Department of Hematology, The First Affiliated Hospital of Jinzhou Medical University, No.2, Section 5, Renmin Street, Guta District, Jinzhou, 121000, Liaoning, China.
Hum Cell. 2021 Jan;34(1):219-228. doi: 10.1007/s13577-020-00441-8. Epub 2020 Oct 15.
Currently, multiple myeloma (MM) is still an incurable disease. Deciphering its pathogenesis will bring new targets for clinical diagnosis and treatment. In the present study, we identified a MM-associated circular RNA (circRNA), circ-MYBL2, which was dramatically decreased in MM tissue and serum samples in comparison to normal samples. Low circ-MYBL2 level was closely correlated with high clinical stage and unfavorable outcome, and serum circ-MYBL2 had excellent accuracy in diagnosing MM. Exogenous circ-MYBL2 expression notably repressed MM cell viability, DNA synthesis and cell cycle progression. Further exploration revealed that circ-MYBL2 exerted the tumor-inhibiting effect by affecting the phosphorylation level of its linear isoform, in which circ-MYBL2 facilitated the binding of Cyclin F to MYBL2, dampening MYBL2 phosphorylation and activation, thereby inhibiting the transcription of a number of well-known proliferation-related oncogenes. Importantly, overexpression of circ-MYBL2 significantly reduced the tumor size of subcutaneous xenografts in nude mice. Taken together, our data unveil a regulatory mechanism linking circ-MYBL2 and its host gene mediated by Cyclin F, providing a potential diagnostic, prognostic and therapeutic target for MM patients.
目前，多发性骨髓瘤（MM）仍然是一种不可治愈的疾病。解析其发病机制将为临床诊断和治疗带来新的靶点。在本研究中，我们鉴定出一种与 MM 相关的环状 RNA（circRNA），circ-MYBL2，其在 MM 组织和血清样本中的表达明显低于正常样本。低水平的 circ-MYBL2 与高临床分期和不良预后密切相关，血清 circ-MYBL2 对 MM 的诊断具有很高的准确性。外源性 circ-MYBL2 表达显著抑制 MM 细胞的活力、DNA 合成和细胞周期进程。进一步的探索表明，circ-MYBL2 通过影响其线性异构体的磷酸化水平发挥抑瘤作用，其中 circ-MYBL2 促进 Cyclin F 与 MYBL2 的结合，抑制 MYBL2 的磷酸化和激活，从而抑制许多已知的与增殖相关的癌基因的转录。重要的是，circ-MYBL2 的过表达显著减少了裸鼠皮下异种移植瘤的大小。总之，我们的数据揭示了一种由 Cyclin F 介导的 circ-MYBL2 与其宿主基因之间的调控机制，为 MM 患者提供了一个有潜在诊断、预后和治疗价值的靶点。
