HPV整合相关miRNA介导PI3K/AKT通路对食管鳞癌干细胞放射敏感性的调控研究

The infection rate of human papillomavirus 16 (HPV16) in esophageal cancer is about 63.6%-81.4% in china. Recent clinical data showed that HPV+ cancers were sensitive to radiation and had better prognosis. HPV16 oncogens predominantly attack the esophageal epithelium stem cell and result in many miRNA expression variations near the HPV integration sites, several of which are overlapped with the miRNA specificly expressed in esophageal cancer stem cell in our precious studies, including miR-21、miR-145、miR-143、 miR-205. The target genes of this overlapped miRNAs mostly participate in the regulation of PI3K/AKT anti-apoptosis signal pathways. Researches found that the sensitization to radiation of HPV+ head and neck tumors were correlated with PI3K/AKT signal pathway and in the meanwhile our studies found that the radioresistance of esophageal cancer stem cell also correlated with the PI3K/AKT signal pathway. So the HPV integration correlated miRNAs are hoped to become regulation targets to increase the radiosensibility of esophageal cancer stem cell. Based on our previous studies about esophageal cancer stem cells and their correlated miRNAs, this subject plan to explore the effects of HPV integration correlated miRNAs on radiosensibility of esophageal cancer stem cell as well as their mediation mechanism through PI3K/AKT signal pathway. The ultimate aim is to increase the radiation efficiency of esophageal cancer patients based on the knowledge of etiopathogenisis and stem cell level.

国内食管癌HPV16感染率为63.6%-81.4%。近年临床资料显示HPV+肿瘤患者放疗更敏感，预后较好。HPV16致癌基因主要攻击食管上皮干细胞，其整合位点处有多种miRNAs表达变化，与我们前期研究食管鳞癌干细胞特异表达的miRNAs有重叠，包括miR-21、miR-145、miR-143、 miR-205，且其靶基因多参与PI3K/AKT抗凋亡通路调节。研究发现HPV+头颈部肿瘤细胞放射敏感性增高与PI3K/AKT通路有关，我们亦证实食管鳞癌干细胞放射抗拒与PI3K/AKT通路活性有关。因此HPV整合相关miRNA有望成为食管鳞癌干细胞放射敏感性的调控靶点。本课题拟在前期食管癌干细胞及相关miRNAs研究基础上，探寻HPV整合相关miRNA对食管鳞癌干细胞放射敏感性的调控及其通过PI3K/AKT抗凋亡通路介导的机制，旨在从病因学、干细胞水平使HPV16+食管癌患者获取最大放疗增益。

背景与目的：探讨高危型人乳头瘤状病毒16在食管鳞癌患者中的感染情况及与食管鳞癌患者预后的关系。收集2008年9月到2009年12月于西安交通大学第一附属医院收治的103例 食管鳞癌组织，同时收集同院同期54例良性食管肿瘤、正常食管组织作为对照组。免疫组化方法检测各组织中HPV16 E6蛋白的表达。对103例食管鳞癌患者进行长期随访，结合免疫组化结 果、患者临床资料和随访记录进行统计学分析。结果显示：HPV16 E6 蛋白在食管鳞癌组和对照组中的阳性率分别为 63.1%（65/103）和22.2%(12/54)，差异有统计学 意 义，χ2 ＝29.69，p＜0.05。食管鳞癌组男性患者HPV16 E6 蛋白阳性率为69.0%（58/84），女性为36.8%（7/19），p＜0.05。HPV16 E6 蛋白表达与患者吸烟与否、病理分级、浸润深度、淋巴结转移、TNM分期和大体分型均无相关性，p＞0.05。食管鳞癌患者5年生存率为11%，Kaplan-Meier分析显示：男性、＞56岁、髓质型、较高的TNM分期和术后未行治疗者具有较差的总生存期（overall survival，OS）和无病生存期（progression-free survival，PFS），p＜0.05；浸润深度较深和淋巴结阳性与较差的OS相关，但与PFS无相关性，p＞0.05；吸烟与否、病理分级与OS和PFS均无相关性，p＞0.05；HPV16 E6 阳性者与较差 的OS和PFS相关，p＜0.05。COX多因素回归分析显示，HPV16 E6 阳性与较差的OS和PFS显著相关，p＜0.05。结论：HPV16 感染有可能参与食管鳞癌的发病过程，HPV阳性有可能是影响食管鳞癌患者预后的独立危险因 素。