Inhibition of nuclear factor-κB activity by small interfering RNA in esophageal squamous cell carcinoma cell lines
Inhibition of nuclear factor-κB activity by small interfering RNA in esophageal squamous cell carcinoma cell lines
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DOI：
10.3892/or.2011.1313
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发表时间：
2011-09-01
期刊：
影响因子：
4.2
通讯作者：
Ikeguchi, Masahide
中科院分区：
文献类型：
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作者：
Hatata, Tomoko;Higaki, Katsumi;Ikeguchi, Masahide
5-氟尿嘧啶（5-FU）化疗是食管鳞癌（ESCC）常用的联合治疗方案，但对某些患者的疗效有限。最近的研究表明，核因子-κ B（NF-κ B）的组成性激活在肿瘤发生中具有关键作用，并且与许多类型的人类癌症的不良预后和对放化疗的抵抗相关。在本研究中，我们评估了靶向NF-κ B的小干扰RNA（NF-κ B siRNA）联合5-FU对培养的两种ESSCs细胞系增殖的影响。免疫荧光和免疫印迹分析显示NF-κ B B蛋白主要定位于食管鳞癌细胞质中。当培养的ESCC暴露于肿瘤坏死因子-α时，NF-κ B转移到细胞核并被激活。NF-κ B活化的食管鳞癌对5-FU敏感性差。当用NF-κ B siRNA转染细胞时，NF-κ B蛋白在细胞质和细胞核中的水平显著降低。与单独用5-FU处理的细胞相比，在用5-FU和NF-κ B siRNA处理的细胞中NF-κ B的转录活性被显著抑制。5-FU以剂量依赖性方式持续抑制ESCC的增殖，并且当与NF-κ B siRNA组合时，这种作用显著增强。提示5-FU联合NF-κ B siRNA治疗食管鳞癌可能为食管鳞癌的治疗提供新的选择。
Chemotherapy with 5-fluorouracil (5-FU) is commonly used in combination therapy for esophageal squamous cell carcinoma (ESCC), but its efficacy is limited in certain patients. Recent studies suggest that constitutive activation of nuclear factor-kappa B (NF-kappa B) has a critical role in tumorigenesis and is associated with poor prognosis and resistance to chemoradiation therapy in many types of human cancers. In the present study, we evaluated the effect of small interfering RNA targeting NF-kappa B (NF-kappa B siRNA) combined with 5-FU on the proliferation of two cell lines of cultured ESSCs. Immunofluorescence and immunoblot analyses revealed that the NF-kappa B protein was localized mostly in the cytoplasm of ESCCs. When cultured ESCCs were exposed to tumor necrosis factor-alpha, NF-kappa B was transferred to the nucleus and activated. ESCCs with activated NF-kappa B had poor sensitivity to 5-FU. When cells were transfected with NF-kappa B siRNA, the levels of NF-kappa B protein were significantly decreased in the cytoplasm and the nucleus. Transcriptional activity of NF-kappa B was significantly suppressed in cells treated with 5-FU and NF-kappa B siRNA compared to cells treated with 5-FU alone. 5-FU consistently suppressed proliferation of ESCCs in a dose-dependent manner, and this effect was significantly enhanced when combined with NF-kappa B siRNA. These results suggest that combination therapy of 5-FU with NF-kappa B siRNA may provide a new therapeutic option for ESCC.