N6-Methyladenosine modification of the TRIM7 positively regulates tumorigenesis and chemoresistance in osteosarcoma through ubiquitination of BRMS1
N6-Methyladenosine modification of the TRIM7 positively regulates tumorigenesis and chemoresistance in osteosarcoma through ubiquitination of BRMS1
复制标题
TRIM7 的 N6-甲基腺苷修饰通过 BRMS1 泛素化正向调节骨肉瘤的肿瘤发生和化疗耐药性
DOI：
10.1016/j.ebiom.2020.102955
复制
发表时间：
2020-09-01
期刊：
影响因子：
11.1
通讯作者：
Zheng, Shuier
中科院分区：
文献类型：
--
作者：
Zhou, Chenliang;Zhang, Zhichang;Zheng, Shuier
背景：转移是骨肉瘤患者的主要死亡原因。其中一些患者对化疗无效，并在短期内死于转移。因此，寻找新的生物标志物对提高骨肉瘤的诊断和治疗水平具有重要意义。TRIM7是TRIM家族的一员，参与肿瘤等多种病理过程，但其在骨肉瘤中的作用尚不清楚。方法：采用CCK-8和Transwell检测细胞增殖、侵袭和迁移。用免疫沉淀和质谱分析鉴定与TRIM7相关的候选蛋白。免疫沉淀法、免疫荧光法、下拉实验和泛素化实验检测TRIM7与其候选蛋白之间的相互作用。结果：TRIM7在骨肉瘤组织中表达上调，是预测预后不良的独立危险因素。TRIM7通过泛素化乳腺癌转移抑制因子1(BRMS1)调节骨肉瘤细胞的迁移和侵袭。此外，在骨肉瘤细胞和TRIM7水平较高的患者来源的异种移植(PDX)小鼠中很容易观察到化疗耐药。在骨肉瘤组织中观察到TRIM7m6A修饰缺失。METTL3和YTHDF2是导致TRIM7基因m6A异常修饰的主要因素。解释：总体而言，我们的研究结果表明，TRIM7通过泛素化BRMS1在骨肉瘤的转移和化疗耐药中起着关键作用。(C)2020作者。爱思唯尔出版公司(Elsevier B.V.)
Background: Metastasis is the leading cause of death in patients with osteosarcoma. Some of these patients fail to respond to chemotherapy and die of metastasis within a short period. Therefore, it is important to identify novel biomarkers to improve the diagnosis and treatment of osteosarcoma. TRIM7 is a member of the tripartite motif (TRIM) family protein that is involved in various pathological conditions including cancer; however, its role in osteosarcoma remains elusive.Methods: Cell proliferation, invasion and migration were measured by CCK-8 and Transwell. Immunoprecipitation and mass spectrometry analysis were used to identify candidate proteins associated with TRIM7. Immunoprecipitation, immunofluorescence, pull down and ubiquitination assay were performed to examine the regulation between TRIM7 and its candidate protein. m6A modification of TRIM7 was measured by RNA immunoprecipitation.Findings: TRIM7 expression was upregulated in osteosarcoma tissues and was an independent risk factor in predicting poor prognosis. TRIM7 regulates osteosarcoma cell migration and invasion through ubiquitination of breast cancer metastasis suppressor 1 (BRMS1). Moreover, chemoresistance was readily observed in osteosarcoma cells and in patient-derived xenograft (PDX) mice with higher TRIM7 levels. Loss of TRIM7 m6A modification was observed in osteosarcoma tissues. METTL3 and YTHDF2 were the main factors involved in the aberrant m6A modification of TRIM7.Interpretation: Overall, our findings show that TRIM7 plays a key role in regulating metastasis and chemoresistance in osteosarcoma through ubiquitination of BRMS1. (C) 2020 The Authors. Published by Elsevier B.V.