Gong Yu, Fu Wenhua
Department of Hematology, Huainanchaoyang Hospital, No. 15 Renmin South Road, Tianjia 'an District, Huainan 232007, Anhui, China.
Department of Hematology, First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei 230022, Anhui, China.
J Leukoc Biol. 2025 Mar 14;117(3). doi: 10.1093/jleuko/qiae237.
The role of MIR654 in Burkitt lymphoma (BL) and whether it impacts expression of MYC and its downstream activated MIR9 is not known. Expression of MYC, MYCN, MYCL, MIR9/3P, MIR654/5P, and MIR654/3P was assessed by quantitative reverse-transcription polymerase chain reaction in biopsy samples from Epstein-Barr virus-negative (EBV-) and EBV+ BL patients and BL cell lines. Effects of modulation of MIR9/3P and MIR654/3P on cell proliferation, apoptosis, and chemosensitivity were evaluated. Luciferase reporter assay was performed to validate the putative target of MIR654/5P. Effects of MIR9/3P and MIR654/3P on tumor burden and disease outcome were evaluated using xenograft model of BL. Expression of MYC, MYCN, and MIR9/3P was higher in all BL patient samples and cell lines. Expression of MIR654/3P was downregulated in EBV- BL patient samples and cell lines compared with either noncancer lymphoid-reactive hyperplasia or EBV+ samples and cell lines. Additionally, MIR654/3P overexpression inhibited cell proliferation, induced apoptosis, and increased chemosensitivity in EBV- BL cell lines. Luciferase reporter assay confirmed that MYC is a target of MIR654/3P in both EBV- and EBV+ BL cell lines; however, the effect of MIR654/3P-mediated targeting of MYC is overridden in EBV+ cells. Administration of MIR654/3P mimic or MIR9/3P antagomir in the xenograft model decreased tumor burden and increased survival. Combined intervention with MIR654/3P mimic and MIR9/3P antagomir had synergistic action on decreasing tumor burden and improving disease outcome. MIR654/3P, as a putative tumor suppressor in EBV- BL, collaborating with MIR9/3P might serve as a therapeutic agent to treat EBV- BL patients in combination with existing chemotherapy and immunotherapy regimes.
MIR654在伯基特淋巴瘤（BL）中的作用以及它是否影响MYC及其下游激活的MIR9的表达尚不清楚。通过定量逆转录聚合酶链反应评估了来自爱泼斯坦-巴尔病毒阴性（EBV-）和EBV+ BL患者的活检样本以及BL细胞系中MYC、MYCN、MYCL、MIR9/3P、MIR654/5P和MIR654/3P的表达。评估了MIR9/3P和MIR654/3P调节对细胞增殖、凋亡和化学敏感性的影响。进行荧光素酶报告基因检测以验证MIR654/5P的假定靶点。使用BL异种移植模型评估了MIR9/3P和MIR654/3P对肿瘤负荷和疾病结局的影响。在所有BL患者样本和细胞系中，MYC、MYCN和MIR9/3P的表达均较高。与非癌性淋巴反应性增生或EBV+样本及细胞系相比，EBV- BL患者样本和细胞系中MIR654/3P的表达下调。此外，MIR654/3P过表达抑制了EBV- BL细胞系中的细胞增殖、诱导了凋亡并增加了化学敏感性。荧光素酶报告基因检测证实，在EBV-和EBV+ BL细胞系中，MYC都是MIR654/3P的靶点；然而，在EBV+细胞中，MIR654/3P介导的靶向MYC的作用被抵消。在异种移植模型中给予MIR654/3P模拟物或MIR9/3P拮抗剂可降低肿瘤负荷并提高生存率。MIR654/3P模拟物和MIR9/3P拮抗剂的联合干预对降低肿瘤负荷和改善疾病结局具有协同作用。MIR654/3P作为EBV- BL中的一种假定肿瘤抑制因子，与MIR9/3P协同作用，可能作为一种治疗剂，与现有的化疗和免疫治疗方案联合用于治疗EBV- BL患者。
