Epstein–Barr病毒编码的miR-BART10在鼻咽癌分化障碍中的作用及调控机制的研究

More than 95% nasopharyngeal carcinomas (NPC) are pathologically diagnosed as undifferentiated cancers, with high malignant degree. The survival of NPC is hard to further improved. Intensive study on the molecular mechanisms of key markers in undifferentiation is an important way to identify new therapeutic strategy and improve survival in NPC. In previous study, we found that Epstein–Barr virus (EB virus) encoded miR-BART10 was overexpressed in undifferentiated NPC. Knocking down miR-BART10 expression led to NPC cell differentiation. Differentiation agent reduced expression of miR-BART10 and EB virus encoded gene LMP1. Knocking down of LMP1 expression led to miR-BART10 downregulation, while LMP1 overexpression increased miR-BART10 expression, but the regulation mechanisms remains unknown. On this basis, we intend to carry out the following researches: study the function and mechanism of miR-BART10 in NPC differentiation block in vitro and in vivo; clarify the regulation mechanism how EB virus encoded gene LMP1 mediates miR-BART10 expression; examine the clinical correlation of miR-BART10, LMP1 and downstream markers in NPC. This research will provide novel targets and compelling evidence to apply differentiation therapy as a novel therapeutic strategy for accurate therapy, to further improve survival in NPC patients.

鼻咽癌95%以上病理分化不良，恶性程度高，疗效难以进一步提高。从分子水平深入探索鼻咽癌分化障碍的关键分子，有利于开辟鼻咽癌精准治疗新途径。我们前期结果发现：①EB病毒编码miRNA-BART10在未分化型鼻咽癌中高表达，且抑制miRNA-BART10表达可促进鼻咽癌细胞向正常细胞方向分化；②诱导分化药物可抑制miR-BART10和病毒编码基因LMP1表达，干扰LMP1表达后miR-BART10表达呈同向改变，但具体机制不详。在此基础上，本项目拟开展以下研究：通过体内外实验阐明miR-BART10在鼻咽癌分化障碍中功能和作用机制；明确EB病毒编码LMP1介导miR-BART10表达的具体调控机制；在300例未分化型鼻咽癌标本中明确miR-BART10、LMP1与鼻咽癌分化障碍的临床相关性。通过本项目的实施，为鼻咽癌诱导分化治疗提供提供新靶点，开辟鼻咽癌精准治疗新途径，以进一步提高疗效。

鼻咽癌恶性程度高，易发生远处转移，依赖现有的诊疗技术难以提高患者生存率。从分子水平深入探索鼻咽癌发生进展的关键分子，有利于开辟个体化治疗的新途径。本项目明确了miR-BART10在鼻咽癌组织中高表达且与不良预后相关，其与TNM分期的结合能有效区分不同危险度的患者；发现miR-BART10能促进鼻咽癌细胞的分化障碍、增殖和转移；通过RNA测序结合生物信息学分析鉴定出miR-BART10的直接靶点ALK7，过表达ALK7可逆转miR-BART10的恶性表型；发现外源性提高miR-BART10水平能促进鼻咽癌细胞的体内成瘤。因此，miR-BART10通过靶向ALK7促进鼻咽癌的分化障碍、增殖和转移。此外，通过本项目支持，我们发现lncRNA DANCR通过增加HIF-1α的稳定性促进鼻咽癌转移；构建了免疫相关lncRNA的预后标签有效预测头颈鳞癌患者预后；明确了肿瘤浸润淋巴细胞在鼻咽癌中的预后价值；探讨了基于磁共振的多个影像特征对鼻咽癌分期的改善作用；基于肿瘤反应和风险因素对中晚期鼻咽癌进行危险分层，提出了个体化治疗策略，为临床试验的开展提供了重要依据。以上研究为指导鼻咽癌的个体化治疗奠定了基础。通过本项目的开展，项目负责人以第一/通讯作者身份共发表高水平SCI论著7篇（其中2篇已接收），包括Clin Transl Med, Radiother Oncol, Oral Oncol, Theranostics, Int J Cancer等。项目负责人所在团队被评为2016年度“广东省南粤创新奖获奖团队”。