Han Lin, Liang Xiao-Hua, Chen Li-Xin, Bao Shi-Min, Yan Zhi-Qiang
The Experimental Animal Center, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences Shanghai, China.
Int J Clin Exp Pathol. 2013 Oct 15;6(11):2357-65. eCollection 2013.
Brain metastases are a frequent and ongoing major complication of non-small cell lung cancer (NSCLC). To deepen our understanding to the underlying mechanisms by which NSCLC cells metastasize to brain and hence to improve the therapy, a high throughput RNAi screening with shRNA library of 153 epigenetic genes was subjected to A549, a NSCLC cell line with high migration ability, to examine the effects of these genes on cell migration by wound-healing assay. The screening results showed that knockdown of 2 genes (KDM5B and SIRT1) dramatically and specifically inhibits A549 migration but not affects the proliferation, which was subsequently confirmed through transwell migration assay. Furthermore, SIRT1 is found to be highly expressed in brain metastasis tissues of NSCLC, compared to the NSCLC tissues, suggesting that SIRT1 may play roles in brain metastasis of NSCLC. The relationship between SIRT1 expression and cell migration ability was further investigated in three NSCLC cell lines and the result indicated that SIRT1 expression is tightly correlated with cell migration ability. Collectively, our work provides potential biomarker and therapeutic target for brain metastasis of NSCLC.
脑转移是非小细胞肺癌（NSCLC）常见且持续存在的主要并发症。为了深入了解NSCLC细胞转移至脑的潜在机制从而改善治疗方法，我们使用包含153个表观遗传基因的shRNA文库对具有高迁移能力的NSCLC细胞系A549进行了高通量RNA干扰筛选，通过伤口愈合试验检测这些基因对细胞迁移的影响。筛选结果显示，敲低2个基因（KDM5B和SIRT1）可显著且特异性地抑制A549细胞迁移，但不影响其增殖，随后通过Transwell迁移试验得以证实。此外，与NSCLC组织相比，SIRT1在NSCLC脑转移组织中高表达，提示SIRT1可能在NSCLC脑转移中发挥作用。我们在三种NSCLC细胞系中进一步研究了SIRT1表达与细胞迁移能力之间的关系，结果表明SIRT1表达与细胞迁移能力密切相关。总体而言，我们的研究为NSCLC脑转移提供了潜在的生物标志物和治疗靶点。
