Department of Breast Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
Int J Oncol. 2022 Dec;61(6). doi: 10.3892/ijo.2022.5434. Epub 2022 Oct 5.
Breast cancer has become the leading cause of death in females. After comprehensive treatment, the lives of patients are still threatened by tumor metastasis and recurrence. Therefore, there is an urgent requirement to find an effective treatment target for breast cancer. Tripartite motif‑containing 35 (TRIM35) is a ubiquitin ligase that has an important role in the recurrence and metastasis of malignant tumors. However, the role of TRIM35 in breast cancer has thus far remained elusive. The expression of TRIM35 was examined in a bioinformatics database and the effects of TRIM35 on the malignant biological behavior of breast cancer were analyzed by Cell Counting Kit‑8, cell migration and invasion assays, flow cytometry and nude mouse xenograft experiments. It was determined that TRIM35 was downregulated in breast cancer tumor tissues and cell lines. Patients with low TRIM35 expression had shorter overall survival. Functional assays revealed that overexpression of TRIM35 inhibited the proliferation, migration and invasion, and promoted apoptosis of breast cancer cells. Furthermore, overexpression of TRIM35 was able to inhibit the Warburg effect in breast cancer cells. Mechanistic analyses indicated that TRIM35 regulates the transition of tetramers and dimers of pyruvate kinase M2 (PKM2) through ubiquitination and thereby affects the Warburg effect. In conclusion, the present results indicated that TRIM35 regulates the tetramer and dimer transition of PKM2 through ubiquitination and affects the malignant biological behavior of breast cancer by modulating the Warburg effect.
乳腺癌已成为女性死亡的主要原因。经过综合治疗，患者的生命仍受到肿瘤转移和复发的威胁。因此，迫切需要寻找乳腺癌的有效治疗靶点。三结构域蛋白 35（TRIM35）是一种泛素连接酶，在恶性肿瘤的复发和转移中具有重要作用。然而，TRIM35 在乳腺癌中的作用迄今仍不清楚。本研究在生物信息学数据库中检测了 TRIM35 的表达，并通过细胞计数试剂盒-8、细胞迁移和侵袭实验、流式细胞术和裸鼠异种移植实验分析了 TRIM35 对乳腺癌恶性生物学行为的影响。结果表明，TRIM35 在乳腺癌肿瘤组织和细胞系中表达下调。TRIM35 低表达的患者总生存期较短。功能实验表明，过表达 TRIM35 抑制乳腺癌细胞的增殖、迁移和侵袭，并促进其凋亡。此外，过表达 TRIM35 能够抑制乳腺癌细胞的瓦博格效应。机制分析表明，TRIM35 通过泛素化调节丙酮酸激酶 M2（PKM2）的四聚体和二聚体的转变，从而影响瓦博格效应。综上所述，本研究结果表明，TRIM35 通过泛素化调节 PKM2 的四聚体和二聚体转变，并通过调节瓦博格效应影响乳腺癌的恶性生物学行为。
