Cai Qing-Yong, Liang Gui-You, Zheng Yi-Feng, Tan Qun-You, Wang Ru-Wen, Li Kun
Affiliated Hospital of Zunyi Medical College, Department of Thoracic and Cardiovascular SurgeryNo. 149, Dalian Road, Zunyi, Guizhou 563003, China.
Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Third Military Medical UniversityNo. 10, Otsubo Yangtze River Branch, Yuzhong District, Chongqing 400042, China.
Am J Transl Res. 2017 Jul 15;9(7):3282-3292. eCollection 2017.
High levels of angiogenesis are associated with poor prognosis and a highly invasive phenotype in esophageal squamous carcinoma. C-C chemokine receptor type 7 (CCR7) is overexpressed in multiple tumor types and has been suggested to act as an oncogene and pro-angiogenic factor. This study aimed to elucidate the effect of CCR7 on the angiogenic capacity of esophageal squamous carcinoma cells in vitro. Expression of CCR7 in esophageal squamous carcinoma cell lines and normal human esophageal epithelial cell line was examined by western blotting and quantitative real-time PCR. CCR7 was stably overexpressed or transiently knocked down in esophageal squamous carcinoma cell lines. Overexpressing CCR7 enhanced the capacity of esophageal squamous carcinoma cell conditioned media to induce human umbilical vein endothelial cells (HUVEC) proliferation and migration and neovascularization in the chicken chorioallantoic membrane (CAM) assay. While silencing CCR7 caused an opposite outcome. Moreover, we demonstrated that CCR7 activated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and regulated its targets, including vascular endothelial growth factor A (VEGF-A), VEGF-C, tumor necrosis factor-α (TNFα), interleukin (IL)-6, IL-8 and transforming growth factor-β (TGF-β) expression. Additionally, CCR7 down-regulation reduced tumor volume and weight in xenograft mouse model, and significantly decreased NF-κB signaling pathway. This study suggests that CCR7 plays an important pro-angiogenic role in esophageal squamous carcinoma via a mechanism linked to activation of the NF-κB pathway; CCR7 may represent a potential target for anti-angiogenic therapy in esophageal squamous carcinoma.
在食管鳞状细胞癌中，高水平的血管生成与预后不良和高度侵袭性表型相关。C-C趋化因子受体7（CCR7）在多种肿瘤类型中过表达，并被认为是一种癌基因和促血管生成因子。本研究旨在阐明CCR7对食管鳞状癌细胞体外血管生成能力的影响。通过蛋白质免疫印迹法和定量实时PCR检测CCR7在食管鳞状癌细胞系和正常人食管上皮细胞系中的表达。在食管鳞状癌细胞系中稳定过表达或瞬时敲低CCR7。过表达CCR7增强了食管鳞状癌细胞条件培养基诱导人脐静脉内皮细胞（HUVEC）增殖、迁移的能力，以及在鸡胚绒毛尿囊膜（CAM）试验中的新血管形成能力。而沉默CCR7则产生相反的结果。此外，我们证明CCR7激活了活化B细胞核因子κB（NF-κB）信号通路，并调节其靶标，包括血管内皮生长因子A（VEGF-A）、VEGF-C、肿瘤坏死因子-α（TNFα）、白细胞介素（IL）-6、IL-8和转化生长因子-β（TGF-β）的表达。此外，在异种移植小鼠模型中，CCR7下调减少了肿瘤体积和重量，并显著降低了NF-κB信号通路。本研究表明，CCR7通过与NF-κB通路激活相关的机制在食管鳞状细胞癌中发挥重要的促血管生成作用；CCR7可能是食管鳞状细胞癌抗血管生成治疗的潜在靶点。
