CircRNA-0013880作为miR-148a海绵促进急性髓系白血病细胞增殖、抑制凋亡的机理研究

Acute myeloid leukemia has a high degree of malignancy and poor prognosis. In recent years, studies on the abnormal expression of non-coding circular RNAs (CircRNA) in the tumorigenesis of acute myeloid leukemia have attracted much attention. In the preliminary work, the applicants first confirmed that CircRNA-0013880 was highly expressed in acute myeloid leukemia patients and cell lines and correlated with clinicopathological data. Further studies found that inhibition of CircRNA-0013880 significantly inhibited the proliferation and promoted apoptosis of acute myeloid leukemia cells. Bioinformatics analysis predicted that CircRNA-0013880 has a targeting relationship with miR-148a. In the previous work, we systematically studied the role of miR-148a as a tumor suppressor gene in acute myeloid leukemia. Based on this, the project intends to further explore the molecular mechanism of CircRNA-0013880 regulation of proliferation and apoptosis of acute myeloid leukemia cells, and attempt to elucidate that CircRNA-0013880, which is abnormally expressed in acute myeloid leukemia cells, can regulate miR-148a by sponge action. Thus, the expression of downstream genes may be effected as well as the possible regulatory pathways of tumor cells, which ultimately leads to changes in the proliferation and apoptosis of acute myeloid leukemia cells.

急性髓系白血病(AML)恶性程度高，预后差。近年来，有关AML中长链非编码环状RNAs(CircRNA)异常表达并影响肿瘤发生发展的研究颇受关注。申请者在前期工作中率先证实CircRNA-0013880在AML患者及细胞系中显著高表达并与临床资料密切相关；抑制CircRNA-0013880可显著抑制AML细胞增殖，促进凋亡。通过生物信息学分析预测得出CircRNA-0013880与miR-148a存在靶向关系。前期的工作中，我们对miR-148a在AML中发挥抑癌基因的作用进行了系统研究。在此基础上，本项目拟深入探讨CircRNA-0013880调控AML细胞增殖、凋亡的分子机制，试图阐明AML细胞中异常表达的CircRNA-0013880可通过海绵作用的方式调控miR-148a，导致其下游基因的表达异常，从而影响相关信号通路，最终导致AML细胞增殖、凋亡水平发生变化。

环状RNA在急性髓系白血病(AML)中发挥着重要作用。在本研究中，在AML患者的骨髓单核细胞(BNCS)中观察到hsa_circ_0013880的表达增加。过表达hsa_circ_0013880促进AML细胞增殖和迁移，减少细胞凋亡。此外，研究发现，USP32作为一种去泛素化酶在AML患者BMNC中同样高表达，而且hsa_circ_0013880能够提高USP32的表达，敲低USP32可以抑制AML细胞的增殖、促进细胞凋亡。研究结果显示，敲低USP32显著增加了AML细胞中泛素化的Raplb水平，Raplb过表达可以逆转USP32敲低的作用，这证实USP32能够通过调节RAS相关蛋白(Rap1b)的稳定性介导AML细胞的增殖。以上研究表明，hsa_circ_0013880作为一种新型调节因子，能够通过hsa_circ_0013880/USP32/Rap1b轴影响AML细胞的增殖和凋亡。hsa_circ_0013880/USP32/Raplb轴的发现，为临床上预防AML或开发有效治疗药物提供新的视角与作用靶点。