p27Kip1介导的细胞周期停滞是弥漫性大B细胞淋巴瘤（DLBCL）细胞粘附介导的耐药（CAM-DR）产生的重要原因。课题组前期发现双特异性酪氨酸磷酸化调节激酶2（DYRK2）可通过调节p27Kip1促进CAM-DR。预实验发现：（1）E3泛素连接酶c-CBL可与DYRK2相互作用并促进DYRK2泛素化；（2）miR-141与CAM-DR有关，且与c-CBL形成正反馈回路。据此推测：miR-141/c-CBL正反馈回路可通过增强DYRK2稳定性促进CAM-DR。本课题拟首先分析c-CBL调节p27Kip1对CAM-DR的影响；其次分析DYRK2与c-CBL相互作用对CAM-DR的影响；接着分析miR-141/c-CBL正反馈回路对CAM-DR的影响；最后结合临床样本及裸鼠模型综合分析miR-141/c-CBL/DYRK2对CAM-DR的影响。研究成果可为CAM-DR的临床干预提供理论基础。

Mounting evidence suggests that p27Kip1-mediated cell cycle arrest is an important reason for the cell adhesion-mediated drug resistance (CAM-DR) phenotype in diffuse large B-cell lymphoma (DLBCL). Recently, we reported that dual specificity tyrosine phosphorylation regulated kinase 2 (DYRK2) could promote the CAM-DR phenotype via regulating p27Kip1 expression. However, the precise mechanisms remain unclear. Our preliminary experiments showed that: (1) c-CBL, an E3 ubiquitin ligase, could interact with DYRK2, thereby increasing the ubiquitination of DYRK2; (2) miR-141 was associated with the CAM-DR phenotype, and formed a positive feedback loop with c-CBL in DLBCL. Therefore, we speculate that the miR-141/c-CBL positive feedback loop may promote the CAM-DR phenotype by enhancing the stability of DYRK2. In this project, we first aim to analyze the effect of c-CBL on p27Kip1 expression and the CAM-DR phenotype. Subsequently, we will investigate the c-CBL-DYRK2 interaction and its effect on the CAM-DR phenotype. Then, we will analyze the effect of the miR-141/c-CBL positive feedback loop on the CAM-DR phenotype. Lastly, the clinical specimens and xenograft nude mouse model will be utilized to further investigate the effect of miR-141/c-CBL/DYRK2 on the CAM-DR phenotype. Our findings will pave the way for a novel therapeutic approach to CAM-DR.