RNA干扰IGF-1R抑制鼻咽癌肝寡转移瘤消融后残留及肝内转移的作用及机制研究

Liver metastases often indicate a poor prognosis in NPC, but there is still a chance of cure for intrahepatic oligometastasis. In recent years, radiofrequency ablation has been widely used in the treatment of intrahepatic metastasis of nasopharyngeal carcinoma based on its nature of minimally invasiveness. However, the high rates of residual tumor and new intrahepatic metastasis after ablation are still great challenges. Previous studies have shown that insulin-like growth factor-1 receptor (IGF-1R) is highly expressed in both primary and hepatic metastases of nasopharyngeal carcinoma. The ligand IGF-1 is mainly synthesized by the liver and can increase proliferation and invasion of pharyngeal carcinoma cells and induced tumor epithelial-mesenchymal transition. Our preliminary experiments showed that RNA interference of IGF-1R could significantly inhibit the proliferation, invasion and epithelial-mesenchymal transition of nasopharyngeal carcinoma cells. Therefore, we propose a scientific hypothesis of using RNA interference of IGF-1R expression to inhibit residual lesions after hepatic metastases ablation and secondary hepatic metastases. In this project, we will establish a nude mice tumor model to explore the effectiveness of intratumoral injection of IGF-1R targeted siRNA and explore its mechanism of action; moreover, we will evaluate the value of combined radiofrequency ablation with intratumoral injection of IGF-1R Targeted siRNAs and determine the mechanism of interaction.

肝转移在鼻咽癌中常提示不良预后，但肝内寡转移的患者仍有治愈机会。近年来，射频消融因其微创、疗效确切的特点广泛应用于鼻咽癌肝内寡转移瘤的治疗，然而消融术后的残留率和肝内新发转移率高仍是治疗的难点。既往的研究表明胰岛素样生长因子-1受体(IGF-1R)在鼻咽癌原发灶及肝转移灶中均存在高表达的现象，其配体IGF-1主要由肝脏合成，能够促进鼻咽癌细胞增殖、侵袭及诱导细胞上皮间质转化。我们前期预实验发现利用RNA干扰IGF-1R能够显著抑制鼻咽癌细胞的增殖、侵袭及上皮间质转化能力。因此我们提出了利用RNA干扰IGF-1R表达抑制肝转移瘤消融后残留病灶以及继发肝内转移的科学假说。本项目将通过建立裸鼠鼻咽癌肝孤立/寡转移瘤模型，探索瘤内注射IGF-1R靶向性siRNA的有效性并探讨其作用机制；通过联用射频消融与瘤内注射IGF-1R靶向性siRNA探究两者用于鼻咽癌肝寡转移治疗最佳的序贯模式及相关机制。

肝转移在鼻咽癌中常提示不良预后，但肝内寡转移的患者仍有治愈机会。近年来，射频消融因其微创、疗效确切的特点广泛应用于鼻咽癌肝内寡转移瘤的治疗，然而消融术后的残留率和肝内新发转移率高仍是治疗的难点。既往的研究表明胰岛素样生长因子-1受体(IGF-1R)在鼻咽癌原发灶及肝转移灶中均存在高表达的现象，其配体IGF-1主要由肝脏合成，能够促进鼻咽癌细胞增殖、侵袭及诱导细胞上皮间质转化。我们前期预实验发现利用RNA干扰IGF-1R能够显著抑制鼻咽癌细胞的增殖、侵袭及上皮间质转化能力。因此我们提出了利用RNA干扰IGF-1R表达抑制肝转移瘤消融后残留病灶以及继发肝内转移的科学假说。本项目在实施过程中，我们成功完成了裸鼠鼻咽癌肝孤立/寡转移瘤模型的建立，将IGF-1R靶向性siRNA行探索性瘤内注射，尝试了不同的分组注药浓度对于肿瘤的抑制情况；我们发现瘤内直接注射siRNA干扰对于肿瘤IGF-1R的抑制不够持久，无法有效抑制消融后残留肿瘤的生长。因此我们改用瘤内注射腺病毒干扰IGF-1R的方法，体外实验提示腺病毒载体IGF-1R敲减能够实现稳定基因敲减效率达70%以上，并明显抑制肿瘤细胞的迁移效率。体内实验部分由于小鼠肝包膜成瘤模型建模不稳定仍在进行之中。另一方面，我们在泛癌水平综合评价了IGF-1以及IGF-1R对于肿瘤预后、免疫微环境的影响，发现其在肝癌、肾癌中的影响非常关键，对于靶向IGF-1/IGF-1R作为消融后辅助治疗在肝癌以及肾癌的价值提供了有力的数据支撑，相应研究成果已发表。截至目前，我们研究的结果提示提高靶向IGF-1R敲减的持续时间和敲减效率是其作为消融治疗后的辅助治疗意义的关键；采用腺病毒载体敲减IGF-1R与消融治疗嵌合仍值得进一步探索。IGF-1R作为靶点的价值可以在肝癌、肾癌中进一步探索。