Endo Fumitaka, Nishizuka Satoshi S, Kume Kohei, Ishida Kazushige, Katagiri Hirokatsu, Ishida Kaoru, Sato Kei, Iwaya Takeshi, Koeda Keisuke, Wakabayashi Go
Molecular Therapeutics Laboratory, Iwate Medical University School of Medicine, Morioka, Japan ; Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan.
Molecular Therapeutics Laboratory, Iwate Medical University School of Medicine, Morioka, Japan ; Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan ; MIAST (Medical Innovation by Advanced Science and Technology) project, Iwate Medical University, Morioka, Japan ; Institute for Biomedical Sciences, Iwate Medical University, Yahaba, Japan.
PLoS One. 2014 Feb 27;9(2):e90155. doi: 10.1371/journal.pone.0090155. eCollection 2014.
Despite of remarkable improvement of postoperative 5-FU-based adjuvant chemotherapy, the relapse rate of gastric cancer patients who undergo curative resection followed by the adjuvant chemotherapy remains substantial. Therefore, it is important to identify prediction markers for the chemotherapeutic efficacy of 5-FU. We recently identified NF-κB as a candidate relapse prediction biomarker in gastric cancer. To evaluate the biological significance of NF-κB in the context of 5-FU-based chemotherapy, we analyzed the NF-κB-dependent biological response upon 5-FU treatment in gastric cancer cell lines. Seven genes induced by 5-FU treatment in an NF-κB-dependent manner were identified, five of which are known p53 targets. Knockdown of RELA, which encodes the p65 subunit of NF-κB, decreased both p53 and p53 target protein levels. In contrast, NF-κB was not affected by TP53 knockdown. We also demonstrated that cell lines bearing Pro/Pro homozygosity in codon72 of p53 exon4, which is important for NF-κB binding to p53, are more resistant to 5-FU than those with Arg/Arg homozygosity. We conclude that NF-κB plays an important role in the response to 5-FU treatment in gastric cancer cell lines, with a possible compensatory function of p53. These results suggest that NF-κB is a potential 5-FU-chemosensitivity prediction marker that may reflect 5-FU-induced stress-response pathways, including p53.
尽管基于5-氟尿嘧啶（5-FU）的术后辅助化疗有了显著改善，但接受根治性切除并进行辅助化疗的胃癌患者的复发率仍然很高。因此，识别5-FU化疗疗效的预测标志物很重要。我们最近将核因子κB（NF-κB）鉴定为胃癌复发预测生物标志物的候选者。为了评估NF-κB在基于5-FU化疗背景下的生物学意义，我们分析了胃癌细胞系中5-FU处理后NF-κB依赖性生物学反应。鉴定出七个以NF-κB依赖性方式由5-FU处理诱导的基因，其中五个是已知的p53靶标。编码NF-κB的p65亚基的RELA的敲低降低了p53和p53靶蛋白水平。相反，NF-κB不受TP53敲低的影响。我们还证明，在p53外显子4的密码子72处具有Pro/Pro纯合性的细胞系（这对于NF-κB与p53结合很重要）比具有Arg/Arg纯合性的细胞系对5-FU更具抗性。我们得出结论，NF-κB在胃癌细胞系对5-FU治疗的反应中起重要作用，p53可能具有补偿功能。这些结果表明，NF-κB是一种潜在的5-FU化疗敏感性预测标志物，可能反映5-FU诱导的应激反应途径，包括p53。
