CXCR2 promotes ovarian cancer growth through dysregulated cell cycle, diminished apoptosis, and enhanced angiogenesis.
CXCR2 promotes ovarian cancer growth through dysregulated cell cycle, diminished apoptosis, and enhanced angiogenesis.
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DOI：
10.1158/1078-0432.ccr-10-0483
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发表时间：
2010-08-01
期刊：
影响因子：
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通讯作者：
Liu J
中科院分区：
文献类型：
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作者：
Yang G;Rosen DG;Liu G;Yang F;Guo X;Xiao X;Xue F;Mercado-Uribe I;Huang J;Lin SH;Mills GB;Liu J
趋化因子受体CXCR2在几种癌症模型中与恶性肿瘤相关；然而，cxcr2介导肿瘤生长的机制仍不清楚。在这里，我们研究了CXCR2在人卵巢癌中的作用。稳定的小发夹RNA在卵巢癌细胞系T29Gro-1、T29H和SKOV3中沉默CXCR2的表达。Western blotting、免疫荧光、酶联免疫吸附法、流式细胞术、电泳迁移位移法、小鼠法检测CXCR2、白细胞介素-8、Gro-1、细胞周期、凋亡、NF-κB DNA结合及肿瘤生长情况。对240例高级别浆液性卵巢癌进行CXCR2免疫组化染色。通过小发夹RNA敲除CXCR2表达可减少裸鼠卵巢癌细胞的肿瘤发生。CXCR2通过调节细胞周期调节蛋白，包括p21 （waf1/cip1）、细胞周期蛋白D1、CDK6、CDK4、细胞周期蛋白A和细胞周期蛋白B1，促进细胞周期进程。CXCR2通过抑制p53、Puma和Bcl-xS磷酸化抑制细胞凋亡；抑制聚adp核糖聚合酶裂解；激活Bcl-xL和Bcl-2。CXCR2通过增加血管内皮生长因子水平和降低血小板反应蛋白-1水平来刺激血管生成，这一过程可能涉及丝裂原活化蛋白激酶和NF-κB。在单因素分析中，高级别浆液性卵巢癌中CXCR2过表达是总生存差（P < 0.001）和早期复发（P = 0.003）的独立预后因素。我们的数据提供了强有力的证据，证明CXCR2通过多种信号通路，包括丝裂原活化蛋白激酶和NF-κB，在卵巢癌中调节细胞周期、凋亡和血管生成。因此，CXCR2有潜力作为治疗靶点并用于卵巢癌的诊断和预后。
Chemokine receptor CXCR2 is associated with malignancy in several cancer models; however, the mechanisms involved in CXCR2-mediated tumor growth remain elusive. Here, we investigated the role of CXCR2 in human ovarian cancer. CXCR2 expression was silenced by stable small hairpin RNA in ovarian cancer cell lines T29Gro-1, T29H, and SKOV3. Western blotting, immunofluorescence, enzyme-linked immunosorbent assay, flow cytometry, electrophoretic mobility shift assay, and mouse assay were used to detect CXCR2, interleukin-8, Gro-1, cell cycle, apoptosis, DNA binding of NF-κB, and tumor growth. Immunohistochemical staining of CXCR2 was done in 240 high-grade serous ovarian carcinoma samples. Knockdown of CXCR2 expression by small hairpin RNA reduced tumorigenesis of ovarian cancer cells in nude mice. CXCR2 promoted cell cycle progression by modulating cell cycle regulatory proteins, including p21 (waf1/cip1), cyclin D1, CDK6, CDK4, cyclin A, and cyclin B1. CXCR2 inhibited cellular apoptosis by suppressing phosphorylated p53, Puma, and Bcl-xS; suppressing poly(ADP-ribose) polymerase cleavage; and activating Bcl-xL and Bcl-2. CXCR2 stimulated angiogenesis by increasing levels of vascular endothelial growth factor and decreasing levels of thrombospondin-1, a process likely involving mitogen-activated protein kinase, and NF-κB. Overexpression of CXCR2 in high-grade serous ovarian carcinomas was an independent prognostic factor of poor overall survival (P < 0.001) and of early relapse (P = 0.003) in the univariate analysis. Our data provide strong evidence that CXCR2 regulates the cell cycle, apoptosis, and angiogenesis through multiple signaling pathways, including mitogen-activated protein kinase and NF-κB, in ovarian cancer. CXCR2 thus has potential as a therapeutic target and for use in ovarian cancer diagnosis and prognosis.