Dai L, Lin Z, Qiao J, Chen Y, Flemington E K, Qin Z
Department of Pediatrics, East Hospital, Tongji University School of Medicine, Shanghai, China.
Research Center for Translational Medicine and Key Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine, Shanghai, China.
Oncogene. 2017 Aug 31;36(35):5068-5074. doi: 10.1038/onc.2017.122. Epub 2017 May 1.
Primary effusion lymphoma (PEL) is a highly aggressive B-cell malignancy that is closely associated with one of oncogenic viruses infection, Kaposi's sarcoma-associated herpesvirus. PEL prognosis is poor and patients barely survive >6 months even following active chemotherapy interventions. There is therefore an urgent need to discover more effective targets for PEL management. We recently found that the ribonucleotide reductase (RR) subunit M2 is potentially regulated by the key oncogenic hepatocyte growth factor/c-MET pathway in PEL. In this study, we set to investigate the role of RR in PEL pathogenesis and to evaluate its potential as a therapeutic target. We report that the RR inhibitor 3-AP actively induces PEL cell cycle arrest through inhibiting the activity of the nuclear factor-κB pathway. Using a xenograft model, we found that 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) effectively suppresses PEL progression in immunodeficient mice. Transcriptome analysis of 3-AP-treated PEL cell lines reveals altered cellular genes, most of whose roles in PEL have not yet been reported. Taken together, we propose that RR and its signaling pathway may serve as novel actionable targets for PEL management.
原发性渗出性淋巴瘤（PEL）是一种侵袭性很强的B细胞恶性肿瘤，与致癌病毒之一卡波西肉瘤相关疱疹病毒感染密切相关。PEL预后较差，即使经过积极的化疗干预，患者存活时间也很少超过6个月。因此，迫切需要发现更有效的PEL治疗靶点。我们最近发现，核糖核苷酸还原酶（RR）亚基M2可能受PEL中关键致癌性肝细胞生长因子/c-MET途径的调控。在本研究中，我们着手研究RR在PEL发病机制中的作用，并评估其作为治疗靶点的潜力。我们报告称，RR抑制剂3-氨基吡啶（3-AP）通过抑制核因子-κB途径的活性，积极诱导PEL细胞周期停滞。使用异种移植模型，我们发现3-氨基吡啶-2-甲醛缩氨基硫脲（3-AP）能有效抑制免疫缺陷小鼠体内PEL的进展。对经3-AP处理的PEL细胞系进行转录组分析，发现细胞基因发生了改变，其中大多数基因在PEL中的作用尚未见报道。综上所述，我们认为RR及其信号通路可能是PEL治疗的新型可操作靶点。
