Targeted Knockdown of EGR-1 Inhibits IL-8 Production and IL-8-mediated Invasion of Prostate Cancer Cells through Suppressing EGR-1/NF-κB Synergy
Targeted Knockdown of EGR-1 Inhibits IL-8 Production and IL-8-mediated Invasion of Prostate Cancer Cells through Suppressing EGR-1/NF-κB Synergy
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DOI：
10.1074/jbc.m109.016246
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发表时间：
2009-12-11
影响因子：
4.8
通讯作者：
Xiao, Weihua
中科院分区：
文献类型：
--
作者：
Ma, Jiajia;Ren, Zijia;Xiao, Weihua
前列腺癌细胞产生的IL-8可能是晚期前列腺癌雄激素非依赖性生长的原因。来自微阵列分析和动物遗传模型的累积证据突出了转录因子早期生长反应-1（EGR-1）在前列腺癌进展中的中心参与。然而，敲低EGR-1是否抑制IL-8产生和IL-8介导的肿瘤转移尚不清楚。在这里，我们表明，EGR-1敲低由一个特定的shRNA-Egr 1抑制基因转录和IL-8的生产的人前列腺癌细胞系DU 145。相反，在EGR-1缺乏的PC 3前列腺癌细胞中EGR-1的强制表达显著增强IL-8的转录和分泌。通过使用野生型和一系列突变型IL-8启动子荧光素酶构建体，我们发现NF-κ B结合位点对于EGR-1调节IL-8是重要的。此外，沉默EGR-1抑制了EGR-1和NF-κ B之间的协同功能相互作用。因此，敲低EGR-1抑制IL-8介导的肿瘤集落形成和侵袭。因此，靶向敲低EGR-1可能是一种有效的治疗前列腺癌的方法。
IL-8 produced by prostate cancer cells may be responsible for the androgen-independent growth of advanced prostate cancers. Accumulating evidence from microarray analyses and animal genetic models highlights the central involvement of the transcription factor early growth response-1 (EGR-1) in prostate carcinoma progression. It is unknown, however, whether knockdown of EGR-1 inhibits IL-8 production and IL-8-mediated tumor metastasis. Here we show that EGR-1 knockdown by a specific shRNA-Egr1 inhibited gene transcription and production of IL-8 by the human prostate cancer cell line DU145. Conversely, enforced expression of EGR-1 in EGR-1-lacking PC3 prostate cancer cells markedly enhanced IL-8 transcription and secretion. By using wild type and a series of mutant IL-8 promoter luciferase constructs, we found that the NF-kappa B binding site is important for EGR-1 regulation of IL-8. Furthermore, silencing EGR-1 suppressed a synergistically functional interaction between EGR-1 and NF-kappa B. Consequently, knockdown of EGR-1 inhibited IL-8-mediated tumor colony formation and invasion. Thus, targeted knockdown of EGR-1 could be an effective therapeutic approach against prostate cancer.