Cancer stem-like cell characteristics induced by EB virus-encoded LMP1 contribute to radioresistance in nasopharyngeal carcinoma by suppressing the p53-mediated apoptosis pathway
Cancer stem-like cell characteristics induced by EB virus-encoded LMP1 contribute to radioresistance in nasopharyngeal carcinoma by suppressing the p53-mediated apoptosis pathway
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EB 病毒编码的 LMP1 诱导的癌症干细胞样特征通过抑制 p53 介导的细胞凋亡途径，有助于鼻咽癌的放射抗性。
DOI：
10.1016/j.canlet.2013.11.006
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发表时间：
2014-03-28
期刊：
影响因子：
9.7
通讯作者：
Huang, Bi-Jun
中科院分区：
文献类型：
--
作者：
Yang, Chang-Fu;Peng, Li-Xia;Huang, Bi-Jun
新的证据证实，癌症干细胞（CSCs）负责恶性肿瘤的放化疗抗性。EB病毒编码的潜伏膜蛋白1（LMP 1）与鼻咽癌（NPC）的复发和不良预后有关。然而，LMP 1是否诱导CSCs的发育以及这种罕见细胞亚群导致NPC辐射抗性的机制仍不清楚。在本研究中，与空载体对照相比，LMP 1转化的NPC细胞显示出显著的辐射抗性。我们发现LMP 1上调了几个干细胞相关基因的表达，通过流式细胞术分析增加了侧群（SP）的细胞数量，增强了球形培养中细胞的自我更新特性，并增强了体内肿瘤起始能力。我们还发现LMP 1正调控CSC标志物CD 44的表达。LMP 1转化的NPC细胞的CD 44（+/高）亚群显示出比LMP 1转化的NPC细胞的CD 44（-/低）亚群更显著的CSC特征;这些特征包括干细胞相关基因的上调、体外自我更新和体内肿瘤起始能力。重要的是，CD 44（+/高）亚群比CD 44（-/低）亚群显示出更强的放射抗性。我们的研究结果还表明，DNA损伤反应（DDR）蛋白ATM、Chk 1、Chk 2和p53的磷酸化在LMP 1诱导的CD 44（+/High）细胞中响应DNA损伤而失活，并且这伴随着p53靶向的促凋亡基因的下调，提示p53介导的凋亡途径失活是CD 44（+/High）细胞辐射抗性的主要原因。综上所述，我们发现LMP 1诱导CSC样CD 44（+/高）细胞的增加，我们确定了LMP 1激活的CSC放射抗性的分子机制，强调了EBV阳性NPC中CSC靶向放射治疗的必要性。(C)2013爱思唯尔爱尔兰有限公司版权所有。
Emerging evidence confirms that cancer stem cells (CSCs) are responsible for the chemoradioresistance of malignancies. EBV-encoded latent membrane protein 1 (LMP1) is associated with tumor relapse and poor prognosis of nasopharyngeal carcinoma (NPC). However, whether LMP1 induces the development of CSCs and the mechanism by which this rare cell subpopulation leads to radioresistance in NPC remain unclear. In the present study, LMP1-transformed NPC cells showed significant radioresistance compared to the empty vector control. We found that LMP1 up-regulated the expression of several stemness-related genes, increased the cell number of side population (SP) by flow cytometry analysis, enhanced the self-renewal properties of the cells in a spherical culture and enhanced the in vivo tumor initiation ability. We also found that LMP1 positively regulated the expression of the CSC marker CD44. The CD44(+/High) subpopulation of the LMP1-transformed NPC cells displayed more significant CSC characteristics than the CD44(-/Low) subpopulation of the LMP1 -transformed NPC cells; these characteristics included the upregulation of sternness-related genes, in vitro self-renewal and in vivo tumor initiation ability. Importantly, the CD44(+/High) subpopulation displayed more radioresistance than the CD44(-/Low) subpopulation. Our results also demonstrated that phosphorylation of the DNA damage response (DDR) proteins, ATM, Chk1, Chk2 and p53, was inactivated in the LMP1-induced CD44(+/High) cells in response to DNA damage, and this was accompanied by a downregulation of the p53-targeted proapoptotic genes, which suggested that the inactivation of the p53-mediated apoptosis pathway was responsible for the radioresistance in the CD44(+/High) cells. Taken together, we found that LMP1 induced an increase in CSC-like CD44(+/High) cells, and we determined the molecular mechanism underlying the radioresistance of the LMP1-activated CSCs, highlighting the need of CSC-targeted radiotherapy in EBV-positive NPC. (C) 2013 Elsevier Ireland Ltd. All rights reserved.