【作者】 杨雪；

【导师】 王子艳；

【作者基本信息】 电子科技大学 ， 生物学， 2023， 硕士

【摘要】 肝癌的发病率和死亡率在全世界都极高。当前肝癌治疗方法以手术为主,但长期预后差,患者术后10年生存率仅为7.2%。促发肝癌的因素复杂,90%以上的肝癌起源于慢性肝病,其中非病毒非酒精性肝炎引起的肝癌发病率正在快速升高。已有研究证实,肝癌细胞糖脂代谢的重编程在肝癌的发生发展过程中发挥重要作用,而且重塑糖脂代谢通路可以达到抑制肝癌细胞生长的目的。调控脂质过氧化和铁离子依赖的铁死亡正在成为肿瘤治疗的新突破口,但是如何通过重塑肿瘤细胞糖脂代谢促发其走向铁死亡仍需深入探讨。转录因子SOX8与多种肿瘤发生相关,但其具体的调控作用与分子机制缺乏深入研究。本论文旨在探索肿瘤细胞中SOX8调控脂质代谢与铁死亡的生物学作用与分子机制。在LM3等肝癌及前列腺癌细胞系中过表达SOX8后,对细胞内的铁死亡信号,脂质合成以及能量代谢进行研究分析,发现SOX8高表达广泛抑制了肿瘤细胞脂肪酸的从头合成相关酶的表达,下调磷酸戊糖代谢途径,减少细胞内NADPH合成,打破细胞内氧化还原平衡,增加活性氧自由基及氧化脂质含量,且破坏了线粒体结构及功能。SOX8提高转铁蛋白及转铁蛋白受体蛋白表达,升高细胞内亚铁离子水平,诱导了肿瘤细胞铁死亡的发生。此外,高表达SOX8显著抑制免疫缺陷小鼠体内的肿瘤生长。本论文主要阐明了SOX8经由糖脂代谢调控肿瘤细胞铁死亡的分子机制。SOX8不仅能抑制脂肪酸的从头合成酶的表达,并且能同时抑制糖酵解、TCA循环和磷酸戊糖途径,从而限制脂质从头合成原料乙酰Co A和NADPH的生成,全面降低脂质合成。此外,SOX8通过下调NADPH的合成破坏了细胞内的抗氧化还原平衡,并损伤线粒体电子传递链造成ROS大量堆积,同时增加铁死亡关键蛋白的表达,促进肿瘤细胞的铁死亡。本研究揭示了转录因子SOX8新的生物学作用,SOX8重塑了肿瘤细胞的糖脂代谢与铁离子代谢,打破了肿瘤细胞的氧化还原平衡,为靶向铁死亡的肿瘤治疗提供了一条新的思路与策略。更多还原

【Abstract】 The incidence and mortality of hepatocellular carcinoma(HCC)are extremely high worldwide.The current treatment for HCC is mainly surgery,but patients with HCC have a poor prognosis and the 10-year survival rate is only 7.2%.The factors that promote HCC are complex.More than 90% of HCC originate from chronic liver disease,and the incidence of HCC caused by non-viral non-alcoholic hepatitis is rapidly increasing.Previous Studies have confirmed that remodeling of glycolipid metabolism plays an important role in HCC progression,and the intervention of glycolipid metabolism pathways would inhibit the growth of HCC cells.Lipid peroxidation and iron-dependent ferroptosis is becoming a new target in cancer treatment.However,how to induce ferroptosis by reprogramming glucose and lipid metabolism of tumor cells needs to be further explored.The transcription factor SOX8 is associated with multiple cancer development,but the regulatory mechanism of SOX8 has not been deeply studied.This project aims to explore the biological role and molecular mechanism of SOX8 in regulating lipid metabolism and ferroptosis in cancer cells.We analyzed the ferroptotic signal,lipid synthesis and energy metabolism by overexpression of SOX8 in HCC and prostate cancer cells.We found that overexpression of SOX8 widely inhibited the expression of de novo synthesis-related enzymes of fatty acids and the expression of enzymes in the cellular pentose phosphate pathway,reduced NADPH synthesis,broken the balance of redox system,destroyed the structure and function of mitochondria,damages the electron transport chain to cause the accumulation of ROS and lipid peroxides.Overexpression of SOX8 increased the expression of ferroptosis-related genes(transferrin,transferrin receptor protein,15-LOX et al)and the intracellular ferrous ion levels,which finally promoted ferroptosis.Moreover,SOX8 inhibited the HCC growth in immunodeficient mice.The study elucidates the molecular mechanism of SOX8 in regulating ferroptosis by participating in glycolipid metabolism of cancer cells.SOX8 could not only inhibit the expression of fatty acid de novo synthase,but also represses glycolysis,TCA cycle and pentose phosphate pathway.SOX8 remodels the glycolipid and iron metabolism of cancer cells to break the redox balance.This study provides a new strategy for targeting ferroptosis in cancer therapy.更多还原