NDRG1/β-catenin/SIRT3功能轴调控胰腺癌糖酵解影响其恶性生物学行为的实验研究

Enhanced aerobic glycolysis contributes to malignancies including uncontrolled proliferation, invasion and metastasis, leading to unfavorable prognosis of pancreatic cancer. Some most recent studies have pointed out that inhibition of malignancies of pancreatic cancer could be achieved via suppression of glycolysis. Our previous studies demonstrated that: Tumor suppressor NDRG1 could inhibit proliferation and glycolysis in pancreatic cancer; the transcription of glycolysis enzyme SIRT3 could be induced by NDRG1; β-catenin could be regulated by NDRG1, and was an effector protein in NDRG1 mediated tumor suppression; β-catenin inhibited expression of SIRT3, leading to enhanced glycolysis. Based on these observations, we put forward the existence of NDRG1/β-catenin/SIRT3 axis, which regulated malignancies of pancreatic cancer thorough glycolysis regulation. The present study aims to carry out the following studies: ①Analyzing the regulatory correlations between NDRG1, β-catenin and SIRT3 to verify the existence of the NDRG1/β-catenin/SIRT3 axis; ② Elucidating the contribution of NDRG1/β-catenin/SIRT3 axis to malignant properties of pancreatic cancer;③Intervening the NDRG1/β-catenin/SIRT3 axis in the hope of providing potential prognostic and treatment targets.

糖代谢异常与胰腺癌增殖、侵袭转移等恶性生物学行为密切相关，是导致胰腺癌不良预后的重要原因。近年来研究结果提示，干预糖酵解可以抑制胰腺癌恶性生物学行为。我们前期研究发现：抑癌因子NDRG1可以抑制胰腺癌恶性增殖以及糖酵解效应；NDRG1可诱导糖酵解关键酶SIRT转录；β-catenin受NDRG1调控，是NDRG1抑制肿瘤恶性生物学行为的效应分子；β-catenin可以调控SIRT3表达，进而抑制胰腺癌的糖酵解。由此我们提出存在NDRG1/β-catenin/SIRT3功能轴，通过调控胰腺癌糖酵解效应，进而影响胰腺癌的恶性生物学行为。本项目拟围绕此功能轴在胰腺癌中开展以下研究：①分析NDRG1、β-catenin和SIRT3分子之间的调控关系，明确此功能轴的存在；②探索此功能轴调控糖酵解效应，进而影响胰腺癌恶性生物学行为的功能研究；③通过体内外实验干预此功能轴，为胰腺癌的诊疗提供潜在靶点。

糖代谢异常与胰腺癌增殖、侵袭转移等恶性生物学行为密切相关，是导致胰腺癌不良预后的重要原因。近年来研究结果提示，干预糖酵解可以抑制胰腺癌恶性生物学行为。我们前期研究发现：抑癌因子NDRG1可以抑制胰腺癌恶性增殖以及糖酵解效应；NDRG1可诱导糖酵解关键酶SIRT转录；β-catenin受NDRG1调控，是NDRG1抑制肿瘤恶性生物学行为的效应分子；β-catenin可以调控SIRT3表达，进而抑制胰腺癌的糖酵解。因此我们在本课题中提出存在NDRG1/β-catenin/SIRT3功能轴，通过调控胰腺癌糖酵解效应，进而影响胰腺癌的恶性生物学行为。本课题在胰腺癌中开展了以下研究：①分析NDRG1、β-catenin和SIRT3分子之间的调控关系，明确此功能轴的存在；②探索此功能轴调控糖酵解效应，进而影响胰腺癌恶性生物学行为的功能研究；③通过体内外实验干预此功能轴，为胰腺癌的诊疗提供潜在靶点。本课题组还发现ARF6及FBW7这两个调控胰腺癌糖酵解代谢分子，与铁死亡关系密切；我们研究发现FBW7通过NR4A1抑制SCD1表达，进而影响脂质过氧化应激反应，参与胰腺癌细胞铁死亡调控。同时，我们还发现MBD1通过调控MET，参与了胆囊癌吉西他滨耐药。本研究结果有望能启发相关抗胰腺癌细胞代谢治疗方式，同时对铁死亡的研究有希望开发新一类肿瘤治疗药物。