Department of Oncology, Third Xiangya Hospital of Central South University, 138 Tongzipo Road, Changsha, 410013, China.
Cell Oncol (Dordr). 2023 Jun;46(3):677-695. doi: 10.1007/s13402-023-00776-y. Epub 2023 Jan 27.
PURPOSE: Circular RNAs (circRNAs) play important roles in tumour progression. This study aimed to explore the mechanism of hsa_circ_0067717 (termed circRNA_0067717) promoting paclitaxel resistance in nasopharyngeal carcinoma (NPC). METHODS: We assayed CNE-1 and HNE-2 parental cell lines and the corresponding paclitaxel-resistant NPC cell lines using circRNA microarrays. RNA pull-down assay, RNA immunoprecipitation, and RNA fluorescence in situ hybridization were used to identify the molecular mechanisms. RESULTS: Here, we confirm that circRNA_0067717 is significantly upregulated in NPC paclitaxel-resistant cells and is associated with paclitaxel resistance in NPC. Mechanistically, circRNA_0067717 functions as a scaffold for TRIM41 protein (a ubiquitin E3 ligase) and p53 protein. In nasopharyngeal carcinoma paclitaxel-resistant cells, the highly expressed circRNA_0067717 can bind to more TRIM41 and p53 protein, promoting TRIM41-induced p53 ubiquitination and degradation, resulting in a decrease in p53 protein level. Moreover, the 1-176 nt area of circRNA_0067717 and the 301-425 nt region of circRNA_0067717 are the binding sites for p53 and TRIM41, respectively. The resistance of NPC cells to paclitaxel can be reduced by blocking these binding regions of circRNA_0067717. CONCLUSION: We demonstrate that circRNA_0067717 acts as a scaffold for TRIM41 and p53, enhancing paclitaxel chemoresistance in NPC by promoting TRIM41-induced p53 degradation via ubiquitination.
目的:环状 RNA(circRNAs)在肿瘤进展中发挥重要作用。本研究旨在探讨 hsa_circ_0067717(称为 circRNA_0067717)促进鼻咽癌(NPC)紫杉醇耐药的机制。
方法:我们使用 circRNA 微阵列检测 CNE-1 和 HNE-2 亲本细胞系和相应的紫杉醇耐药 NPC 细胞系。采用 RNA 下拉实验、RNA 免疫沉淀和 RNA 荧光原位杂交来鉴定分子机制。
结果:在这里,我们证实 circRNA_0067717 在 NPC 紫杉醇耐药细胞中显著上调,并与 NPC 中的紫杉醇耐药相关。在机制上,circRNA_0067717 作为 TRIM41 蛋白(一种泛素 E3 连接酶)和 p53 蛋白的支架。在鼻咽癌紫杉醇耐药细胞中,高表达的 circRNA_0067717 可以与更多的 TRIM41 和 p53 蛋白结合,促进 TRIM41 诱导的 p53 泛素化和降解,导致 p53 蛋白水平降低。此外,circRNA_0067717 的 1-176nt 区域和 circRNA_0067717 的 301-425nt 区域分别是 p53 和 TRIM41 的结合位点。通过阻断 circRNA_0067717 的这些结合区域,可以降低 NPC 细胞对紫杉醇的耐药性。
结论:我们证明 circRNA_0067717 作为 TRIM41 和 p53 的支架,通过促进 TRIM41 诱导的 p53 降解来增强 NPC 中的紫杉醇化疗耐药性,从而促进 p53 降解。
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