硫氧还蛋白调控HIF-2α应对肝癌转移过程中的氧化应激

Metastasis and recurrence seriously affect the long-term prognosis of patients with hepatocellular carcinoma (HCC). Thioredoxin(TXN) has been proved to be a key molecule to promote metastasis. The overexpression of TXN is closely associated with the metastasis of HCC, and responsible for the stable expression of HIF-2α. Sustained expression of HIF-2α may induce apoptosis in inducible pluripotent stem cells, but not in cancer stem cells or embryonic stem cells. The adaptive changes of tumor cells during metastasis are quite similar to the characteristcs of self-renewal stem cells. Oxidative stress inhibits metastasis by tumor cells. However, the potential mechanism of TXN, also known as a potent anti-oxidant, is still not clear. Previously we found that TXN may be benefitial to DNA damage repair during hypoxia, modulates the stability and activity of HIF-2α, and involves in regulation of cellular stemness. This project will focus on the effects of TXN and HIF-2α during oxidative stress. The post-translational modification of TXN on HIF-2α during oxidative stress and the subsequent cellular response will be investigated in detail. The relationship between the function of TXN/HIF-2α and oxidative stress during metastasis will be elucidated. This study will help to understand the underlying mechanism of TXN in coping with oxidative stress to promote metastasis of HCC.

转移复发严重影响肝癌疗效。TXN是促进转移的关键分子，与肝癌转移密切相关，过表达TXN诱导肝癌细胞中HIF-2α的稳定表达。稳定表达HIF-2α可促进成熟的诱导多能干细胞iPSC凋亡，但对肿瘤干细胞或胚胎干细胞无杀伤作用。肿瘤细胞转移过程中应对氧化应激的适应性改变与干细胞的自我更新的特点极为相似。氧化应激抑制肿瘤细胞转移，而TXN具有强抗氧化作用，但其对抗氧化应激的具体机制尚不清楚。前期发现TXN有助于缺氧导致的DNA损伤修复，调控HIF-2α的稳定性与活性，参与肝癌干细胞样细胞的分化调节。本项目系统研究TXN及HIF-2α应对氧化应激促进肝癌转移的作用关系。重点阐述氧化应激时TXN介导的翻译后修饰调节对HIF-2α活性的影响及后续细胞反应，阐明肝癌转移过程中TXN/HIF-2α功能变化与氧化应激的关系。该研究将有助于明确TXN应对氧化应激促进转移的机制，为肝癌转移的防治提供新的理论依据。

肝癌的转移复发影响肝癌疗效的关键。TXN作为调控氧化应激的关键分子，与肝癌转移密切相关，氧化应激抑制肿瘤细胞转移，而TXN具有强抗氧化作用，但其对抗氧化应激促进肝癌转移的具体机制尚不清楚。本研究发现，缺氧预处理后的肝癌细胞通过尾静脉注射的方法注入裸鼠体内，其在肺中存活的时间与对照组相比明显延长，表明HIF-2α在肝癌细胞应对氧化应激发生转移的过程中亦发挥重要作用。前期研究表明过表达TXN可诱导肝癌细胞中HIF-2α的稳定表达，进一步探究后发现TXN通过调控SENP1的表达，影响HIF-2α的SUMO化进而改变HIF-2α的稳定性。同时SIRT1的SUMO化也受到影响，使得SIRT1的活性改变，进而影响HIF-2α的活性。本项目系统研究了TXN与HIF-2α的相互作用关系，以及两者在应对氧化应激促进肝癌转移的作用关系。重点阐述了氧化应激时TXN介导的翻译后修饰调节对HIF-2α活性和稳定性的影响，同时发现可能通过EMT通路促进肝癌转移，该研究阐明了肝癌转移过程中TXN/HIF-2α功能变化与氧化应激的关系，将有助于明确TXN应对氧化应激促进肝癌转移的机制，为防治肝癌的转移提供新的理论依据。