CXCL5 induces tumor angiogenesis via enhancing the expression of FOXD1 mediated by the AKT/NF-κB pathway in colorectal cancer
CXCL5 induces tumor angiogenesis via enhancing the expression of FOXD1 mediated by the AKT/NF-κB pathway in colorectal cancer
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CXCL5 通过增强结直肠癌中 AKT/NF-kappa B 通路介导的 FOXD1 表达来诱导肿瘤血管生成
DOI：
10.1038/s41419-019-1431-6
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发表时间：
2019-02-21
影响因子：
9
通讯作者：
Lu, Ai-Guo
中科院分区：
文献类型：
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作者：
Chen, Chun;Xu, Zhuo-Qing;Lu, Ai-Guo
CXCL5在肿瘤血管生成中的作用机制尚未完全确定。在这里，我们研究了CXCL5对结直肠癌（CRC）肿瘤血管生成的影响。免疫组化法检测结直肠癌组织中CXCL5和CD31的表达。在体外研究中使用用shCXCR 2和shFOXD 1慢病毒质粒稳定转染的HUVEC细胞系。通过体内外分子生物学实验，我们发现CXCL 5在肿瘤组织中表达上调，且其水平与CD 31的表达呈正相关。接下来，我们使用重组人CXCL5（rhCXCL5）刺激HUVECs，发现它们的管形成能力，增殖和迁移通过激活AKT/NF-κ B/FOXD 1/VEGF-A途径以CXCR 2依赖的方式增强。然而，CXCR 2和FOXD 1的沉默或AKT和NF-κ B B途径的抑制可以减弱rhCXCL 5刺激的HUVECs在体外的管形成能力，增殖和迁移。rhCXCL5可以促进Matrigel栓塞中的体内血管生成，并且CXCL5的过表达也可以增加裸鼠皮下异种移植瘤模型中的体内微血管密度。总之，我们的研究结果支持CXCL5作为一种血管生成因子，可以通过肿瘤血管生成促进CRC中的细胞转移。此外，我们提出FOXD 1是VEGF-A的一种新的调节剂。这些观察结果为CXCL5在肿瘤抗血管生成中的治疗应用开辟了新的途径。
The mechanisms underlying the role of CXCL5 in tumor angiogenesis have not been fully defined. Here, we examined the effect of CXCL5 on tumor angiogenesis in colorectal cancer (CRC). Immunohistochemistry was used to monitor the expression of CXCL5 and CD31 in CRC patients' tissues. HUVEC cell lines stably transfected with shCXCR2 and shFOXD1 lentivirus plasmids were used in an in vitro study. Based on some molecular biological experiments in vitro and in vivo, we found that CXCL5 was upregulated in tumor tissues and that its level positively correlated with the expression of CD31. Next, we used recombinant human CXCL5 (rhCXCL5) to stimulate HUVECs and found that their tube formation ability, proliferation, and migration were enhanced by the activation of the AKT/NF-kappa B/FOXD1/VEGF-A pathway in a CXCR2-dependent manner. However, silencing of CXCR2 and FOXD1 or inhibition of the AKT and NF-kappa B pathways could attenuate the tube formation ability, proliferation, and migration of rhCXCL5-stimulated HUVECs in vitro. rhCXCL5 can promote angiogenesis in vivo in Matrigel plugs, and the overexpression of CXCL5 can also increase microvessel density in vivo in a subcutaneous xenotransplanted tumor model in nude mice. Taken together, our findings support CXCL5 as an angiogenic factor that can promote cell metastasis through tumor angiogenesis in CRC. Furthermore, we propose that FOXD1 is a novel regulator of VEGF-A. These observations open new avenues for therapeutic application of CXCL5 in tumor anti-angiogenesis.