Radiation Sensitivity of Esophageal Adenocarcinoma: The Contribution of the RNA-Binding Protein RNPC1 and p21-Mediated Cell Cycle Arrest to Radioresistance
Radiation Sensitivity of Esophageal Adenocarcinoma: The Contribution of the RNA-Binding Protein RNPC1 and p21-Mediated Cell Cycle Arrest to Radioresistance
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DOI：
10.1667/rr2776.1
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发表时间：
2012-03-01
影响因子：
3.4
通讯作者：
Maher, Stephen G.
中科院分区：
文献类型：
--
作者：
Hotte, Gijsbert J.;Linam-Lennon, Niamh;Maher, Stephen G.
Hotte，G.J.，Lynam-Lennon，N.，Reynolds，J.V.和Maher，S.G.食管腺癌的辐射敏感性：RNA结合蛋白RNPC1和p21介导的细胞周期停滞对放射抵抗的贡献。径向的。结果177,272-279(2012)：放化疗(NEO-CRT)日益成为食道癌治疗的标准治疗方案，无论是作为多模式方案的新辅助治疗，还是作为主要治疗。不幸的是，近60%的患者对neo-CRT反应很小或没有反应。因此，通过在治疗前或治疗早期识别无反应者，了解耐药的分子机制可能会为重大进展奠定基础。我们之前发现RNPC1基因在对neo-CRT反应不佳的食道癌患者的肿瘤中上调，RNPC1基因对稳定p21很重要。我们假设RNPC1通过p21介导的细胞周期积累/停滞机制参与放射治疗的抵抗。分析表明，P53和RNPC1在JH-EsoAd1细胞系中表达最高，在OE19细胞中表达最低。这与G(0)/G(1)中细胞的聚集有关。P21的表达在OE19细胞中最高，在OE33细胞中最低，与相对固有的辐射敏感性有关。将编码GFP标记的RNPC1的真核表达载体(pCMV6-AC-GFP)导入OE33细胞，定量聚合酶链式反应(QPCR)和荧光显微镜观察证实其高效表达。RNPC1-GFP的过表达通过RNPC1蛋白和p21转录本之间的直接物理相互作用导致p21转录本和蛋白水平的显著增加。此外，RNPC1过表达导致G(0)/G(1)细胞周期显著积累，并显著增强细胞对辐射的抗性。我们得出结论，RNPC1参与了肿瘤对放射治疗的抵抗，这可能是通过p21介导的G(0)/G(1)积聚机制发生的。因此，RNPC1可能成为增强肿瘤放射敏感性的潜在治疗靶点。(C)2012年，由辐射研究学会提供
Hotte, G. J., Lynam-Lennon, N., Reynolds, J. V. and Maher, S. G. Radiation Sensitivity of Esophageal Adenocarcinoma: The Contribution of the RNA-Binding Protein RNPC1 and p21-Mediated Cell Cycle Arrest to Radioresistance. Radial. Res. 177, 272-279 (2012).Radiation combined with chemotherapy (neo-CRT) is increasingly the standard of care for the treatment of esophageal cancer, either as neoadjuvant therapy in multimodal protocols or as primary therapy. Unfortunately, similar to 60% of patients demonstrate little or no response to neo-CRT. Accordingly, understanding the molecular mechanisms of resistance to therapy may underpin significant advances through the identification of nonresponders either before or early in treatment. We previously identified the RNPC1 gene, which is important in stabilizing p21, as being upregulated in the tumors of esophageal cancer patients who had a poor response to neo-CRT. We hypothesize that RNPC1 contributes to resistance to radiation therapy through a p21-mediated cell cycle accumulation/arrest mechanism. Analysis revealed that p53 and RNPC1 expression were highest in the JH-EsoAd1 cell line and lowest in OE19 cells. This was associated with accumulation of cells in G(0)/G(1). p21 expression, which was highest in OE19 cells and lowest in OE33 cells, was associated with relative intrinsic sensitivity to radiation. OE33 cells were transfected with a plasmid (pCMV6-AC-GFP) encoding a C-terminal GFP-tagged RNPC1, and overexpression was confirmed by qPCR and fluorescence microscopy. Overexpression of RNPC1-GFP resulted in significantly increased levels of the p21 transcript and protein through a direct physical interaction between the RNPC1 protein and the p21 transcript. Furthermore, RNPC1 overexpression led to significant G(0)/G(1) cell cycle accumulation and significantly enhanced cellular resistance to radiation. We conclude that RNPC1 contributes to tumor resistance to radiotherapy, which likely occurs through a p21-mediated G(0)/G(1) accumulation mechanism. Therefore, RNPC1 may represent a potential therapeutic target for enhancing tumor sensitivity to radiation. (C) 2012 by Radiation Research Society