Department of Internal Medicine, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241000, Anhui, China.
Department of Respiratory Medicine, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, 2 Zheshan West Road, Wuhu, 241000, Anhui, China.
Cell Commun Signal. 2022 May 9;20(1):62. doi: 10.1186/s12964-022-00875-7.
Recent studies have indicated that some members of the tripartite motif (TRIM) proteins function as important regulators for non-small cell lung cancer (NSCLC), However, the regulatory mechanism underpinning aberrant expression of TRIM in NSCLC remains unclear. Here we report that TRIM15 plays important roles in NSCLC progression through modulating Keap1-Nrf2 signaling pathway.
TRIM15 expression was evaluated by western blot analysis, tissue microarray-based immunohistochemistry analysis. The interactions between TRIM15 and Keap1 were analyzed by co-immunoprecipitation (Co-IP) and immunofluorescence co-localization assay. The correlation between TRIM15 and Keap1 was measured by Co-IP and ubiquitination analysis in vitro. Gain- and lost-of-function experiments were used to detect TRIM15 promotes proliferation and invasion of NSCLC cells both in vitro and vivo.
Here, we revealed that TRIM15 was frequently upregulated in NSCLC samples and associated with poor prognosis. Functionally, TRIM15 knockdown resulted in decreased cancer cell proliferation and metastasis, whereas ectopic TRIM15 expression facilitated tumor cancer cell proliferation and metastasis in vitro and in vivo. Moreover, TRIM15 promoted cell proliferation and metastasis depends on its E3 ubiquitin ligase. Mechanistically, TRIM15 directly targeted Keap1 by ubiquitination and degradation, the principal regulator of Nrf2 degradation, leading to Nrf2 escaping from Keap1-mediated degradation, subsequently promoting antioxidant response and tumor progression.
Therefore, our study characterizes the pivotal roles of TRIM15 promotes NSCLC progression via Nrf2 stability mediated by promoting Keap1 ubiquitination and degradation and could be a valuable prognostic biomarker and a potential therapeutic target in NSCLC. Video Abstract.
最近的研究表明，三部分基序（TRIM）蛋白的某些成员作为非小细胞肺癌（NSCLC）的重要调节剂。然而，TRIM 在 NSCLC 中异常表达的调节机制尚不清楚。在这里，我们报告 TRIM15 通过调节 Keap1-Nrf2 信号通路在 NSCLC 进展中发挥重要作用。
通过 Western blot 分析、组织微阵列免疫组织化学分析评估 TRIM15 的表达。通过共免疫沉淀（Co-IP）和免疫荧光共定位分析分析 TRIM15 和 Keap1 之间的相互作用。通过 Co-IP 和体外泛素化分析测量 TRIM15 和 Keap1 之间的相关性。通过体外和体内 gain- 和 loss-of-function 实验检测 TRIM15 促进 NSCLC 细胞的增殖和侵袭。
在这里，我们揭示了 TRIM15 在 NSCLC 样本中经常上调，并与预后不良相关。功能上，TRIM15 敲低导致癌细胞增殖和转移减少，而异位 TRIM15 表达促进了体外和体内肿瘤癌细胞的增殖和转移。此外，TRIM15 促进细胞增殖和转移依赖于其 E3 泛素连接酶。机制上，TRIM15 通过泛素化和降解直接靶向 Keap1，这是 Nrf2 降解的主要调节因子，导致 Nrf2 逃避 Keap1 介导的降解，随后促进抗氧化反应和肿瘤进展。
因此，我们的研究通过促进 Keap1 泛素化和降解来表征 TRIM15 通过 Nrf2 稳定性促进 NSCLC 进展的关键作用，并可能成为 NSCLC 的有价值的预后生物标志物和潜在的治疗靶点。
