DPP-4i经Nrf2/ROS途径促肿瘤迁移/侵袭的作用与机制研究

Diabetic patients with tumor are more and more. Medications used to treat hyperglycemia may have the potential impact on the biological behavior of tumors, and evaluation of the effect of anti-diabetic drugs is very important to the regimen. We have found in 7 kinds of tumor cells which were closely associated with diabetes that, DPP-4i (the drug newly listed on domestic market) promoted the migration and invasion of tumor cells obviously in Transwell experiments, and the effect of DPP-4i may induced by the increase of the persistence of tumor migration with the time-lapse microscopy and trank-plot analysis, and even promoted the pseudopod formation of the tumor cells which were observed under the microscopy. So, it is speculated that DPP-4i could promote the migration and invasion of tumor. In the reasearch, we will analyze the potential effect of DPP-4i on the tumor in different models (including tumor cells, and nude mice), the possible downstream pathways (DPP-4i promotes the migration and invasion of tumor cells may be associated with Nrf2/ROS according to the results of our studies), and than to explore the key role of Nrf2/ROS pathway in tumor (we had the Nrf2-shRNA plasmid). With the research, we will reveal the molecular links between DPP-4i and tumors, providing new evidence for therapeutic regimens of diabetic patients with tumor, and analyze the mechanism of signaling cascade, then providing the evidence for the role of microenviroment in migration and invasion.

糖尿病合并肿瘤人群日益扩增，而选取的降糖措施可能对肿瘤生物学行为产生影响，系统评价该影响对用药选择具有重要意义。项目组前期发现：在与糖尿病关系最密切的7种肿瘤细胞中，新型降糖药DPP-4i显著促进Transwell（+基质胶）效应与肿瘤转移相关蛋白表达；活细胞显示，该效应源于对瘤细胞定向迁移能力上调，并促其伪足形成。据此推测：DPP-4i可能促瘤细胞迁移与侵袭。项目拟于体外与裸鼠内，经荧光素酶标记、活体成像等阐明DPP-4i对肿瘤生物学行为这一潜在的影响；寻找其下游信号级联途径（预实验提示可能与核因子E2相关因子2（Nrf2）/活性氧簇（ROS）相关）；解析Nrf2/ROS对该作用的关键调控（Nrf2 shRNA病毒课题组具备）；从而揭示DPP-4i与肿瘤生物学行为关联，解析其信号级联机制，旨在探索糖尿病合并肿瘤合理用药原则，为深入理解肿瘤微环境影响瘤细胞转移/侵袭机制提供依据。

本课题组前期于肿瘤细胞内发现降糖药物可激活核因子E2相关因子2（Nrf2）及其下游Ⅱ相解毒酶上调；经Nrf2-siRNA与特异激动剂SF证实，该上调促进ROS堆积所致肿瘤细胞迁移与侵袭。此外在角质化细胞Hacat内发现高糖致ROS堆积，实验结果阐示Nrf2尚具备负性调控炎性转录因子NF-κB潜能；据此推测：降糖药物促糖尿病溃疡的额外获益。结合课题组的前期工作基础，我们将前期研究结果与临床应用相结合于糖尿病下肢血管病变、糖尿病溃疡的治疗工作中；从而制订基于不同并发症的糖尿病个体化抗氧化策略，为糖尿病血管并发症新药研发提供了新靶点，为抗氧化剂合理应用的临床实践带来新改变；针对不同并发症的糖尿病患者选择精准临床诊疗方案，为临床合理用药带来新认知。加强基础研究向临床应用转化，在抗氧化治疗策略的基础上，联合局部清创及下肢血管介入技术全面控制糖尿病血管并发症，尤其是下肢血管病变。