCR4在SCLC体内器官选择性转移中的作用仍有待阐明。因此，在本研究中，我们使用细胞内细胞因子策略构建了CXCR4基因敲除的SBC - 5细胞表型，发现CXCR4的下调抑制了细胞迁移和侵袭，但在体外不影响细胞增殖或凋亡。在体内实验中，CXCR4的敲除抑制了肺、肝和骨中转移灶的发展，但没有减少向肾脏的转移。我们的数据表明，CXCR4是参与特定器官如肺、骨和肝转移灶发展的候选基因，这些器官可分泌高浓度的SDF - 1，即CXCR4的唯一配体。因此，CXCR4可能被证明是预防和有效治疗SCLC所致转移灶的一个有前景的靶点。
