TRIM31调控HO-1泛素化在乳腺癌恶性进展与铁死亡中的作用和机制

高侵袭转移性乳腺癌细胞具备适应应激条件下生存的能力，能够降低对化疗药物的应答，导致肿瘤转移与复发，是乳腺癌患者死亡的最主要原因。本项目组前期研究发现TRIM31在乳腺癌肿瘤组织中表达降低；而TRIM31能结合HO-1促进其泛素化降解，导致细胞内氧化还原内稳态紊乱进而抑制乳腺癌细胞生长转移，结果表明乳腺癌细胞通过降低TRIM31表达促进其生长转移；但同时发现干扰TRIM31使乳腺癌细胞对铁死亡诱导剂Erastin与BSO更敏感；提示TRIM31功能具有条件差异性。本项目拟在前期工作基础上，阐明TRIM31通过介导HO-1泛素化降解进而调控乳腺癌生长转移的分子机制；探究TRIM31/HO-1信号轴在乳腺癌细胞铁死亡中的作用；分析乳腺癌细胞TRIM31表达降低机制；结合临床样本明确TRIM31/HO-1信号轴作为乳腺癌恶性进展标志物的潜在临床价值，为铁死亡诱导剂精准应用于乳腺癌治疗提供新的策略。

Highly invasive and metastatic breast cancer (BC) cells have the ability to adapt to various stressful conditions, and decrease sensitivity of cancer cells to chemotherapeutic drugs, leading to tumor metastasis and recurrence, which is the major cause of cancer-related deaths in BC patients. Recently, we found that both the mRNA and protein levels of TRIM31 were significantly down-regulated in BC tissues compared to normal tissues. Overexpression of TRIM31 declined the growth and metastasis of BC cells in vitro and in vivo. We demonstrated that TRIM31 interacted with HO-1, and promoted HO-1 protein ubiquitination and degradation, resulting in reduced enzyme activity of HO-1 and disruption of intracellular redox homeostasis. However, knockdown of TRIM31 markedly enhanced the cytotoxicity of Erastin and BSO, and the elevated intracellular Fe2+ level and lipid peroxidation triggered by Erastin and BSO. These data suggest that TRIM31 is a multifunction protein that regulates cell survival in a state condition dependent manner. In the present project, we aim to investigate the molecular mechanism by which TRIM31-mediated HO-1 protein ubiquitination and degradation contribute to the growth and metastasis of BC cells, and clarify the role of TRIM31/HO-1 axis in ferroptosis of BC cells. The decreased expression of TRIM31 in BC will be further explored. Moreover, we will evaluate the pathological correlations of TRIM31/HO-1 axis with metastasis, adjuvant chemotherapy, recurrence, and prognosis of BC patients. Our finding will highlight the significance of TRIM31/HO-1 axis in the progression and prognosis of BC, and provide a new strategy for the anti-cancer therapeutic potential of ferroptosis inducing compounds in BC.