Leukemia inhibitory factor promotes nasopharyngeal carcinoma progression and radioresistance
Leukemia inhibitory factor promotes nasopharyngeal carcinoma progression and radioresistance
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DOI：
10.1172/jci63428
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发表时间：
2013-12-01
影响因子：
15.9
通讯作者：
Chang, Yu-Sun
中科院分区：
文献类型：
--
作者：
Liu, Shu-Chen;Tsang, Ngan-Ming;Chang, Yu-Sun
EB病毒相关鼻咽癌（NPC）的放射抗性与这种癌症患者的预后不良有关。在这里，我们发现NPC患者血清白血病抑制因子（LIF）水平升高，并且较高的LIP水平与局部肿瘤复发相关。此外，NPC细胞的体外研究和体内异种移植小鼠研究表明，LIF对NPC肿瘤生长和辐射抗性有重要作用。使用这些模型系统，我们发现LIP处理激活mTORC 1/p70 S6 K信号通路，增强肿瘤生长，抑制DNA损伤反应，并增强放射抗性。用可溶性LIF受体（sLIFR）、LIP拮抗剂或mTOR抑制剂雷帕霉素治疗可逆转LIP介导的效应，导致生长停滞并增加对γ射线的敏感性。免疫组织化学（IHC）分析人类鼻咽癌活检显示，LIF和LIFR过表达的肿瘤细胞和LIP的表达与激活的p-p70 S6 K的存在。最后，我们发现EBV编码的蛋白质潜伏膜蛋白1（LMP 1）增强LIP的产生。总之，我们的研究结果表明，LIP促进NPC肿瘤的发生，并建议血清LIP水平可以预测局部复发和鼻咽癌患者的放射敏感性。
Radioresistance of EBV-associated nasopharyngeal carcinoma (NPC) is associated with poor prognosis for patients with this form of cancer. Here, we found that NPC patients had increased serum levels of leukemia inhibitory factor (LIF) and that higher LIP levels correlated with local tumor recurrence. Furthermore, in vitro studies with NPC cells and in vivo xenograft mouse studies demonstrated that LIF critically contributes to NPC tumor growth and radioresistance. Using these model systems, we found that LIP treatment activated the mTORC1/p70S6K signaling pathway, enhanced tumor growth, inhibited DNA damage responses, and enhanced radioresistance. Treatment with either soluble LIF receptor (sLIFR), a LIP antagonist, or the mTOR inhibitor rapamycin reversed LIP-mediated effects, resulting in growth arrest and increased sensitivity to gamma irradiation. Immunohistochemical (IHC) analyses of human NPC biopsies revealed that LIF and LIFR were overexpressed in tumor cells and that LIP expression correlated with the presence of the activated p-p70S6K. Finally, we found that the EBV-encoded protein latent membrane protein 1 (LMP1) enhances LIP production. Together, our findings indicate that LIP promotes NPC tumorigenesis and suggest that serum LIP levels may predict local recurrence and radiosensitivity in NPC patients.