Department of Medical Oncology, The First Affiliated Hospital of Fujian Medical University, , Fuzhou, Fujian Province, 350005, China.
Key Laboratory of Gastrointestinal Cancer, Ministry of Education, Fujian Medical University, Fuzhou, Fujian Province, 350108, China.
BMC Cancer. 2024 Sep 18;24(1):1158. doi: 10.1186/s12885-024-12887-2.
Post-translational modification pathway of protein ubiquitination is intricately associated with tumorigenesis. We previously reported elevated ubiquitin-conjugating enzyme 2T (UBE2T) as an independent risk factor in stage I lung adenocarcinoma and promoting cellular proliferation. However, its underlying mechanisms needed further investigation.
Immunohistochemistry was used to assess the expression of UBE2T and retinoic acid receptor-related orphan receptor α (RORA) in stage I LUAD. Cell proliferation, migration, and invasion of LUAD cell lines were measured by Cell Counting Kit-8 assay (CCK-8), Colony-forming assay and Transwell assay, respectively. Western blot analysis was performed to determine the expression of epithelial-mesenchymal transition (EMT) markers. A xenograft model was established to evaluate the proliferative capacity of UBE2T and its interaction with RORA in promoting LUAD. Mechanistic insights into the promotion of early-stage LUAD by UBE2T were obtained through luciferase reporter assay, chromatin immunoprecipitation and co-immunoprecipitation.
UBE2T and RORA expression was significantly up- and down-regulated in early-stage LUAD patients which's proved to be associated with unfavorable outcomes, strengthened cell proliferation, migration, EMT and invasion through its interaction with RORA both in vivo and in vitro. The growth NSCLC xenografts was reduced by down-expression of UBE2T but was suppressed by RORA knockout. Mechanistically, UBE2T mediated the ubiquitination of the intermediate transcription factor PBX1, which played a transcriptional role in downstream regulation of RORA.
The oncogenic role of UBE2T and the UBE2T-PBX1-RORA axis in driving malignant progression in Stage I LUAD had been established. UBE2T might be a novel and promising therapeutic target for LUAD treatment.
蛋白质泛素化的翻译后修饰途径与肿瘤发生密切相关。我们之前报道过，泛素结合酶 2T（UBE2T）作为 I 期肺腺癌的独立危险因素，促进细胞增殖。然而，其潜在机制仍需进一步研究。
采用免疫组织化学法检测 I 期 LUAD 中 UBE2T 和维甲酸受体相关孤儿受体 α（RORA）的表达。采用细胞计数试剂盒-8（CCK-8）法、集落形成实验和 Transwell 实验分别检测 LUAD 细胞系的细胞增殖、迁移和侵袭。Western blot 分析用于检测上皮间质转化（EMT）标志物的表达。建立异种移植模型，评估 UBE2T 及其与 RORA 相互作用在促进 LUAD 增殖中的作用。通过荧光素酶报告基因检测、染色质免疫沉淀和免疫共沉淀实验，获得 UBE2T 促进早期 LUAD 的机制见解。
UBE2T 和 RORA 的表达在早期 LUAD 患者中明显上调和下调，这与不良结局相关，通过其与 RORA 的相互作用，在体内和体外均增强了细胞增殖、迁移、EMT 和侵袭。UBE2T 表达下调可减少 NSCLC 异种移植瘤的生长，但 RORA 敲除可抑制其生长。机制上，UBE2T 介导中间转录因子 PBX1 的泛素化，在 RORA 的下游调节中发挥转录作用。
UBE2T 的致癌作用及其在驱动 I 期 LUAD 恶性进展中的 UBE2T-PBX1-RORA 轴已被确立。UBE2T 可能是 LUAD 治疗的一个新的有前途的治疗靶点。
