G-MDSCs诱导的SENP3活化调控膀胱癌细胞EMT在新辅助化疗耐药中的机制研究

The mechanism of drug resistance in bladder cancer with neoadjuvant chemotherapy （NAC）is an urgent problem. Our previous study has confirmed that granulocytic myeloid-derived suppressor cells(G-MDSCs) are closely related to chemoresistance in bladder cancer. G-MDSCs is an inducing factor for ROS, which can induce EMT. We also find ROS promoted the expression of SENP3, and SENP3 was associated with EMT in bladder cancer tissues. Whether ROS secreted by G-MDSCs activates SENP3, which induces the occurrence of EMT leading to chemoresistance, and the mechanism remains to be further studied. In this study, we used G-MDSCs and bladder cancer cells co-culture system and mouse bladder cancer to clarify the role of G-MDSCs in the activation of SENP3 by secreting ROS，which regulate the occurrence of EMT on chemoresistance; To explore SENP3 regulating the de-SUMO modification of EMT related transcription factors and driving the process of EMT; To evaluate the effects of SENP3 and selected key transcription factors on neoadjuvant chemotherapy sensitivity and prognosis. This study will clarify the mechanism of G-MDSCs and tumor cells interaction on neoadjuvant chemotherapy and provide a theoretical basis for personalised treatment.

膀胱癌新辅助化疗（NAC）耐药是临床急待解决的难题。我们研究发现：粒细胞型髓源性抑制细胞（G-MDSCs）与NAC耐药相关；G-MDSCs通过分泌ROS调控膀胱癌细胞EMT发生；且ROS促进SENP3表达；组织标本中进一步证实SENP3与EMT相关。那么G-MDSCs分泌的ROS，是否通过活化SENP3，进而诱导膀胱癌细胞EMT发生，介导NAC耐药?尚待深入研究。本研究将以体外G-MDSCs和膀胱癌细胞共培养系统和原位肌层浸润性膀胱癌小鼠为模型，明确G-MDSCs通过分泌ROS活化SENP3介导膀胱癌EMT发生在NAC耐药中的作用；探寻SENP3对何种关键转录因子进行de-SUMO修饰，从而驱动EMT发生的分子机制；评估SENP3和筛选的关键转录因子对NAC敏感性及预后的影响。本研究将阐明G-MDSCs和肿瘤细胞的相互作用在NAC耐药中的机制，并为个体化治疗提供理论依据。

膀胱癌新辅助化疗耐药是临床面临的难题。我们前期研究发现粒细胞型髓源性抑制细胞（G-MDSC）与膀胱癌新辅助化疗耐药相关。但是G-MDSC导致新辅助化疗耐药的机制尚不明确。本项目中，我们通过G-MDSC与膀胱肿瘤细胞的共培养体系，证实G-MDSCs通过分泌ROS调控膀胱癌细胞发生EMT,导致化疗耐药，同时发现ROS可瞬时激活膀胱癌细胞中SENP3的表达。进一步利用原位膀胱癌小鼠模型证实了G-MDSC通过分泌ROS在新辅助化疗耐药中的作用。最后通过收集的新辅助化疗后行切除手术的膀胱癌患者组织样本发现SENP3和新辅助化疗敏感性具有相关性。综上所述，G-MDSCs通过分泌ROS活化SENP3导致膀胱癌细胞发生EMT,进而导致新辅助化疗耐药。通过我们的研究为膀胱癌新辅助化疗敏感性提供特异标志物，为膀胱癌新辅助化疗耐药的应对提供新思路。