BPIFB1通过GLUT1调控糖代谢重编程介导鼻咽癌放疗敏感的分子机制研究

Nasopharyngeal carcinoma (NPC) is a head and neck epithelial malignancy that occurs frequently in Southern China. Radiotherapy is the primary treatment for NPC, but recurrence and metastasis caused by radioresistance remains a serious obstacle to successful treatment in many cases. As we have reported, BPIFB1, a relatively specific nasopharyngeal gene which is significantly downregulated in NPC, can promote apoptosis after irradiation and enhance radiosensitivity of NPC. Recently, we have found that BPIFB1 can also regulate the expression of GLUT1, the key protein of glycolysis. As we know, radioresistance of NPC is closely related to abnormal metabolism, however, the mechanism is yet to be further elucidated. On the basis of a comprehensive analysis of literatures and our preliminary data, our project proposes the following hypothesis: the formation of BPIFB1/IKBIP/IKK-β complex can downregulate GLUT1 expression by repressing NF-κB signaling, which slows down the glocolysis of NPC cells and inhibits the activation of the DNA repair initiation effector gene ATM, thereby attenuating the pentose phosphate pathway (PPP) and restoring oxidative phosphorylation (OXPHOS), and in consequence, resulting in the enhanced reactive oxyen species (ROS) and a reduction of DNA repair, ultimately leading to apoptosis and radiosensitivity of NPC cells. This project is to further enrich our knowledge of the role of BPIFB1 in the pathology of NPC, to provide novel potential targets for the treatment, and new molecular markers for the prognosis of NPC.

鼻咽癌是高发于中国南方地区的恶性肿瘤，放疗是其临床治疗的首选方案，而放疗抵抗是治疗失败的主要原因。我们首次克隆的鼻咽部相对特异表达基因BPIFB1在鼻咽癌中低表达，可促进鼻咽癌的放疗敏感性，但其中的机制尚不清楚。我们的初步研究发现BPIFB1可下调GLUT1并抑制鼻咽癌细胞的糖酵解，而肿瘤的异常代谢与放疗抵抗的发生相关，但机制有待研究。经文献分析结合预实验结果，本项目的科学假说为：BPIFB1与IKBIP、IKK-β蛋白形成的复合体通过抑制NF-κB通路的激活下调GLUT1的表达，进而减缓鼻咽癌细胞的糖酵解并抑制修复启动效应基因ATM的活化，从而减弱磷酸戊糖途径并恢复氧化磷酸化，诱导活性氧的增多和DNA损伤修复的减少，最终增强鼻咽癌细胞的放疗敏感性。本项目的完成将进一步拓展我们对BPIFB1在鼻咽癌发生发展中作用机制的认识，为鼻咽癌临床治疗提供新的靶点和思路，为预后判断提供新的分子标记。

鼻咽癌是高发于中国南方地区的头颈部恶性肿瘤，代谢异常是鼻咽癌发生发展的重要促进因素。BPIFB1是一种鼻咽部相对特异表达蛋白，在鼻咽癌中表达下调，且BPIFB1的低表达与鼻咽癌患者的不良预后相关，但其中涉及的具体机制仍需进一步研究。本项目在临床样本、体外实验和动物模型中探究了BPIFB1调控的代谢重编程在鼻咽癌发生发展中的作用及分子机制。. 我们发现BPIFB1可以通过调控鼻咽癌的代谢重编程抑制血管生成拟态，从而抑制鼻咽癌的发生发展，具体机制为：BPIFB1通过下调JNK/AP1信号抑制GLUT1的转录，降低鼻咽癌细胞的糖酵解水平，糖酵解的改变减少了组蛋白H3K27的乙酰化水平，下调了血管生成拟态相关分子VEGFA、VE-cadherin和MMP2的表达，最终导致血管生成拟态抑制。本研究拓展了我们对BPIFB1在鼻咽癌发生发展过程中的调控作用的认知，为鼻咽癌的治疗以及抗肿瘤血管生成靶向药物的开发提供了新的参考方向和理论依据。