Li Jianguo, Chen Yaqi, Guo Xuecong, Bai Xiaofei, Xu Xu, Han Tong, Tan Ailing, Liu Nana, Xia Yuchen, Sun Qiaoyi, Guo Xudong, Chen Jie, Kang Jiuhong
Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
Department of Hematology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Mol Ther Nucleic Acids. 2022 Jan 25;27:1064-1077. doi: 10.1016/j.omtn.2022.01.015. eCollection 2022 Mar 8.
Individuals with diffuse large B cell lymphoma (DLBCL) infected with hepatitis B virus (HBV) have worse chemotherapy efficacy and poorer outcomes. It is still unclear whether long noncoding RNAs (lncRNAs) serve as prognostic and therapeutic targets in the chemotherapy resistance of individuals with DLBCL and HBV infection. Here we found that the core component of HBV (HBX) directly upregulated the expression of lncNBAT1, which was closely associated with the chemotherapy outcomes of HBV-infected individuals with DLBCL. Upregulation of lncNBAT1 reduced the sensitivity of DLBCL cells to chemotherapeutic agents (methotrexate [MTX] or cytarabine [Ara-C]) that induced S phase arrest, whereas knockdown of lncNBAT1 significantly relieved the chemoresistance of HBX-expressing DLBCLs. Mechanistically, lncNBAT1 could interact with the signal transducer and activator of transcription 1 (STAT1) to prevent its enrichment at the promoter region of the functional target gene apolipoprotein B mRNA editing enzyme catalytic subunit 3A (APOBEC3A), inhibiting expression of APOBEC3A and inducing resistance to MTX in DLBCL cells. Furthermore, clinical data analysis showed that lncNBAT1 and APOBEC3A expression was closely related to the poor prognosis and short survival of individuals with DLBCL. Our findings suggest a potential prognostic marker and a candidate lncRNA target for treating HBV-infected individuals with DLBCL.
感染乙型肝炎病毒（HBV）的弥漫性大B细胞淋巴瘤（DLBCL）患者化疗疗效较差，预后也更差。目前尚不清楚长链非编码RNA（lncRNA）是否作为感染HBV的DLBCL患者化疗耐药的预后和治疗靶点。在此，我们发现HBV的核心成分（HBX）直接上调lncNBAT1的表达，lncNBAT1与感染HBV的DLBCL患者的化疗结果密切相关。lncNBAT1的上调降低了DLBCL细胞对诱导S期阻滞的化疗药物（甲氨蝶呤[MTX]或阿糖胞苷[Ara-C]）的敏感性，而敲低lncNBAT1则显著缓解了表达HBX的DLBCL的化疗耐药性。机制上，lncNBAT1可与信号转导和转录激活因子1（STAT1）相互作用，阻止其在功能靶基因载脂蛋白B mRNA编辑酶催化亚基3A（APOBEC3A）启动子区域富集，抑制APOBEC3A表达并诱导DLBCL细胞对MTX产生耐药性。此外，临床数据分析表明，lncNBAT1和APOBEC3A的表达与DLBCL患者的不良预后和较短生存期密切相关。我们的研究结果提示了一种潜在的预后标志物以及治疗感染HBV的DLBCL患者的lncRNA候选靶点。
