LncRNA DYNLRB2-AS1 通过抑制 DHX9 蛋白的泛素化降解促进吉西他滨对鼻咽癌的耐药性

IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Drug Resistance Updates Pub Date : 2024-06-14 DOI:10.1016/j.drup.2024.101111
Kai-Lin Chen , Sai-Wei Huang , Ji-Jin Yao , Shi-Wei He , Sha Gong , Xi-Rong Tan , Ye-Lin Liang , Jun-Yan Li , Sheng-Yan Huang , Ying-Qin Li , Yin Zhao , Han Qiao , Sha Xu , Shengbing Zang , Jun Ma , Na Liu
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引用次数: 0

摘要

以吉西他滨(GEM)为基础的诱导化疗是局部区域晚期鼻咽癌(NPC)的标准治疗方法。然而,仍有约15%的患者对含吉西他滨的化疗产生耐药性,导致治疗失败。然而,人们对GEM耐药的内在机制仍然知之甚少。在此,我们基于微阵列分析鉴定了221个调控失调的lncRNA,其中DYNLRB2-AS1是GEM耐药NPC细胞系中上调最多的lncRNA之一。研究表明,DYNLRB2-AS1含有致癌lncRNA,它能促进鼻咽癌GEM耐药、细胞增殖,但抑制细胞凋亡。从机理上讲,DYNLRB2-AS1可直接与DHX9蛋白结合,阻止其与E3泛素连接酶PRPF19的相互作用,从而阻断PRPF19介导的DHX9降解,最终在GEM存在的情况下促进DNA损伤的修复。在临床上,DYNLRB2-AS1表达较高表明接受诱导化疗的鼻咽癌患者总生存率较低。总之,本研究发现致癌 lncRNA DYNLRB2-AS1 是局部晚期鼻咽癌患者的独立预后生物标志物,也是克服鼻咽癌 GEM 化疗耐药性的潜在治疗靶点。
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LncRNA DYNLRB2-AS1 promotes gemcitabine resistance of nasopharyngeal carcinoma by inhibiting the ubiquitination degradation of DHX9 protein

Gemcitabine (GEM) based induction chemotherapy is a standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). However, approximately 15 % of patients are still resistant to GEM-containing chemotherapy, which leads to treatment failure. Nevertheless, the underlying mechanisms of GEM resistance remain poorly understood. Herein, based on a microarray analysis, we identified 221 dysregulated lncRNAs, of which, DYNLRB2-AS1 was one of the most upregulated lncRNAs in GEM-resistance NPC cell lines. DYNLRB2-AS1 was shown to function as contain an oncogenic lncRNA that promoted NPC GEM resistance, cell proliferation, but inhibited cell apoptosis. Mechanistically, DYNLRB2-AS1 could directly bind to the DHX9 protein and prevent its interaction with the E3 ubiquitin ligase PRPF19, and thus blocking PRPF19-mediated DHX9 degradation, which ultimately facilitated the repair of DNA damage in the presence of GEM. Clinically, higher DYNLRB2-AS1 expression indicated an unfavourable overall survival of NPC patients who received induction chemotherapy. Overall, this study identified the oncogenic lncRNA DYNLRB2-AS1 as an independent prognostic biomarker for patients with locally advanced NPC and as a potential therapeutic target for overcoming GEM chemoresistance in NPC.

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来源期刊
Drug Resistance Updates
Drug Resistance Updates 医学-药学
CiteScore
26.20
自引率
11.90%
发文量
32
审稿时长
29 days
期刊介绍: Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research
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