Myosin II-YAP 信号轴调节胰腺癌CAFs活化介导125I放射性粒子辐射抵抗的机制研究

Iodin-125 seeds implantation has shown to have certain efficacy in pancreatic carcinoma treatment. However, less significant long term survival improvement resulting from radioresistance is the bottle neck of its limited clinical application. Mechanotransduction between cancer associated fibroblasts (CAFs) and stiffness matrix is the key process of pancreatic fibrosis, which is the major reason for its radioresistance. Our preliminary studies observed that enhanced activation of YAP/myosin II is associated with radioresistance patients in Iodin-125seeds therapy. Myosin II-YAP signaling axis plays a key role in cell-matrix mechanotransduction. Therefore, we propose that myosin II-YAP signaling axis could contribute to radioresistance by activating CAFs and regulating mechanotransduction with stiffness matrix. This study aims to clarify the regulatory mechanism of myosin II-YAP signaling axis in ionizing radiation induced stiffness matrix via in vitro and vivo models, which will provide a new theoretical and experimental evidence in improving the effect of pancreatic radiotherapy.

125I放射性粒子组织间植入治疗胰腺癌的短期疗效已经被临床接受，但辐射抵抗导致的远期生存率改善不明显是其临床应用瓶颈。从微环境入手改善胰腺癌辐射抵抗是目前热点。持续并加重的基质硬化是胰腺癌辐射抵抗关键机制之一，其中癌症相关成纤维细胞(CAFs)与硬化基质之间的生物力转导过程是基质硬化的重要环节。本课题组前期借助病理和蛋白芯片通过生物信息学方法发现YAP和Myosin II在辐射抵抗临床病例中活化增高。Myosin II-YAP信号轴是细胞-基质间生物力转导的关键轴。因此我们认为辐射可通过Myosin II-YAP信号轴调节胰腺癌CAFs活化，进而影响基质硬化,导致辐射抵抗。本研究拟从细胞、分子以及动物实验水平来验证 Myosin II-YAP信号轴在辐射导致基质硬化中的调控机制，以期为进一步提高125I放射性粒子植入胰腺癌治疗疗效找到新的突破口。

胰腺癌是人类死亡率最高的肿瘤之一, 80%无法手术切除，平均中位生存率仅 6 个月。胰腺癌的治疗一直是医学界面临的一个重大难题和严峻挑战。以基质硬化为特征的间质纤维化不仅可从物理上削弱辐射射线的穿透力，也妨碍了药物传递，引起放化疗双重抵抗；并且硬化的基质可妨碍免疫细胞的侵入，削弱免疫治疗的效果。另外，大量炎症细胞在硬化的基质中聚集，可分泌多种炎性因子，进一步加重基质硬化。因此，辐射导致的胰腺癌基质硬化是一个自我循环升级的“恶巢”。我们认为阻断该过程是解决临床辐射远期疗效不明显的关键所在。本项目通过相关实验论证了：1）通过体外细胞实验验证里RhoA通过激活YAP途径增强了CAFs的活性，进而导致辐射抵抗，明确可通过抑制RhoA表达而抑制CAFs活性，从而降低胰腺癌细胞的辐射抵抗。2）通过体外细胞实验验证异质核核糖核蛋白hnRNPC确实通过调控IQGAP3表达来调控胰腺癌EMT过程。3）基于与胰腺癌相似的基质硬化造成的特殊酸性环境，构建局部释放药物及基因载体，在局部载药实现减缓胰腺癌辐射抵抗上做出一定探索。本项目研究成果将为削弱胰腺癌基质硬化提供思路及依据。