Rui Su, Ziqi Wen, Xingri Zhan, Yiling Long, Xiuyuan Wang, Chuting Li, Yubin Su, Jia Fei
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引用次数: 0
摘要
BCR-ABL1依赖性伊马替尼耐药因其复杂性和多样性而没有有效的治疗方法。我们曾报道,CDH13 致癌基因在 BCR-ABL1 依赖性耐药的 CML 细胞系中低水平表达。然而,它对 CML 耐药细胞的影响和机制仍然未知。本研究探讨了基于saRNA的CDH13激活对BCR-ABL1依赖性伊马替尼耐药CML的影响及其内在机制,并提出了一种克服伊马替尼耐药的独特治疗方法。具体而言,该研究利用DSIR(Designer of Small Interfering RNA)网站工具,生成了靶向CDH13启动子区域的saRNA,并利用qPCR和Western印迹法进行了验证。在预测的序列中,C2和C3能有效提高CDH13 mRNA和蛋白质的表达,并抑制细胞的相对活力和形成克隆的能力。在促进K562-IMR细胞中CDH13的表达后,它栖息于NF-κB信号通路,并诱导伊马替尼耐药的CML细胞凋亡。还观察到 LNP-saRNA(C3)限制了 K562-IMR 细胞在体内的生长。综上所述,saRNA激活CDH13的表达可通过抑制NF-κB信号通路促进细胞凋亡,从而克服CML患者对伊马替尼的BCR-ABL1依赖性耐药性。
Small RNA activation of CDH13 expression overcome BCR-ABL1-independent imatinib-resistance and their signaling pathway studies in chronic myeloid leukemia.
BCR-ABL1-independent resistance to imatinib has no effective treatment due to its complexity and diversity. We previously reported that the CDH13 oncogene was expressed at low levels in BCR-ABL1-independent resistant CML cell lines. However, its effects on CML resistant cells and mechanisms remain unknown. This study investigated the effects of saRNA-based CDH13 activation on BCR-ABL1-independent imatinib resistance in CML and its underlying mechanism, and proposes a unique treatment method to overcome imatinib resistance. Specifically, this study demonstrated that using the DSIR (Designer of Small Interfering RNA) website tool, saRNAs targeting the CDH13 promoter region were generated and validated using qPCR and western blotting. Among the predicted sequences, C2 and C3 efficiently elevated CDH13 mRNA and protein expression, as well as inhibited the relative vitality of cells and the ability to form clones. After promoting CDH13 expression in K562-IMR cells, it inhabited the NF-κB signaling pathway and induced apoptosis in imatinib-resistant CML cells. LNP-saRNA (C3) was also observed to limit the growth of K562-IMR cells in vivo. From the above, the activation of CDH13 expression by saRNA promotes cell apoptosis by inhibiting the NF-κB signaling pathway to overcome to BCR-ABL1-independent resistance to imatinib in patients with CML.
期刊介绍:
Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism.
Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following:
Experimental medicine
Cancer
Immunity
Internal medicine
Neuroscience
Cancer metabolism