Department of Gynecology, Women's Hospital of Nanjing Medical University (Nanjing Women and Children's Healthcare Hospital), 123 Mochou Rd, Nanjing, 210004, Jiangsu, China.
Nanjing Maternal and Child Health Care Institute, Women's Hospital of Nanjing Medical University (Nanjing Women and Children's Healthcare Hospital), Nanjing, 210004, Jiangsu, China.
Mol Cell Biochem. 2024 Dec;479(12):3405-3424. doi: 10.1007/s11010-023-04920-y. Epub 2024 Feb 17.
The E3 ubiquitin ligase Tripartite-motif 3 (TRIM3) is known to play a crucial role in tumor suppression in various tumors through different mechanisms. However, its function and mechanism in ovarian cancer have yet to be elucidated. Our study aims to investigate the expression of TRIM3 in ovarian cancer and evaluate its role in the development of the disease. Our findings revealed a significant decrease in TRIM3 mRNA and protein levels in ovarian cancer tissues and cells when compared to normal ovarian epithelial tissues and cells. Furthermore, we observed a negative correlation between the protein level of TRIM3 and the FIGO stage, as well as a positive correlation with the survival of ovarian cancer patients. Using gain and loss of function experiments, we demonstrated that TRIM3 can inhibit cell proliferation, migration and invasion of the ovarian cancer cells in vitro, as well as suppress tumor growth in vivo. Mechanistic studies showed that TRIM3 interacts with lactate dehydrogenase A, a key enzyme in the glycolytic pathway, through its B-box and coiled-coil domains and induces its ubiquitination and proteasomal degradation, leading to the inhibition of glycolytic ability in ovarian cancer cells. RNA-sequencing analysis revealed significant alterations in the phosphatidylinositol signaling pathways upon TRIM3 overexpression. Additionally, overexpression of TRIM3 inhibited the phosphorylation of AKT. In conclusion, our study demonstrated that TRIM3 exerts a tumor-suppressive effect in ovarian cancer, at least partially, by downregulating LDHA and inhibiting the AKT signaling pathway, and thus leading to the inhibition of glycolysis and limiting the growth of ovarian cancer cells.
E3 泛素连接酶三基序蛋白 3（TRIM3）已知通过不同的机制在各种肿瘤中发挥肿瘤抑制作用。然而，其在卵巢癌中的功能和机制尚未阐明。我们的研究旨在探讨 TRIM3 在卵巢癌中的表达，并评估其在疾病发展中的作用。我们的研究结果表明，与正常卵巢上皮组织和细胞相比，卵巢癌组织和细胞中的 TRIM3 mRNA 和蛋白水平显著降低。此外，我们观察到 TRIM3 蛋白水平与 FIGO 分期呈负相关，与卵巢癌患者的生存呈正相关。通过增益和缺失功能实验，我们证明 TRIM3 可以抑制卵巢癌细胞在体外的增殖、迁移和侵袭，以及抑制体内肿瘤生长。机制研究表明，TRIM3 通过其 B 盒和卷曲螺旋结构域与糖酵解途径中的关键酶乳酸脱氢酶 A（lactate dehydrogenase A，LDHA）相互作用，并诱导其泛素化和蛋白酶体降解，从而抑制卵巢癌细胞的糖酵解能力。RNA 测序分析显示，TRIM3 过表达后，磷脂酰肌醇信号通路发生显著改变。此外，TRIM3 过表达抑制 AKT 的磷酸化。总之，我们的研究表明，TRIM3 通过下调 LDHA 并抑制 AKT 信号通路，在卵巢癌中发挥肿瘤抑制作用，至少部分是通过抑制糖酵解和限制卵巢癌细胞的生长来实现的。
