环状RNA:口咽鳞癌预后标志物筛选及其在疾病进展中的作用机制研究

Oropharyngeal squamous cell carcinoma (OPSCC) is a highly malignant head and neck cancer with poor prognosis and high mortality. The current factors for evaluating the prognosis of OPSCC are TNM staging, tumor location, age and HPV status, by which we cannot thoroughly and effectively predict the prognosis of OPSCC. Thus, exploring a reliable prognostic biomarker for OPSCC has become an urgent clinical problem. In our previous studies, we found that the profiles of circular RNA expression of OPSCC are disease-specific, OPSCC has an abnormally high expression of hsa_circ_004788. Bioinformatics analysis suggests that hsa_circ_004788 might inhibit the expression of miR-31 which is an oncogene miRNA, and is involved in the malignant progression of OPSCC and closely related to the prognosis. This project focuses on the verification of the correlation between expression levels of hsa_circ_004788 and the malignant progression of OPSCC, and to evaluate its feasibility as a prognostic marker for OPSCC. We further investigate the regulatory effects of hsa_circ_004788 on miR-31, which targets tumor-suppressive gene LATS2 in the mechanism of malignant progression of OPSCC. The aim of this study is to find an effective prognostic marker for OPSCC and explore a more effective individualized treatment plan.

口咽鳞癌是高度恶性的头颈部肿瘤，其预后差，病死率高。目前主要通过TNM分期、肿瘤部位、年龄及HPV状态等因素判断口咽鳞癌预后，然而口咽鳞癌具有较强的异质性，致使上述指标无法全面有效判断其预后，亟待通过大样本研究发现更为可靠的预后标志物。本课题组发现口咽鳞癌的环状RNA表达谱具有特异性，hsa_circ_004788异常低表达，生物信息学预测提示其可负向调控具有促癌作用的miR-31的表达，参与口咽鳞癌的恶性进展，并与预后密切相关。本项目拟重点验证hsa_circ_004788表达水平与口咽鳞癌恶性进展的相关性，全面评估其作为口咽鳞癌预后标志物的可行性，深入研究hsa_circ_004788调控miR-31并靶向抑制LATS2参与口咽鳞癌恶性进展的具体机制，以期在发现口咽鳞癌预后标志物的基础上，探索更为有效的个体化治疗方案。

口咽鳞癌是常见的头颈部肿瘤，预后较差。目前通过TNM分期、肿瘤部位、年龄及HPV判断预后。流行病学数据显示口咽鳞癌具有强的肿瘤异质性，现有方法不能全面准确的判断预后，发现更为准确有效的预后标志物成为亟待解决的科学问题。本项目初步证明口咽鳞癌患者组织中环状RNA的表达谱具有疾病特异性，扩大样本量验证后发现，hsa_circ_004788在口咽鳞癌组织中呈现显著低表达，在111例临床标本的检测中发现，hsa_circ_004788在口咽鳞癌患者组织中表达水平和口咽鳞癌恶性程度呈负相关；hsa_circ_004788表达水平越低，病人不良预后越显著，ROC曲线进一步证实，在原有临床数据基础上建立的预后评估模型中，联合组织中hsa_circ_004788表达量进行分级，可显著提高预后判断准确性。在口咽鳞癌细胞中降低hsa_circ_004788表达，细胞的增殖，迁移能力均明显增加。靶基因预测miR-31存在hsa_circ_004788结合位点，过表达hsa_circ_004788之后靶基因miR-31表达下调。干涉hsa_circ_004788之后靶基因miR-31表达上调。这提示hsa_circ_004788和miR-31之间可能存在相互抑制关系。荧光素酶报告实验证实hsa_circ_004788和miR-31之间存在直接相互作用。且随着口咽鳞癌病理分级的增高，miR-31的表达水平逐渐增加，与hsa_circ_004788趋势相反，证明hsa_circ_004788和miR-31存在负相关。上述结果从功能学角度进一步验证流行病学研究结果，探讨环状RNA 作为口咽鳞癌治疗新靶点的可能性，为口咽鳞癌治疗提供新的思路。