SIRT2介导成纤维细胞AKR1C3去乙酰化作用及相关胰腺癌耐药研究

化疗耐药是造成胰腺癌治疗失败的主要原因，目前研究主要围绕胰腺癌细胞本身，但进展有限。最近发现，肿瘤相关成纤维细胞（CAFs）激活致基质结缔组织化可能是胰腺癌耐药的关键因素，但机制远未阐明。申请人发现醛酮还原酶AKR1C3在胰腺癌耐药患者CAFs显著高表达，与CAFs激活和胶原合成密切相关。进一步研究显示SIRT2下调AKR1C3蛋白的乙酰化修饰，进而抑制CAFs激活，提示SIRT2对AKR1C3的调控可能是CAFs参与胰腺癌耐药的关键事件。基于此，本项目将利用PDX模型和CAFs-肿瘤细胞3D模型，研究AKR1C3乙酰化修饰对CAFs激活和耐药的影响，揭示SIRT2通过去乙酰化作用调控胰腺癌耐药的机制和通路；从而明确AKR1C3以及SIRT2的去乙酰化调控对CAFs激活及胰腺癌耐药的关键作用，从蛋白乙酰化调控的角度解析CAFs激活与结缔组织化的关键机制，为胰腺癌耐药治疗提供新思路和新策略。

Chemotherapy resistance is the main cause for the failure of pancreatic carcinoma treatment, and researches mainly focus on pancreatic carcinoma cells are without breakthroughs. It was recently discovered that the activation of cancer-associated fibroblasts (CAFs) may be a key role in drug resistance in pancreatic carcinoma, but the mechanism is far from elucidated. The applicant found that aldehyde ketone reductase AKR1C3 was significantly high expression in CAFs in patients with drug resistance, which was positively related to CAFs activation and collagen synthesis. Further research will adopt PDX model and CAFs-carcinoma cells model to show that SIRT2 regulate the deacetylation modification of AKR1C3 protein, thereby inhibiting the activation of CAFs, suggesting SIRT2-mediated the deacetylation of AKR1C3 may be a key event for CAFs activation in drug resistance in pancreatic carcinoma. This project will focus on the mechanism of drug resistance in pancreatic carcinoma through SIRT2-mediated deacetylation; Therefore, the key role of acetylation modification of AKR1C3 and SIRT2 on CAFs activation and pancreatic carcinoma drug resistance was revealed, providing new strategy for chemotherapy.