CXCL1 promotes tumor growth through VEGF pathway activation and is associated with inferior survival in gastric cancer.
CXCL1 promotes tumor growth through VEGF pathway activation and is associated with inferior survival in gastric cancer.
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DOI：
10.1016/j.canlet.2015.01.033
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发表时间：
2015-04
期刊：
影响因子：
9.7
通讯作者：
Zhe-wei Wei;Guanggai Xia;Ying Wu;Wei Chen;Zhen Xiang;R. Schwarz;R. Brekken;N. Awasthi;Yu-Long He;Chang-hua Zhang
中科院分区：
文献类型：
--
作者：
Zhe-wei Wei;Guanggai Xia;Ying Wu;Wei Chen;Zhen Xiang;R. Schwarz;R. Brekken;N. Awasthi;Yu-Long He;Chang-hua Zhang
趋化因子（C-X-C 基序）配体 1 (CXCL1) 调节肿瘤-间质相互作用和肿瘤侵袭。然而，CXCL1 对胃肿瘤生长和患者生存的确切作用仍不清楚。在本研究中，通过免疫组织化学（IHC）检测了98例胃癌患者原发肿瘤组织中CXCL1、血管内皮生长因子（VEGF）和磷酸信号转导器和转录激活因子3（p-STAT3）的蛋白表达。使用Lipofectamine 2000试剂或慢病毒载体构建CXCL1过表达细胞系。体外和体内评估了 CXCL1 对 VEGF 表达和局部肿瘤生长的影响。 CXCL1 在 41.4% 的患者中呈阳性表达，并与 VEGF 和 p-STAT3 表达相关。较高的CXCL1表达与晚期肿瘤分期和较差的预后相关。AGS和SGC-7901细胞的体外研究表明，CXCL1增加细胞迁移，但对细胞增殖影响不大。 CXCL1 激活胃癌 (GC) 细胞中的 VEGF 信号传导，该信号传导可通过 STAT3 或趋化因子（C-X-C 基序）受体 2 (CXCR2) 阻断来抑制。 CXCL1 还增加了 GC 细胞中 p-STAT3 的表达。在体内，CXCL1 增加了异种移植局部肿瘤的生长、磷酸 Janus 激酶 2 (p-JAK2)、p-STAT3 水平、VEGF 表达和微血管密度。这些结果表明，CXCL1 通过激活 VEGF 信号传导增加局部肿瘤生长，这可能对观察到的较差的 GC 存活率具有机制影响。 CXCL1/CXCR2 通路可能有效改善胃癌的抗血管生成治疗。
The chemokine (C-X-C motif) ligand 1 (CXCL1) regulates tumor–stromal interactions and tumor invasion. However, the precise role of CXCL1 on gastric tumor growth and patient survival remains unclear. In the current study, protein expressions of CXCL1, vascular endothelial growth factor (VEGF) and phospho-signal transducer and activator of transcription 3 (p-STAT3) in primary tumor tissues from 98 gastric cancer patients were measured by immunohistochemistry (IHC). CXCL1 overexpressed cell lines were constructed using Lipofectamine 2000 reagent or lentiviral vectors. Effects of CXCL1 on VEGF expression and local tumor growth were evaluatedin vitroandin vivo. CXCL1 was positively expressed in 41.4% of patients and correlated with VEGF and p-STAT3 expression. Higher CXCL1 expression was associated with advanced tumor stage and poorer prognosis.In vitrostudies in AGS and SGC-7901 cells revealed that CXCL1 increased cell migration but had little effect on cell proliferation. CXCL1 activated VEGF signaling in gastric cancer (GC) cells, which was inhibited by STAT3 or chemokine (C-X-C motif) receptor 2 (CXCR2) blockade. CXCL1 also increased p-STAT3 expression in GC cells.In vivo, CXCL1 increased xenograft local tumor growth, phospho-Janus kinase 2 (p-JAK2), p-STAT3 levels, VEGF expression and microvessel density. These results suggested that CXCL1 increased local tumor growth through activation of VEGF signaling which may have mechanistic implications for the observed inferior GC survival. The CXCL1/CXCR2 pathway might be potent to improve anti-angiogenic therapy for gastric cancer.