Department of Encephalopathy, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
J Exp Clin Cancer Res. 2019 Feb 6;38(1):57. doi: 10.1186/s13046-019-1070-x.
Several members of the tripartite motif-containing (TRIM) protein family have been reported to serve as vital regulators of tumorigenesis. Recent studies have demonstrated an oncogenic role of TRIM 14 in multiple human cancers; however, the importance of this protein in glioblastoma remains to be elucidated.
The expression levels of TRIM14 were analyzed in a series of database and were examined in a variety of glioblastoma cell lines. Two independent TRIM14 shRNA were transfected into LN229 and U251 cells, and the effect of TRIM14 depletion was confirmed. Transwell assay and wound healing assay assay were carried out to assess the effect of TRIM14 depletion on glioblastoma cell invasion and migration. Western blotting was performed to screen the downstream gene of TRIM14. The stability analysis and Ubiquitylation assays and Orthotopic xenograft studies were also performed to investigate the role of TRIM14 and the relationship with downstream gene. Human glioblastoma tissues were obtained and immunohistochemical staining were carried out to confirm the clinical significance of TRIM14.
In this study, we showed that TRIM14 was upregulated in human glioblastoma specimens and cell lines, and correlated with glioblastoma progression and shorter patient survival times. Functional experiments showed that decreased TRIM14 expression reduced glioblastoma cell invasion and migration. Furthermore, we identified that zinc finger E-box binding homeobox 2 (ZEB2), a transcription factor involved in epithelial-mesenchymal transition, is a downstream target of TRIM14. Further investigation revealed that TRIM14 inactivation significantly facilitated ZEB2 ubiquitination and proteasomal degradation, which led to aggressive invasion and migration. Our findings provide insight into the specific biological role of TRIM14 in tumor invasion.
Our findings provide insight into the specific biological role of TRIM14 in tumor invasion, and suggest that targeting the TRIM14/ZEB2 axis might be a novel therapeutic approach for blocking glioblastoma.
已报道三联基序蛋白家族（TRIM）的几个成员可作为肿瘤发生的重要调节因子。最近的研究表明，TRIM14 在多种人类癌症中发挥致癌作用；然而，该蛋白在胶质母细胞瘤中的重要性仍有待阐明。
在一系列数据库中分析了 TRIM14 的表达水平，并在各种胶质母细胞瘤细胞系中进行了检测。将两个独立的 TRIM14 shRNA 转染到 LN229 和 U251 细胞中，并验证了 TRIM14 耗竭的效果。通过 Transwell 测定和划痕愈合试验来评估 TRIM14 耗竭对胶质母细胞瘤细胞侵袭和迁移的影响。通过 Western blot 筛选 TRIM14 的下游基因。还进行了稳定性分析、泛素化测定和原位异种移植研究，以研究 TRIM14 的作用及其与下游基因的关系。获得了人类胶质母细胞瘤组织，并进行了免疫组织化学染色，以确认 TRIM14 的临床意义。
在这项研究中，我们表明 TRIM14 在人类胶质母细胞瘤标本和细胞系中上调，并与胶质母细胞瘤的进展和患者生存时间缩短相关。功能实验表明，降低 TRIM14 的表达可减少胶质母细胞瘤细胞的侵袭和迁移。此外，我们鉴定出锌指 E 框结合同源盒 2（ZEB2），一种参与上皮间质转化的转录因子，是 TRIM14 的下游靶标。进一步的研究表明，TRIM14 的失活显著促进了 ZEB2 的泛素化和蛋白酶体降解，从而导致侵袭和迁移的侵袭性增加。我们的研究结果提供了关于 TRIM14 在肿瘤侵袭中的特定生物学作用的见解。
我们的研究结果提供了关于 TRIM14 在肿瘤侵袭中的特定生物学作用的见解，并表明靶向 TRIM14/ZEB2 轴可能是阻止胶质母细胞瘤的一种新的治疗方法。
