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.

中文翻译：

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LncRNA DYNLRB2-AS1通过抑制DHX9蛋白泛素化降解促进鼻咽癌吉西他滨耐药


基于吉西他滨 (GEM) 的诱导化疗是局部晚期鼻咽癌 (NPC) 的标准治疗方法。然而，大约15%的患者仍然对含有GEM的化疗产生耐药性，从而导致治疗失败。然而，人们对 GEM 抵抗的潜在机制仍然知之甚少。在此，基于微阵列分析，我们鉴定了221个失调的lncRNA，其中DYNLRB2-AS1是GEM抗性NPC细胞系中表达最上调的lncRNA之一。 DYNLRB2-AS1 被证明含有致癌 lncRNA，可促进 NPC GEM 抵抗、细胞增殖，但抑制细胞凋亡。从机制上讲，DYNLRB2-AS1可以直接结合DHX9蛋白并阻止其与E3泛素连接酶PRPF19的相互作用，从而阻断PRPF19介导的DHX9降解，最终促进GEM存在下DNA损伤的修复。临床上，较高的DYNLRB2-AS1表达表明接受诱导化疗的鼻咽癌患者的总生存期较差。总体而言，本研究将致癌 lncRNA DYNLRB2-AS1 确定为局部晚期 NPC 患者的独立预后生物标志物，并作为克服 NPC 中 GEM 化疗耐药性的潜在治疗靶点。