Activation of NF-kappaB signaling by inhibitor of NF-kappaB kinase beta increases aggressiveness of ovarian cancer.
Activation of NF-kappaB signaling by inhibitor of NF-kappaB kinase beta increases aggressiveness of ovarian cancer.
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DOI：
10.1158/0008-5472.can-09-3912
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发表时间：
2010-05-15
期刊：
影响因子：
11.2
通讯作者：
Annunziata CM
中科院分区：
文献类型：
--
作者：
Hernandez L;Hsu SC;Davidson B;Birrer MJ;Kohn EC;Annunziata CM
NF-κB家族转录因子与卵巢癌的发生发展有关，但组成性NF-κB信号在卵巢癌中的意义尚不清楚。我们假设组成型NF-κB信号通路定义了一个卵巢癌亚群，该亚群对该通路的治疗靶向敏感。我们用IKKβ的小分子抑制剂研究了NF-κB在卵巢癌中的生物学相关性，并通过针对IKKβ的RNA干扰证实了这一点。我们利用IKKβ的药理学和遗传学操作开发了卵巢癌中IKKβ信号传导的基因表达特征。在独立收集的原发性卵巢癌患者中，IKKβ蛋白自身表达和9基因卵巢癌特异性IKKβ标记与不良预后相关（p=0.02）。卵巢癌中的IKKβ信号调节基因的转录，这些基因参与了广泛的细胞效应，已知这些细胞效应增加了细胞的侵袭性。我们从功能上验证了IKKβ信号对增殖、侵袭和粘附的影响。通过小分子激酶抑制剂或通过IKKβ的shRNA耗竭下调IKKβ活性，阻断了所有这些细胞功能，反映了所鉴定的靶基因的负调控。卵巢癌中由IKKβ控制的功能的多样性表明，如果特异性IKKβ抑制剂治疗集中于肿瘤表达提示依赖IKKβ活性的分子谱的患者，则该途径的治疗阻断可能有效。
The NF-κB family of transcription factors has been implicated in the propagation of ovarian cancer, but the significance of constitutive NF-κB signaling in ovarian cancer is unknown. We hypothesized that constitutive NF-κB signaling defines a subset of ovarian cancer susceptible to therapeutic targeting of this pathway. We investigated the biological relevance of NF-κB in ovarian cancer using a small molecule inhibitor of IKKβ, and confirmed with RNA interference towards IKKβ. We developed a gene expression signature of IKKβ signaling in ovarian cancer using both pharmacologic and genetic manipulation of IKKβ. The expression of IKKβ protein itself and the 9-gene ovarian cancer-specific IKKβ signature were related to poor outcome in independently collected sets of primary ovarian cancers (p=0.02). IKKβ signaling in ovarian cancer regulated the transcription of genes involved in a wide range of cellular effects known to increase the aggressive nature of the cells. We functionally validated the effect of IKKβ signaling on proliferation, invasion and adhesion. Downregulating IKKβ activity, either by a small molecule kinase inhibitor or by shRNA depletion of IKKβ, blocked all of these cellular functions, reflecting the negative regulation of the target genes identified. The diversity of functions controlled by IKKβ in ovarian cancer suggest that therapeutic blockade of this pathway could be efficacious if specific IKKβ inhibitor therapy is focused to patients whose tumors express a molecular profile suggestive of dependence on IKKβ activity.