Constitutive NF-κB Activation in Colorectal Carcinoma Plays a Key Role in Angiogenesis, Promoting Tumor Growth
Constitutive NF-κB Activation in Colorectal Carcinoma Plays a Key Role in Angiogenesis, Promoting Tumor Growth
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DOI：
10.1158/1078-0432.ccr-08-1383
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发表时间：
2009-04-01
影响因子：
11.5
通讯作者：
Omata, Masao
中科院分区：
文献类型：
--
作者：
Sakamoto, Kei;Maeda, Shin;Omata, Masao
目的：核因子κ B （nf - κ B）是多种生物过程中重要的转录因子。在包括结直肠癌在内的许多肿瘤中都发现了组成型nf - κ B的激活。然而，这种激活在结直肠癌中的确切作用尚不清楚。实验设计：在结直肠癌组织和细胞系中评估组成型NF-kappa B的激活。为了抑制NF-kappa B的激活，我们建立了通过RNA干扰稳定敲低I -kappa B激酶γ （NF-kappa B必需调节剂）的癌细胞，这是I -kappa B激酶复合物的调节亚基。观察野生型细胞（WT）和敲低型细胞（KD）的细胞生长和凋亡情况。微阵列和蛋白质阵列分析也做了。为了确定血管生成的累及程度，我们使用了人脐静脉内皮细胞。将这些细胞移植到裸鼠体内，观察肿瘤大小、血管分布和化学药物敏感性。结果：在40%的结直肠癌组织和67%的细胞系中观察到组成型NF-kappa B活化。WT和KID的体外细胞增殖无明显差异，而KD中肿瘤坏死因子- α和5-氟尿嘧啶介导的细胞凋亡增加。一些血管生成趋化因子在KD中降低。WT上清培养的人脐静脉内皮细胞比KD上清培养的人脐静脉内皮细胞显示出更多的分支点，表明组成型nf - κ B激活参与了血管生成。KD组皮下肿瘤扩张被抑制至23%，血管也减少。通过5-氟尿嘧啶治疗，KID（6%）比WT（50%）更大程度地抑制肿瘤扩张。结论：抑制NF-kappa B可能是一种有效的治疗结直肠癌的方式，特别是在组成性NF-kappa B激活的情况下。
Purpose: Nuclear factor kappa B (NF-kappa B) is an important transcription factor in various biological processes. Constitutive NF-kappa B activation has been noted in many tumors, including colorectal cancers. However, the precise role of this activation in colorectal cancer is unclear.Experimental Design: Constitutive NF-kappa B activation was evaluated in colorectal cancer tissues and cell lines. To inhibit NF-kappa B activation, we established cancer cells with stable knockdown of I kappa B kinase gamma (NF-kappa B essential modulator), which is the regulatory subunit of the I kappa B kinase complex, by RNA interference. Cell growth and apoptosis were evaluated in wild-type cells (WT) and knocked-down cells (KD). Microarray and protein array analysis were also done. To determine involvement of angiogenesis, human umbilical vein endothelial cells were used. By s.c. transplantation of the cells into nude mice, tumor sizes, vascularity, and chemodrug sensitivity were analyzed.Results: Constitutive NF-kappa B activation was observed in 40% of colorectal cancer tissues and 67% of cell lines. Cell proliferation was not different between WT and KID in vitro, whereas apoptosis mediated by tumor necrosis factor-alpha and 5-fluorouracil were increased in KD. Several angiogenic chemokines were decreased in KD. Human umbilical vein endothelial cells incubated in WT supernatant showed more branch points than in KD, suggesting that constitutive NF-kappa B activation was involved in angiogenesis. Subcutaneous tumor expansion was suppressed to 23% in KD, and vessels were also decreased. By 5-fluoruracil treatment, tumor expansion was suppressed to a greater extent in KID (to 6%) than in WT (to 50%).Conclusion: NF-kappa B inhibition may represent a potent treatment modality in colorectal cancer, especially in cases with constitutive NF-kappa B activation.