马蔺子素放射增敏治疗中肿瘤HKⅡ表达变化及RNAi抑制其表达对放射敏感性的影响

The Warburg effect is the main production mode of most malignant tumors, and it is closely related to tumor occurrence and development; Tumor glucose metabolism target for Warburg effect has been a hotspot in recent years. Radiosensitizing therapy can significantly improve the treatment eddect of tumor, however its relationship with Warburg effect is still unclear. We have studied the radiosensitizing effect of irisquinone on a VX2 transplant tumor model during three-dimensional radiotherapy using 18F-FDG PET/CT, it was found that tumor 18F-FDG uptake greatly decreased after radiosensitizing therapy. It has indicated a close relationship between the radiosentizing therapy and Warburg effect. The research idea of this project is to observe the changes of Warburg effect during the radiation sensitizing treatment of irisquinone from cellular and molecular level at the base of our previous work. Investigate the radiosensitivity of tumor cells after knocking down the expression of hexokinaseⅡ(HKⅡ) gene with RNA interference. Glucose metabolism, hypoxia and proliferation of tumor were dynamic monitored by molecular imaging. There will be an effect of "1+1> 2" if the two treatment methods are integrated .This study develop a new direction for synergistic sensitizing treatment.

Warburg效应是大多数恶性肿瘤的主要产能方式，与肿瘤发生、发展密切相关，针对Warburg效应的肿瘤糖代谢靶向治疗是近年来研究热点；放射增敏疗法对提高肿瘤治疗疗效作用显著，但其与肿瘤Warburg效应的关系尚未完全清楚。我们前期通过18F-FDG PET/CT显像观察我国自主研发的放射增敏剂马蔺子素对兔VX2肿瘤的增敏作用，发现放射增敏治疗后肿瘤对FDG摄取明显减低，说明放射增敏疗法与肿瘤糖代谢关系密切。本课题组拟在前期动物实验基础上，进行细胞水平和分子水平深层次探索，研究马蔺子素放射增敏治疗过程中肿瘤Warburg效应关键酶己糖激酶Ⅱ（HKⅡ）的变化情况，及运用RNA干扰技术阻断HKⅡ基因表达后对肿瘤放射敏感性的影响，同时采用分子影像学方法监测肿瘤糖代谢、乏氧及增殖状况。力图将放射增敏疗法及阻断Warburg效应联合应用，达到"1+1≥2"的效果，为肿瘤协同增敏治疗开拓新方向。

Warburg效应是大多数恶性肿瘤的主要产能方式，与肿瘤发生、发展密切相关，针对Warburg效应的肿瘤糖代谢靶向治疗是近年来研究热点。放射增敏疗法对提高肿瘤治疗疗效作用显著，但其与肿瘤Warburg效应的关系尚未完全清楚。我们前期通过18F-FDG PET/CT显像观察我国自主研发的放射增敏剂马蔺子素对兔VX2肿瘤的增敏作用，发现放射增敏治疗后肿瘤对FDG摄取明显减低，说明放射增敏疗法与肿瘤糖代谢关系密切。本课题组在前期动物实验基础上，进行了细胞水平和分子水平深层次探索，研究马蔺子素放射增敏治疗过程中肿瘤Warburg效应关键酶己糖激酶Ⅱ（HKⅡ）的变化情况，并运用RNA干扰技术阻断HKⅡ基因表达，观察对肿瘤放射敏感性的影响，同时采用PET/CT分子显像监测肿瘤糖代谢、乏氧及增殖状况。体内外研究结果均显示，马蔺子素对人乳腺癌MDA-MB231细胞具有放射增敏作用，其增敏作用机制主要通过降低肿瘤细胞内GSH的含量，阻碍细胞损伤修复而增加放射治疗效果,同时下调HKⅡ基因的表达来抑制MDA-MB231细胞的Warburg效应；HK2与乳腺癌MDA-MB231细胞放射敏感性有关，阻断基因HK2的表达可抑制乳腺癌MDA-MB231细胞的增殖，增加细胞的放疗敏感性和凋亡率；PET/CT显像观察肿瘤摄取显像剂的程度变化可评估放射增敏剂早期增敏疗效，直观的显示肿瘤代谢、乏氧及增殖状态，为实验研究提供早期疗效评价。本研究将放射增敏疗法及阻断Warburg效应联合应用，达到了“1+1≥2”的效果，HK2有望在乳腺癌的临床放射治疗中成为一个重要的靶点，为肿瘤协同增敏治疗开拓了新方向。