Expression of CXCR4 and its down-regulation by IFN-γ in head and neck squamous cell carcinoma
Expression of CXCR4 and its down-regulation by IFN-γ in head and neck squamous cell carcinoma
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DOI：
10.1158/1078-0432.ccr-04-1470
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发表时间：
2005-04-15
影响因子：
11.5
通讯作者：
Harabuchi, Y
中科院分区：
文献类型：
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作者：
Katayama, A;Ogino, T;Harabuchi, Y
目的：CXCR4通过其独特的配体基质细胞衍生因子-1 （SDF-1）参与细胞迁移和增殖，其功能性表达已在多种肿瘤中被报道。然而，CXCR4的表达及其在头颈部鳞状细胞癌（HNSCC）中的功能作用尚不清楚。在本研究中，我们研究了CXCR4在HNSCC细胞系中的表达并分析了其功能。我们还尝试使用细胞因子，如白细胞介素-1、肿瘤坏死因子- α和ifn - γ来调节CXCR4的表达。最后，我们研究了CXCR4表达与HNSCC患者临床特征的相关性。实验设计：本研究采用6株HNSCC细胞系。逆转录pcr和流式细胞术分析显示CXCR4在细胞因子刺激或不刺激下的表达。在matrigel包被的趋化室中检测sdf -1介导的细胞迁移。采用3-（4,5-二甲基噻唑-2-基）2，E -二苯基溴化四唑试验分析sdf -1介导的细胞增殖。Western blot分析sdf -1介导的信号通路。对56例HNSCC患者的活检标本进行免疫组织学分析。结果：CXCR4在HSQ-89、IMC-3和Nakamura细胞中表达显著。在cxcr4阳性细胞中观察到sdf -1介导的细胞迁移和增殖。在cxcr4阳性细胞中，SDF-1还促进细胞外信号调节激酶1/2和Akt信号通路的快速磷酸化。CXCR4中和可抑制sdf -1介导的细胞迁移和CXCR4阳性细胞的增殖。在测试的三种细胞因子中，ifn - γ显著降低CXCR4的表达和sdf -1诱导的CXCR4阳性细胞的细胞迁移和增殖。免疫组织学分析显示，晚期颈部病变患者和远处转移患者的CXCR4表达明显升高，且CXCR4表达患者的病因特异性生存期明显缩短。此外，多因素分析证实CXCR4阳性是病因特异性死亡的独立因素。结论：我们的研究结果可能为未来通过下调CXCR4表达抑制HNSCC患者肿瘤转移和进展的治疗药物提供新的思路。
Purpose: The functional expression of CXCR4, which plays roles in cell migration and proliferation in response to its unique ligand stromal cell - derived factor-1 (SDF-1), has been reported in variety of carcinomas. However, CXCR4 expression and its functional role in head and neck squamous cell carcinomas (HNSCC) remain unclear. In this study, we investigated CXCR4 expression and analyzed its functions in HNSCC cell lines. We also attempted to regulate CXCR4 expression using cytokines, such as interleukin-1, tumor necrosis factor-alpha, and IFN-gamma. Finally, we investigated correlation between CXCR4 expression and clinical features in patients with HNSCC.Experimental Design: Six HNSCC cell lines were used in this study. Reverse transcription-PCR and flow cytometry analysis were shown for CXCR4 expressions with or without stimulations of cytokines. SDF-1-mediated cell migration was assayed in Matrigel-coated chemotaxis chamber. The SDF-1-mediated cell proliferation was analyzed by 3- (4,5-dimethylthiazol-2-yl) 2,E -diphenyltetrazolium bromide assay. The SDF-1-mediated signaling pathways were analyzed by Western blot analysis. Biopsy specimens from 56 patients with HNSCC were used for immunohistologic analysis.Results: The significant CXCR4 expression was found in HSQ-89, IMC-3, and Nakamura cells. The SDF-1-mediated cell migration and proliferation were observed in CXCR4-positive cells. SDF-1 also promoted rapid phosphorylation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways in CXCR4-positive cells. The SDF-1-mediated cell migration and proliferation of CXCR4-positive cells were inhibited by neutralization of CXCR4. Among three cytokines tested, IFN-gamma significantly reduced CXCR4 expression and SDF-1-induced cell migration and proliferation of CXCR4-positive cells. Immunohistologic analysis revealed that patients with advanced neck status and patients who developed distant metastases showed significantly higher CXCR4 expression, and the cause-specific survival of patients with CXCR4-expression was significantly shorter. Furthermore, multivariate analysis confirmed that CXCR4 positive was the independent factor for cause-specific death.Conclusion: Our results may provide an insight into future therapeutic agent that inhibits tumor metastasis and progression via down-regulating CXCR4 expression in patients with HNSCC.