声动力对人舌鳞癌治疗的特异靶点与调控机制的研究

Sonodynamic therapy (SDT) is an innovative anti-cancer method which could induce apoptosis of cancer cells and no harm to healthy tissues. It has incomparable advantages which traditional surgery，chemotherapy and radiotherapy could not compare to. However, the anti-cancer mechanism of SDT is still unknown and clinical applications are difficult to control, which inhibit the development of clinical application. To realize the clinical application of SDT, we should solve those important problems of grasp the controllability of SDT and reveal the key control points in complicated mechanism. Base on our previous results that the cell cycle progression could significantly affect the apoptosis level which induced by SDT, the aims of the present study are establish the relationship between LIU-SDT-induced apoptosis and cell cycle intervention, determine the key link of the Quality Control in cell cycle progression. We first began to study the sensitivity of SAS cells in different cycle phases to SDT at same conditions by morphological, cellular and molecular biology methods in vivo and in vitro experiments. We want to find out the key protein factors which have relationship with Quality Control of cell cycle and apoptosis induced by SDT, analysis the relationship which exists between apoptosis induction and cell cycle interference, explore the pro-apoptotic regulatory mechanism of SDT. Consequently, it will provide controllable and synergistic targets for SDT being used in clinical cancer treatment.

声动力治疗（SDT）是一种有效促进癌细胞凋亡，对健康组织无损的革新抗癌疗法，具有传统手术及放、化疗无可比拟的优势。但SDT致癌细胞损伤更深层次的生物化学及调控机制尚不清楚，阻碍了此疗法的临床应用进程。 把握SDT治疗的可控性，揭示其治疗机制中的关键控制点，是将SDT应用于临床必须解决的重要问题。因此, 本项目基于细胞周期的进程会明显影响SDT的促凋亡水平的前期发现，将SDT诱导的细胞凋亡和细胞周期干预相联系, 确定其干扰细胞周期质量控制的关键环节，深入探讨SDT的促凋亡作用。拟用形态学、细胞及分子生物学手段，在细胞和动物水平，首次观察处于不同周期的舌鳞癌SAS细胞对相同条件SDT反应的敏感性，找到SDT影响细胞周期质控及与促凋亡通路间双向联系的因子，揭示SDT促舌癌细胞凋亡的调控机制，为SDT应用于临床治疗寻找到可控及联合增效的靶点。

声动力治疗（SDT）是一种有效促进癌细胞凋亡，对健康组织无损的革新抗癌疗法，具有传统手术及放、化疗无可比拟的优势。但SDT致癌细胞损伤更深层次的生物化学及调控机制尚不清楚，阻碍了此疗法的临床应用进程。 把握SDT治疗的可控性，揭示其治疗机制中的关键控制点，是将SDT应用于临床必须解决的重要问题。本项目通过对比不同声敏DVDMS和ALA代谢生成物PPIX的吸收发射光谱，在不同人舌鳞癌细胞（SAS，HSC-3和SCC-154细胞）中的吸收及药物毒性，筛选出针对不通舌鳞癌细胞声敏剂最佳浓度、孵育时间。细胞与裸鼠移植瘤模型实验发现，SDT可有效抑制肿瘤细胞的生长增殖，并可有效诱导细胞凋亡和自噬。人舌鳞癌组织样本检测发现GADD45α与MTK-1，p-JNK与 p-P38的表达随口腔癌的恶性分化程度的降低而表达增高，且GADD45α与MTK-1具有共定位及功能互作关系，体外实验证实SDT可消除GADD45α与MTK-1的互作作用从而诱导口腔鳞癌细胞的死亡，是SDT诱导舌鳞癌细胞死亡的重要靶点。SDT的抑瘤过程亦涉及ROS的生成，核损伤导致的细胞周期检查点蛋白的激活，及周期抑制和促凋亡双重相关蛋白P53的表达上调。本项目为SDT抑瘤作用调控机制的研究提供新的靶点，为未来SDT肿瘤治疗的临床应用提供了新的思路。