Kwon Oh-Hyung, Kim Jong Hwan, Kim Seon-Young, Kim Yong Sung
Medical Genomics Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
Int J Oncol. 2014 Feb;44(2):583-90. doi: 10.3892/ijo.2013.2211. Epub 2013 Dec 9.
Chemoresistance is one of the most serious problems in the treatment of cancer. In the present study, we show that Fn14 promotes resistance to 5-fluorouracil (5-FU) in gastric cancer (GC). We found that 5-FU treatment upregulated Fn14 expression in various cancer cell lines, including GC cell lines, and that knockdown of Fn14 using shRNA accelerated 5-FU sensitivity. In contrast, Fn14 overexpression or TWEAK treatment promoted resistance to 5-FU. Furthermore, we investigated the mechanisms underlying Fn14-mediated chemoresistance. We first revealed that 5-FU-mediated upregulation of Fn14 occurred as a result of NF-κB activation, indicating that 5-FU-mediated NF-κB activation was the principal event underlying Fn14 upregulation and 5-FU resistance in GC. Taken together, our results suggest that Fn14 is a novel therapeutic target and that inhibition of Fn14 combined with 5-FU treatment may be an effective molecular therapeutic strategy to treat 5-FU-resistant gastric cancers.
化疗耐药是癌症治疗中最严重的问题之一。在本研究中，我们发现Fn14可促进胃癌（GC）对5-氟尿嘧啶（5-FU）的耐药性。我们发现5-FU处理可上调包括GC细胞系在内的多种癌细胞系中Fn14的表达，并且使用短发夹RNA（shRNA）敲低Fn14可增强5-FU敏感性。相反，Fn14过表达或肿瘤坏死因子样弱凋亡诱导因子（TWEAK）处理可促进对5-FU的耐药性。此外,我们研究了Fn14介导的化疗耐药机制。我们首先发现5-FU介导的Fn14上调是由核因子κB（NF-κB）激活所致，这表明5-FU介导的NF-κB激活是GC中Fn14上调和5-FU耐药的主要原因。综上所述，我们的结果表明Fn14是一个新的治疗靶点，抑制Fn14并联合5-FU治疗可能是治疗5-FU耐药胃癌的一种有效的分子治疗策略。
