Ran Qijie, Xu Dehong, Wang Qi, Wang Dongsheng
Department of Hematology, General Hospital of Central Theater Command, Wuhan, China.
Department of Neurosurgery, The Fifth People's Hospital of Dalian, Dalian, China.
Front Oncol. 2022 May 30;12:835299. doi: 10.3389/fonc.2022.835299. eCollection 2022.
Multiple myeloma has a long course, with no obvious symptoms in the early stages. However, advanced stages are characterized by injury to the bone system and represent a severe threat to human health. The results of the present work indicate that the hypermethylation of miR-23 promoter mediates the aberrant expression of uPA/PLAU (urokinase plasminogen activator, uPA) in multiple myeloma cells. miR-23, a microRNA that potentially targets uPA's 3'UTR, was predicted by the online tool miRDB. The endogenous expressions of uPA and miR-23 are related to disease severity in human patients, and the expression of miR-23 is negatively related to uPA expression. The hypermethylation of the promoter region of miR-23 is a promising mechanism to explain the low level of miR-23 or aberrant uPA expression associated with disease severity. Overexpression of miR-23 inhibited the expression of uPA by targeting the 3'UTR of uPA, not only in MM cell lines, but also in patient-derived cell lines. Overexpression of miR-23 also inhibited and invasion of MM cells in a nude mouse model. The results therefore extend our knowledge about uPA in MM and may assist in the development of more effective therapeutic strategies for MM treatment.
多发性骨髓瘤病程较长，早期无明显症状。然而，晚期以骨骼系统损伤为特征，对人类健康构成严重威胁。目前的研究结果表明，miR-23启动子的高甲基化介导了多发性骨髓瘤细胞中uPA/PLAU（尿激酶型纤溶酶原激活剂，uPA）的异常表达。在线工具miRDB预测，miR-23是一种可能靶向uPA 3'UTR的微小RNA。uPA和miR-23的内源性表达与人类患者的疾病严重程度相关，且miR-23的表达与uPA表达呈负相关。miR-23启动子区域的高甲基化是解释与疾病严重程度相关的miR-23低水平或uPA异常表达的一个有前景的机制。miR-23的过表达通过靶向uPA的3'UTR抑制了uPA的表达，不仅在骨髓瘤细胞系中如此，在患者来源的细胞系中也是如此。miR-23的过表达在裸鼠模型中也抑制了骨髓瘤细胞的增殖和侵袭。因此，这些结果扩展了我们对骨髓瘤中uPA的认识，并可能有助于开发更有效的骨髓瘤治疗策略。
