Hsu Wan-Yi, Chiou Shyh-Shin, Lin Pei-Chin, Liao Yu-Mei, Yeh Chung-Yu, Tseng Yu-Hsin
Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan, R.O.C.
Division of Hematology and Oncology, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan, R.O.C.
Biomed Rep. 2023 Dec 13;20(2):20. doi: 10.3892/br.2023.1708. eCollection 2024 Feb.
Cytarabine is an important medicine for acute myeloid leukemia (AML) treatment, however, drug resistance hinders the treatment of AML. Although microRNA (miRNA or miR) alteration is one of the well-recognized mechanisms underlying drug resistance in AML, few studies have investigated the role and function of miRNAs in the development of cytarabine resistance. In the present study, total RNA was isolated from parental HL60 and cytarabine-resistant HL60 (R-HL60) cells. Subsequently, miRNAs and mRNAs were detected using small RNA sequencing and gene expression array, respectively. Differentially expressed mRNAs (DEMs) and differentially expressed genes (DEGs) with more than two-fold changes between HL60 and R-HL60 cells were screened out. Negatively associated miRNA-mRNA pairs were selected as candidate miRNA-mRNA target pairs according to the miRDB, Targetscan or miRTar databases. Functional enrichment analysis of DEGs included in the candidate miRNA-mRNA pairs was performed. The results indicated that 10 DEGs (, , , , , , , , and were simultaneously involved in seven Gene Ontology pathways related to the regulation of migration ability, namely the 'regulation of cell migration', 'regulation of locomotion', 'regulation of cellular component movement', 'cell migration', 'locomotion', 'cell motility', and 'localization of cell'. DEMs predicted to negatively regulate the aforementioned 10 DEGs were paired with DEGs into 16 candidate miRNA-mRNA pairs related to the regulation of migration ability. In addition, migration assays revealed that the migration ability of R-HL60 cells was greater than that of HL60 cells. These findings provide a new perspective for the treatment of cytarabine-resistant AML and advance our understanding of altered migration ability underlying cytarabine resistance development, specifically related to miRNAs.
阿糖胞苷是治疗急性髓系白血病（AML）的一种重要药物，然而，耐药性阻碍了AML的治疗。尽管微小RNA（miRNA或miR）改变是AML耐药性公认的潜在机制之一，但很少有研究调查miRNA在阿糖胞苷耐药性发展中的作用和功能。在本研究中，从亲本HL60和阿糖胞苷耐药的HL60（R-HL60）细胞中分离出总RNA。随后，分别使用小RNA测序和基因表达阵列检测miRNA和mRNA。筛选出HL60和R-HL60细胞之间变化超过两倍的差异表达mRNA（DEM）和差异表达基因（DEG）。根据miRDB、Targetscan或miRTar数据库，选择负相关的miRNA-mRNA对作为候选miRNA-mRNA靶对。对候选miRNA-mRNA对中包含的DEG进行功能富集分析。结果表明，10个DEG（，，，，，，，，和）同时参与了7条与迁移能力调节相关的基因本体论途径，即“细胞迁移调节”、“运动调节”、“细胞成分运动调节”、“细胞迁移”、“运动”、“细胞运动性”和“细胞定位”。预测对上述10个DEG起负调节作用的DEM与DEG配对，形成16个与迁移能力调节相关的候选miRNA-mRNA对。此外，迁移试验显示R-HL60细胞的迁移能力大于HL60细胞。这些发现为耐阿糖胞苷AML的治疗提供了新的视角，并加深了我们对阿糖胞苷耐药性发展中迁移能力改变的理解，特别是与miRNA相关的理解。
