血清microRNA-93在鼻咽癌远处转移中的作用及机制研究

Distant metastasis is the major treatment failure of nasopharyngeal carcinoma (NPC).TNM staging alone can not accurately predict the distant metastasis-free survival rate . It is an urgent and important clinical issue to forecast as soon as possible the cases with high risk of metastasis and give appropriate treatments. Recent studies have indicated that serum micoRNAs (miRNAs) can be used as biomarkers to predict distant metastasis. Our preliminary experiments shows that: ① A signature consisting of 8 serum miRNAs discriminates metastasis NPC patients from non-metastasis ones with 100% accurateness，and miR-93 expression was significantly increased in serum of distant metastasis NPC patients；② NPC cells significantly inhibit migration and invision after transiently transfected with miR-93 inhibitor. But the function of miR-93 in NPC and its mechanism is unclear. In this study, we will retrospectively collect serum samples and clinical data of 600 NPC patients and detect expression of serum miRNAs by quantitative PCR to clarify the prediction role of serum miR-93 in metastasis and prognosis of NPC, to provide predictive biomarkers for metastasis, and to provide guidance for molecular typing and "individualized" treatment of NPC. Furthermore, we will do experimental studies in vitro and in vivo to elucidate the role of miR -93 in metastasis of NPC and its mechanism to provide new targets for "individualized" treatment of NPC.

远处转移是鼻咽癌治疗失败的主要模式，单纯TNM分期不能准确预测预后。寻找分子指标来预测高转移风险病例并给予恰当治疗是临床急需解决的重要问题。近年发现血清miRNA可作为预测肿瘤转移的分子指标。课题组回顾性收集了600例初诊鼻咽癌血清标本及其临床资料，预实验结果显示：①一组8个血清miRNA分子能够准确区分远处转移和无转移的鼻咽癌，且miR-93在远处转移鼻咽癌血清中表达明显升高；②瞬转miR-93的inhibitor可抑制鼻咽癌细胞株的迁移和侵袭能力，但miR-93在鼻咽癌中的作用和机制不详。本申请项目在此基础上，拟采用定量PCR方法在600例临床信息及随访完整的鼻咽癌患者血清样本，进一步明确血清miR-93在预测鼻咽癌预后及远处转移的作用，为鼻咽癌分子分型和"个体化"治疗提供指导；并进一步阐明miR-93在鼻咽癌转移中的作用及机制，从而为鼻咽癌治疗提供新靶点奠定基础。

在现代治疗模式下，远处转移已成为鼻咽癌治疗失败的主要模式。然而我们的前期研究发现尽管治疗方法和强度相似，同一分期内病例的是否转移存在着较大差异。提示单一TNM分期不能准确预测鼻咽癌转移风险，从而造成治疗模式缺乏“个体化”，提示需要寻找新的分子进一步区分患者的转移风险。在本课题的资助下，收集2003 年至2005 年在中山大学肿瘤防治中心初、具有齐全的临床资料和随访资料齐全的鼻咽癌患者石蜡组织标本，抽提总RNA，用定量PCR检测miRNA的表达水平，结合临床和随访资料分析，取得如下成果：.1. 发现在鼻咽癌中miR-93呈高表达，其通过靶向作用于Dab2基因促进鼻咽癌细胞的迁移、侵袭和转移。以上实验结果以论著形式发表在2015年Cancer Letters（IF: 5.6）杂志上，并于2015 年在美国“7th ASTRO’s 2015 Annual Meeting”会议，被选作ePoster Presentation 交流。.2. 发现一组4个血清miRNA构成的Signature（four-microRNA signature，包括miR-22, miR-572, miR-638 and miR-1234）是鼻咽癌患者预后的独立预测因子；它结合TNM临床分期能提高对鼻咽癌患者预后预测的准确性。以上实验结果以论著形式发表在2014年Int J Cancer（IF: 5.0）杂志上。.上述研究成果为鼻咽癌个体治疗靶向治疗奠定了基础，共发表SCI收录论文4篇，总IF 19.3。做为“鼻咽癌个体化治疗研究与应用”的一部分，被评为2014年度教育部科技进步一等奖、广东省科技进步一等奖及中华医学会科技进步一等奖。