hsa_circ_0003183/miR-224/CD59信号通路在利妥昔单抗耐药 弥漫大B细胞淋巴瘤中的机制研究

揭示弥漫大B细胞淋巴瘤（DLBCL）利妥昔单抗耐药分子机制对DLBCL治疗至关重要。课题组前期发现在DLBCL中CD59高表达与DLBCL利妥昔单抗治疗预后负相关；miR-224可下调CD59的表达；进一步研究发现hsa_circ_0003183负调控miR-224。预实验表明IFN-α能增加利妥昔单抗的CDC效应。课题组拟提出以下假说：利妥昔单抗耐药形成过程中，hsa_circ_0003183上调，导致miR-224表达下调，进而CD59表达上调，后者抑制利妥昔单抗的CDC效应，表现为利妥昔单抗药敏性下降和耐药；IFN-α可能通过调控hsa_circ_0003183/miR-224/CD59通路提高利妥昔单抗的敏感性。课题组拟从分子水平、细胞水平和动物水平进行研究。本课题揭示DLBCL细胞利妥昔单抗耐药的分子机制，为DLBCL耐药的临床干预提供理论基础。

Revealing the molecular mechanism of diffuse large B-cell lymphoma (DLBCL) developing rituximab resistance is urgent needed. Our previous study showed that high expression of CD59 was negatively correlated with the prognosis of DLBCL patients treated rituximab. Moreover, our study demonstrated that miR-224 could down-regulate of expression of CD59 in DLBCL. Our research group found that hsa_circ_0003183 could down-regulate miR-224 in DLBCL and IFN-α enhanced complement-dependent cytotoxicity (CDC) in DLBCL. Given these evidences, we could reasonably hypothesize that in the process of developing rituximab resistance, hsa_circ_0003183 was up-regulated, hence miR-224 was down-regulated and as a result CD59 was up-regulated. The latter could inhibit CDC effects induced by rituximab, and eventually drug resistance developed. IFN-α enhanced rituximab sensitivity in DLBCL probably via targeting hsa_circ_0003183/miR-224/CD59 signal pathway. To validate this, we plan to continue this research in three levels, namely molecular level, cell level and animal level. This study will unveil the underlying mechanism of rituximab resistance progression in DLBCL, providing theoretical basis for the clinical interventions and new insight for drug development of DLBCL rituximab resistance.