四君子汤通过AnnexinA3介导ATP7A/7B激活P53信号通路逆转大肠癌奥沙利铂耐药的机制研究

化疗耐药是影响结直肠癌治疗和患者预后的重要原因，因此研究其耐药机制对于改善预后至关重要。文献表明，AnnexinA3高表达的肿瘤细胞对铂类药物的耐药性明显增强，本课题组前期结果显示，AnnexinA3在结肠癌耐药细胞高表达，且能够负向调控P53信号通路，但其机制尚未明确。另有研究显示，铜转运蛋白ATP7A/7B参与调控铂类药物的摄入与外排，ATP7A/7B蛋白高表达可以诱导肿瘤细胞对铂类药物耐药，本课题组前期发现结肠癌耐药细胞中ATP7A/7B的表达水平显著高于亲本细胞，且健脾益气代表方四君子汤能够增加结直肠癌化疗药物敏感性。因此，我们提出科研假设: AnnexinA3作用于ATP7A/7B，抑制P53信号通路激活，从而介导L-OHP耐药，四君子汤通过调控该通路逆转结直肠癌对奥沙利铂的耐药。本项目拟从临床水平、细胞分子生物学和动物水平，展开对四君子汤药效和作用机制的探讨。

Chemotherapy resistance is an important factor affecting the treatment and prognosis of colon cancer, therefore, it is crucial to study the mechanism of chemotherapy resistance for improving the prognosis.Previous reports have suggested that the tumor cells with high expression of AnnexinA3 have significantly increased resistance to platinum drugs. We also found that AnnexinA3 is highly expressed in colon cancer resistant cells and can negatively regulate the P53 signaling pathway. However, the mechanism that AnnexinA3 negatively regulates the P53 signaling pathway remains unclear. Studies also have shown that the copper transporter ATP7A/7B is involved in regulating the uptake and efflux of Platinum-based drugs, and high expression of ATP7A/7B protein can induce tumor cells resistance to platinum drugs. Our previous research showed that the expression of ATP7A/7B in colon cancer resistant cells was significantly higher than parent cells, and the Sijunzi Decoction can positively increase the sensitivity of chemotherapy drugs in colon cancer. Therefore, we speculated that the mechanism of AnnexinA3 mediating L-OHP resistance is that AnnexinA3 inhibits activation of the P53 signaling pathway via ATP7A/7B, and Sijunzi Decoction reverses colon cancer resistance to oxaliplatin by regulating the Annexin A3/ATP7A/7B/P53 signaling pathway. We will study the efficacy and mechanism of Sijunzi Decoction from the clinical level, cell molecular biology and animal level by the project.