沉默长链非编码 RNA XIST 通过上调 microRNA-29a 的表达抑制 MYC 下调从而抑制急性髓系白血病的耐药性。

Silencing long non-coding RNA XIST suppresses drug resistance in acute myeloid leukemia through down-regulation of MYC by elevating microRNA-29a expression.

机构信息

Department of Hematology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, Henan, P. R. China.

出版信息

Mol Med. 2020 Nov 24;26(1):114. doi: 10.1186/s10020-020-00229-4.

BACKGROUND

Long non-coding RNAs (lncRNAs) are biomarkers participating in multiple disease development including acute myeloid leukemia (AML). Here, we investigated molecular mechanism of X Inactive-Specific Transcript (XIST) in regulating cellular viability, apoptosis and drug resistance in AML.

METHODS

XIST, miR-29a and myelocytomatosis oncogene (MYC) expression in AML bone marrow cells collected from 62 patients was evaluated by RT-qPCR and Western blot analysis. Besides, the relationship among XIST, miR-29a and MYC was analyzed by dual luciferase reporter assay, RIP, and RNA pull down assays. AML KG-1 cells were treated with anti-tumor drug Adriamycin. The role of XIST/miR-29a/MYC in cellular viability, apoptosis and drug resistance in AML was accessed via gain- and loss-of-function approaches. At last, we evaluated role of XIST/miR-29a/MYC on tumorigenesis in vivo.

RESULTS

XIST and MYC were up-regulated, and miR-29a was down-regulated in AML bone marrow cells. Silencing XIST inhibited cellular activity and drug resistance but promoted cellular apoptosis of KG-1 cells by down-regulating MYC. XIST inhibited miR-29a expression to up-regulate MYC. Moreover, silencing XIST inhibited tumorigenesis of AML cells in vivo.

CONCLUSIONS

Overall, down-regulation of XIST decreased MYC expression through releasing the inhibition on miR-29a, thereby reducing drug resistance, inhibiting viability and promoting apoptosis of AML cells.

背景

长非编码 RNA（lncRNA）是参与包括急性髓细胞白血病（AML）在内的多种疾病发展的生物标志物。在这里，我们研究了 X 失活特异性转录物（XIST）在调节 AML 细胞活力、凋亡和耐药性方面的分子机制。

方法

通过 RT-qPCR 和 Western blot 分析评估了 62 例 AML 患者骨髓细胞中 XIST、miR-29a 和髓细胞瘤致癌基因（MYC）的表达。此外，通过双荧光素酶报告基因检测、RIP 和 RNA 下拉实验分析了 XIST、miR-29a 和 MYC 之间的关系。用抗肿瘤药物阿霉素处理 AML KG-1 细胞。通过增益和失活功能方法评估 XIST/miR-29a/MYC 在 AML 细胞活力、凋亡和耐药性中的作用。最后，我们评估了 XIST/miR-29a/MYC 对体内肿瘤发生的作用。