CK2 modulation of NF-kappaB, TP53, and the malignant phenotype in head and neck cancer by anti-CK2 oligonucleotides in vitro or in vivo via sub-50-nm nanocapsules.
CK2 modulation of NF-kappaB, TP53, and the malignant phenotype in head and neck cancer by anti-CK2 oligonucleotides in vitro or in vivo via sub-50-nm nanocapsules.
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DOI：
10.1158/1078-0432.ccr-09-3200
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发表时间：
2010-04-15
期刊：
影响因子：
--
通讯作者：
Chen Z
中科院分区：
文献类型：
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作者：
Brown MS;Diallo OT;Hu M;Ehsanian R;Yang X;Arun P;Lu H;Korman V;Unger G;Ahmed K;Van Waes C;Chen Z
目的：探讨CK2亚基在体外和体内对头颈部鳞状细胞癌（HNSCC）中NF-κB和TP53介导的信号激活和基因表达、恶性表型和化疗敏感性的影响。Western blot和免疫组织化学检测CK2亚基蛋白表达。CK2亚基被siRNA敲低，并通过DNA结合、Western blot和荧光素酶报告基因检测检测NF-κB的激活。采用定量RT-PCR检测基因表达。通过MTT、流式细胞术和迁移试验检测细胞生长、存活、活力和对顺铂的敏感性。利用抗CK2α/α ‘寡脱氧核苷酸（ODN）包封在低于50 nm的纳米纤维原胶囊中，实现了CK2α/α ’在HNSCC异种移植模型中的体内靶向作用。CK2亚基蛋白在HNSCC细胞系和组织中过表达。CK2亚基的敲低不同程度地抑制了i -κB α降解、NF-κB核定位、磷酸化、DNA结合和报告细胞活性。CK2亚单位调节基因表达和恶性表型，参与细胞周期和迁移，而CK2α在体外促进增殖、抗凋亡和顺铂耐药中起关键作用。此外，体内递送抗CK2α/α ' ODN纳米胶囊可显著抑制HNSCC异种移植模型中的肿瘤生长，这与CK2和NF-κB调节分子、TP53家族蛋白和诱导凋亡有关。我们的研究揭示了CK2在协同调节NF-κB活化、TP53/p63表达和下游基因表达中的新作用。体外和体内HNSCC模型中CK2的下调显示出抗肿瘤作用以及对顺铂的致敏作用。
To investigate the expression of CK2 subunits, and CK2 effects on NF-κB and TP53 mediated signal activation and gene expression, the malignant phenotype, and chemosensitivity in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo. Protein expression of CK2 subunits was investigated by Western blot and immunohistochemistry. CK2 subunits were knocked down by siRNA, and NF-κB activation was examined using DNA binding, Western blot, and luciferase reporter assays. Gene expression was measured by quantitative RT-PCR. Cell growth, survival, motility, and sensitivity to cisplatin were measured by MTT, flow cytometry and migration assays. In vivo targeting of CK2α/α′ in HNSCC xenograft models was achieved using anti-CK2α/α′ oligodeoxynucleotide (ODN) encapsulated in sub-50 nm tenfibgen nanocapsules. CK2 subunit proteins were overexpressed in HNSCC lines and tissues. Knockdown of CK2 subunits differentially inhibited IκBα degradation, NF-κB nuclear localization, phosphorylation, DNA binding, and reporter activity. CK2 subunits modulated gene expression and the malignant phenotype involved in cell cycle and migration, while CK2α is critical to promote proliferation, anti-apoptosis and cisplatin resistance in vitro. Further, in vivo delivery of anti-CK2α/α′ ODN nanocapsules significantly suppressed tumor growth in HNSCC xenograft models, in association with modulation of CK2 and NF-κB regulated molecules, TP53 family proteins, and induction of apoptosis. Our study reveals a novel role of CK2 in co-regulating NF-κB activation, and TP53/p63 expression, and downstream gene expression. Downregulation of CK2 in HNSCC models in vitro and in vivo demonstrates antitumor effects as well as sensitization to cisplatin.