A growth-related oncogene/CXC chemokine receptor 2 autocrine loop contributes to cellular proliferation in esophageal cancer
A growth-related oncogene/CXC chemokine receptor 2 autocrine loop contributes to cellular proliferation in esophageal cancer
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DOI：
10.1158/0008-5472.can-05-2871
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发表时间：
2006-03-15
期刊：
影响因子：
11.2
通讯作者：
Parker, MI
中科院分区：
文献类型：
--
作者：
Wang, B;Hendricks, DT;Parker, MI
生长相关癌基因（GRO）是CXC趋化因子亚家族的一员，在炎症和伤口愈合中起重要作用。已发现CXC趋化因子与肿瘤发生、血管生成和转移有关。虽然GRO在几种人类癌症中表达升高，但GRO及其受体CXCR2在食管癌中的表达和作用尚不清楚。本研究采用实时逆转录- pcr （RT-PCR）和免疫组织化学方法发现GRO α、GRO β和CXCR2在食管肿瘤组织中表达上调。此外，GRO α、GRO β和CXCR2在食管癌细胞系WHCO1中组成性表达，WHCO1被用作模型系统。GRO β通过细胞外信号调节激酶1/2 （ERK1/2）途径增强EGR-1的转录，该途径可被CXCR2的特异性拮抗剂（SB 225002）或GRO β的特异性抗体阻断。经SB 225002处理的WHCO1细胞增殖能力降低40%。通过实时RT-PCR检测，稳定的WHCO1 GRO α RNA干扰（RNAi）克隆显示GRO α mRNA水平降低43%，荧光显微镜检测GRO α水平降低，磷酸化ERK1/2水平降低60%。表达GRO β RNAi的稳定克隆显示GRO β mRNA水平降低了约95%，荧光显微镜下GRO β水平降低，磷酸化ERK1/2水平降低了80%。此外，这些表达GRO α RNAi和GRO β RNAi的克隆分别显示出20%和50%的细胞增殖下降。我们的研究结果表明GRO α - cxcr2和GRO β - cxcr2信号通路在食管癌细胞增殖过程中起着重要作用，这种自分泌信号通路可能参与食管癌的发生。
Growth-related oncogene (GRO), a member of the CXC chemokine subfamily, plays a major role in inflammation and wound healing. CXC chemokines have been found to be associated with tumorigenesis, angiogenesis, and metastasis. Although elevated expression of GRO has been reported in several human cancers, the expression and role of GRO and its receptor, CXCR2, in esophageal cancer are poorly understood. This study used real-time reverse transcription-PCR (RT-PCR) and immunohistochemical approaches to show that GRO alpha, GRO beta, and CXCR2 are up-regulated in esophageal tumor tissue. Furthermore, GRO alpha, GRO beta, and CXCR2 are constitutively expressed in WHCO1, an esophageal cancer cell line that was used as a model system here. GRO beta enhances transcription of EGR-1, via the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, which can be blocked by a specific antagonist of CXCR2 (SB 225002) or specific antibody to GRO beta. WHCO1 cells treated with SB 225002 exhibited a 40% reduction in cell proliferation. A stable WHCO1 GRO alpha RNA interference (RNAi) clone displayed a 43% reduction in GRO alpha mRNA levels as determined by real-time RT-PCR, reduced levels of GRO alpha by fluorescence microscopy, and a 60% reduction in the levels of phosphorylated ERK1/2. A stable clone expressing GRO beta RNAi displayed > 95% reduction in GRO beta mRNA levels, reduced levels of GRO beta by fluorescence microscopy, and an 80% reduction in the levels of phosphorylated ERK1/2. Moreover, these GRO alpha RNAi- and GRO beta RNAi-expressing clones displayed a 20% and 50% decrease in cell proliferation, respectively. Our results suggest that GRO alpha-CXCR2 and GRO beta-CXCR2 signaling contributes significantly to esophageal cancer cell proliferation and that this autocrine signaling pathway may be involved in esophageal tumorigenesis.