EBV-miR-BART10-3p通过代谢重编程影响鼻咽癌放疗抵抗的机制

Radiotherapy is the primary treatment for nasopharyngeal carcinoma (NPC), but recurrenc and metastasis caused by radioresistance remains a serious obstacle to successful treatment in many cases. As we have reported, BART10-3p, a microRNA encoded by Epstein-Barr virus (EBV) facilitates epithelial-mesenchymal transition (EMT) and promotes invasion and metastasis of NPC through target-inhibiting BTRC, an E3 ubiquitin ligase gene, and decelerating ubiquitinating degradation of downstream substrates such as Snail. Recently, we have found that BART10-3p is also contributed to NPC radiotherapy resistance. EMT is not only a prerequisite of cancer metastasis, but also accompanied by a series of molecular events in cancer cells, such as metabolic reprogramming, its 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: BART10-3p target-inhibits BTRC, which decelerates ubiquitinating degradation of Snail and MDM2 (a suppressor of p53); Increased Snail and decreased p53 co-lead tumor cell metabolism astray to the bypass of pentose phosphate pathway; and in consequence, resulting in the enhanced DNA repair capacity, ultimately leading to radiation resistance. This project is to further enrich our knowledge of the role of EBV in the pathology of NPC, to provide novel potential targets for the treatment, and new molecular markers for the prognosis of NPC.

放疗是鼻咽癌临床首选方案，放疗抵抗导致复发转移是鼻咽癌治疗失败的根本原因。我们报道了EB病毒编码的miRNA BART10-3p抑制E3泛素连接酶BTRC延缓Snail等转录因子泛素化降解，驱动肿瘤细胞上皮-间质转化(EMT)促进鼻咽癌侵袭转移；我们还发现BART10-3p与鼻咽癌放疗抵抗同样密切相关。近年学术界认为EMT不仅是肿瘤转移前奏，也伴随代谢重编程等一系列分子事件，但机制有待研究。经文献分析结合我们的预实验结果，本项目科学假说为：BART10-3p抑制BTRC，阻滞Snail和MDM2(p53抑制因子)泛素化降解(Snail上调、p53下调)，Snail和p53协同调控肿瘤细胞糖代谢通路往磷酸戊糖旁路偏移，DNA损伤修复能力增强，导致放疗抵抗。本项目的完成将进一步拓展我们对EB病毒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。

放疗是鼻咽癌临床首选方案，放疗抵抗导致复发转移是鼻咽癌治疗失败的根本原因。我们先在较大样本的鼻咽癌组织中检测了EBV编码的miRNA BART10-3p及BTRC的表达情况及它们与鼻咽癌患者预后的关系，发现EBV-miR-BART10-3p在鼻咽癌中高表达且和BTRC基因的表达呈显著负相关；EBV-miR-BART10-3p的高表达与鼻咽癌的颈部淋巴结转移以及远处转移呈正相关，是鼻咽癌患者新的不良预后因素；同时BTRC的低表达也与鼻咽癌的不良预后密切相关。因此EBV-miRNA-BART10-3p和BTRC可以作为鼻咽癌的分子诊断和预后标志物。EBV-miR-BART10-3p通过靶向BTRC基因的3’-UTR抑制其编码的蛋白βTrCP的表达，干扰βTrCP对β-catenin和Snail的泛素化降解调控，使β-catenin和Snail在鼻咽癌细胞内聚集，进而促进鼻咽癌的EMT，增强鼻咽癌细胞的侵袭转移能力。BART10-3p抑制BTRC，阻滞Snail和MDM2(p53抑制因子) 泛素化降解(Snail上调、p53下调)，Snail和p53协同调控肿瘤细胞糖代谢通路往磷酸戊糖旁路偏移，DNA损伤修复能力增强，导致放疗抵抗。