Down‐regulated miR‐331–5p and miR‐27a are associated with chemotherapy resistance and relapse in leukaemia

Abstract

Multidrug resistance (MDR) and disease relapse are challenging clinical problems in the treatment of leukaemia. Relapsed disease is frequently refractory to chemotherapy and exhibits multiple drug resistance. Therefore, it is important to identify the mechanism by which cancer cells develop resistance. In this study, we used microRNA (miRNA) microarray and qRT-PCR approaches to investigate the expression of miRNAs in three leukaemia cell lines with different degrees of resistance to doxorubicin (DOX) compared with their parent cell line, K562. The expression of miR-331–5p and miR-27a was inversely correlated with the expression of a drug-resistant factor, P-glycoprotein (P-gp), in leukaemia cell lines with gradually increasing resistance. The development of drug resistance is regulated by the expression of the P-gp. Transfection of the K562 and, a human promyelocytic cell line (HL) HL60 DOX-resistant cells with miR-331–5p and miR-27a, separately or in combination, resulted in the increased sensitivity of cells to DOX, suggesting that correction of altered expression of miRNAs may be used for therapeutic strategies to overcome leukaemia cell resistance. Importantly, miR-331–5p and miR-27a were also expressed at lower levels in a panel of relapse patients compared with primary patients at diagnosis, further illustrating that leukaemia relapse might be a consequence of deregulation of miR-331–5p and miR-27a.

The network of P-glycoprotein and microRNAs interactions

“…129 Direct regulation of MDR-1 has also been described for miR-331-5p (with the description of a putative miR-331-5p binding site) in resistant K562=DOX leukemia cells. 130 In this study, an inverse correlation between MDR-1 expression and miR-331-5p levels was shown. Furthermore, miR-331-5p overexpression was shown to increase the sensitivity of resistant K562=DOX cells to doxorubicin, through the inhibition of MDR-1 gene expression.…”

“…130 miR-27a expression was shown to inversely correlate with MDR-1 expression and to increase cell sensitivity to doxorubicin. 130 miRs acting at the post-transcriptional level-possible indirect regulation Several miRs have been described as "indirect regulators" of P-gp, by targeting other mRNAs, which code for intermediate proteins or transcription factors involved in MDR-1 gene activation 128 (Fig. 2 and Table 2).…”

MDR1 in immunity: friend or foe?

“…36,37 MDR1 is also regulated at RNA level by micro RNAs (miR) such as miR-145, miR-27a and miR-331-5p that bind directly the 3ʹUTR of ABCB1 mRNA to decrease MDR1 expression. 38,39 Some other miR (miR-137) indirectly decrease MDR1 expression by targeting the YB-1 transcription factor that upregulates MDR1 expression by fixation on ABCB1 promoter. 40,41 …”

Inferences of individual drug responses across diverse cancer types using a novel competing endogenous RNA network

“…Moreover, the GO functional annotation analysis was performed and found that the four genes were annotated with drug responses related GO terms (Table S6), such as cell cycle, apoptotic process, and DNA damage response. In the STAD DRCEs, four lncRNA, RP11‐473O4.3, LINC01184, LINC00641, and ENSG00000248175, competed for binding to miR‐331, miR‐335, and miR‐106b, which are known to be associated with chemotherapy resistance (Feng et al ., 2011; Kim et al ., 2015; Xia et al ., 2008), thereby regulating their target genes. Consequently, the six DRCEs, hsa‐miR‐335_KLF8_LINC00641, hsa‐miR‐106b_APC_ENSG00000248175, hsa‐miR‐106b_APC_LINC01184, hsa‐miR‐106b_CCND2_ENSG00000248175, hsa‐miR‐331_ATRX_ENSG00000248175, and hsa‐miR‐331_ATRX_RP11‐473O4.3, may affect 5‐FU drug responses (Fig.…”