CD147通过GLUT1调控糖酵解介导宫颈癌放疗抵抗的分子机制研究

Although radiotherapy is the most effective treatment for local advanced cervical carcinoma, radioresistance is one of the most important clinical problems. Therefore, to reveal the molecular mechanism of radiation resistance is very important, and finding some new radiosensitizers may be novel therapeutic strategies. Our previous work showed that the expression of CD147 in patients with cervical carcinoma was closely associated with the radiation resistance and prognosis. Inhibition of CD147 expression significantly increased sensitivity to radiation in vitro and in vivo experiments, and this radiosensitizing effect may be relevant to the expression of Glut1. However, the molecular mechanism of CD147-induced radiation resistance remains to be further explored. Firstly, We intend to investigate whether CD147 could interfere with the redox state to induce radiation resistance through the glycolytic pathway. Secondly, duing to the glucose transport as the first rate-limiting step of the glycolysis, we want to explore whether CD147 upregulates the glycolytic pathway depending on the interaction with GLUT1. Therefore, inhibition the expression or activation of CD147 could be an effective treatment strategy to overcome the radiation resistance in cervical carcinoma based on these sturdily scientific research results.

对于早期宫颈癌，手术和放疗的疗效相当；对于中晚期宫颈癌，放疗是最有效的治疗手段。但宫颈癌的放疗抵抗是影响疗效的主要原因之一。因此，如何识别放疗抵抗的病例，开发新的放疗增敏措施以提高疗效应是宫颈癌治疗的研究重点。我们的前期工作表明，宫颈癌组织样本中CD147的高表达与放疗抵抗及预后密切相关；体内外实验中，抑制CD147的表达，宫颈癌对放射线的敏感性明显增加，该效应与GLUT1存在一定的相关性。但CD147所致放疗抵抗的分子机制仍有待进一步探讨。本项目拟从体内外水平探讨CD147对宫颈癌细胞糖酵解途径的影响，明确CD147引起的糖代谢异常是否通过改变细胞氧化还原状态进而影响宫颈癌的放射敏感性；深入探讨CD147与GLUT1相互作用的分子机制及其对CD147介导的放疗抗性的影响，进一步阐明CD147影响宫颈癌放疗敏感性的分子机制。本项目有望为CD147成为宫颈癌治疗新靶点提供坚实的理论依据。

中晚期宫颈癌的标准治疗方案为含铂类的同步放化疗，但是加入化疗在一定程度上增加了毒性反应的发生率。寻找高效低度的个体化同步化疗方案是目前亟待解决的临床问题。本课题组通过对以顺铂为基础的3 种同步化疗方案进行疗效及毒性反应的回顾与比较，发现多西他赛/ 紫杉醇联合顺铂3 周方案的疗效优于传统顺铂单药每周方案，单药顺铂3 周方案的有效率高于每周方案，但差异无统计学意义，尚需要大样本临床试验验证。同时，本课题组还探索了低级别胶质瘤患者术前常规磁共振成像特征的预后价值、低级别胶质瘤患者术前血常规中性粒细胞/淋巴细胞比值的预后价值、早期鼻咽癌患者TOMO与VMAT放疗计划的剂量学比较。