Miyazaki Hiroshi, Patel Vyomesh, Wang Huixin, Edmunds Ryan K, Gutkind J Silvio, Yeudall W Andrew
Philips Institute, Virginia Commonwealth University, Richmond, Virginia 23298-0566, USA.
Cancer Res. 2006 Apr 15;66(8):4279-84. doi: 10.1158/0008-5472.CAN-05-4398.
We report a novel role for the CXC-chemokine, CXCL5, in the proliferation and invasion of head and neck squamous cell carcinoma (HNSCC). Previously, we reported transcriptional up-regulation of CXCL5 in metastatic cells. In this study, we provide biological validation of these findings and show that CXCL5 is intimately involved in tumor cell proliferation, migration, and invasion. Cells derived from a lymph node metastasis, but not from a synchronous primary tumor, secreted CXCL5 as judged by Western blotting of conditioned media. We used RNA interference to generate cell lines (shL5) in which CXCL5 expression was greatly reduced, and tested whether this modulated the cell phenotype. shL5 cells showed decreased proliferation compared with cells harboring nontargeting control sequences. In addition, we found that the ability of shL5 cells to migrate and invade in vitro through a basement membrane substitute was greatly impaired compared with control cells. Finally, whereas control cells were highly tumorigenic in nude mice, the tumorigenic potential in vivo of shL5 cells was found to be ablated. Taken together, these data suggest that CXCL5 production contributes to both enhanced proliferation and invasion of squamous cell carcinomas and that targeting of chemokine pathways may represent a potential therapeutic modality for these lesions.
我们报告了CXC趋化因子CXCL5在头颈部鳞状细胞癌（HNSCC）增殖和侵袭中的新作用。此前，我们报道了CXCL5在转移细胞中的转录上调。在本研究中，我们对这些发现进行了生物学验证，并表明CXCL5密切参与肿瘤细胞的增殖、迁移和侵袭。通过对条件培养基进行蛋白质印迹分析判断，源自淋巴结转移灶而非同步原发性肿瘤的细胞分泌CXCL5。我们使用RNA干扰生成了CXCL5表达大幅降低的细胞系（shL5），并测试了这是否会调节细胞表型。与携带非靶向对照序列的细胞相比，shL5细胞的增殖能力下降。此外，我们发现与对照细胞相比，shL5细胞在体外通过基底膜替代物迁移和侵袭的能力受到极大损害。最后，虽然对照细胞在裸鼠中具有高度致瘤性，但发现shL5细胞在体内的致瘤潜力被消除。综上所述，这些数据表明CXCL5的产生有助于鳞状细胞癌的增殖和侵袭增强，并且靶向趋化因子途径可能是这些病变的一种潜在治疗方式。
