环状RNA调控AKT/ERK通路介导T细胞淋巴瘤化疗增敏的机制研究

T-cell lymphoma is a major subtype of aggressive lymphoma. Patients with T-cell lymphoma usually present with a poor prognosis, with rapid progress, easy relapse and resistance to chemotherapy. Dysregulation of AKT and ERK signaling pathway plays a key role in the progression and chemoresistance of T-cell lymphoma. Our previous study demonstrated that microRNA187 (miR187) was upregulated in T-cell lymphoma, which activated AKT/ERK pathway, promoted cell proliferation and induced chemoresistance. Recent studies showed that circRNA could competitively bind to miRs and inhibit their downstream cascades, thus exerting an anti-tumor effect. Our study also showed circRNA000632 specifically binds to miR187 and has a negative correlation with miR187. Based on the results of our previous work, the aim of this study is to clarify 1) the relationship between circRNA, AKT/ERK and disease progression in T-cell lymphoma, 2) to further explore the therapeutic potential of non-chemotherapeutic agents such as non-coding RNA mimics and proteasome inhibitors. These results will be helpful to elucidate molecular mechanism of chemoresistance and to develop potential targeted therapy strategy in T-cell lymphoma.

T细胞淋巴瘤是侵袭性淋巴瘤的重要类型，疾病进展迅速、化疗耐药、易复发、预后差。 AKT和ERK通路的异常调控是影响T淋巴瘤细胞增殖和化疗耐药的关键因素。我们的前期结果发现，microRNA187（miR187）在T淋巴瘤细胞中高表达，激活AKT/ERK通路，促进细胞增殖，引起化疗耐药。最新研究显示，环状RNA（circRNA）通过竞争性结合微小miRs，抑制下游的信号通路，调节肿瘤生长和化疗敏感性，发挥抗淋巴瘤的作用。前期研究也发现circRNA000632和 miR187特异性结合，且两者表达呈负相关。本课题为前期工作的延伸和深化，将进一步阐明circRNA000632对miR187的调控机制，证实T细胞淋巴瘤中circRNA、AKT/ERK通路与化疗耐药和疾病进展的内在联系，研究circRNA模拟物或蛋白酶体抑制剂等非化疗药物的治疗潜力，进一步探讨淋巴瘤的耐药机制，探索靶向治新策略。

淋巴瘤的发病增长率位于全球前十位，其中T细胞淋巴瘤以及EBV+的DLBCL是侵袭性淋巴瘤的重要类型，疾病进展迅速、化疗耐药、易复发、预后差。AKT和ERK通路的异常调控是影响淋巴瘤细胞增殖和化疗耐药的关键因素。我们的前期结果发现，microRNA187(miR187)在T淋巴瘤细胞中高表达，激活AKT/ERK通路，促进细胞增殖，引起化疗耐药。最新研究显示，环状RNA(circRNA)通过竞争性结合微小miRs，抑制下游的信号通路，抑制周期阻滞，调节肿瘤生长和化疗敏感性，发挥抗淋巴瘤的作用。我们发现在外周T细胞淋巴瘤中circ0027458、EBV+的DLBCL中circ0066971增加G0/G1期细胞比例抑制肿瘤细胞生长，抑制RAS/AKT/ERK通路抑制肿瘤进展，且circ0066971促进肿瘤细胞侵袭，通过抑制记忆CD8 T细胞参于肿瘤免疫抑制肿瘤生长。本课题为前期工作的延伸和深化，将进一步阐明circRNA对miR的调控机制，证实侵袭性细胞淋巴瘤中circRNA、AKT/ERK通路与化疗耐药和疾病进展的内在联系，研究circRNA模拟物等非化疗药物的治疗潜力，进一步探讨淋巴瘤的耐药机制，探索靶向治新策略