miR-138 might reverse multidrug resistance of leukemia cells

doi:10.1016/j.leukres.2009.10.002

Leukemia Research

Volume 34, Issue 8, August 2010, Pages 1078-1082

https://doi.org/10.1016/j.leukres.2009.10.002 Get rights and content

Abstract

Here we firstly investigated the role of miR-138 in multidrug resistance of leukemia cells. miR-138 was found up-regulated in the vincristine-induced multidrug resistance (MDR) leukemia cell line HL-60/VCR as compared with HL-60 cells. Up-regulation of miR-138 could reverse resistance of both P-glycoprotein-related and P-glycoprotein-non-related drugs on HL-60/VCR cells, and promote adriamycin-induced apoptosis, accompanied by increased accumulation and decreased releasing amount of adriamycin. miR-138 could significantly down-regulate the expression of P-glycoprotein, Bcl-2, and the transcription of the multidrug resistance gene 1. Further study of the biological functions of miR-138 might be helpful for developing possible strategies to treat leukemia.

Introduction

Leukemia was a major cause of cancer-related mortality and morbidity in China, and the total number of cases was predicted to rise as a result of population growth [1]. The biology of leukemia was of aggressive local invasion, early metastasis, and resistance to chemotherapy. So far, the pathogenic mechanism resulting in multidrug resistance (MDR) of leukemia was not fully elucidated.

MicroRNAs (miRNAs) were a class of 22-nucleotide noncoding RNAs, which were evolutionarily conserved and functioned as negative regulators of gene expression [2]. Single-stranded miRNAs could bind messenger RNAs of potentially hundreds of genes at the 3′ untranslated region with perfect or near-perfect complementarity, resulting in degradation or inhibition of the target messenger RNA, respectively. Emerging evidences revealed that the small RNAs might play key roles in various biological processes, including cell proliferation, apoptosis, tumorigenesis and MDR [3], [4]. But up to date the miRNAs involved in MDR of leukemia was not reported yet.

miR-138 might act as a tumor suppresser and might serve as a therapeutic target for patients with head and neck squamous cell carcinoma (HNSCC). Ectopic transfection of miR-138 suppressed cell invasion and led to cell cycle arrest and apoptosis of HNSCC cells. Knockdown of miR-138 enhanced cell invasion and suppressed apoptosis of HNSCC cells [5]. Taken together, miR-138 was assumed to play potential roles in mediating some physiologic and pathological functions of tumor. So far, the role of miR-138 in MDR remained largely unknown.

This was the first report to examine the role of miR-138 in the modulation of MDR of leukemia. The results suggested that up-regulation of miR-138 could reverse MDR phenotype of leukemia cells by down-regulation of P-gp and promotion of apoptosis.

Section snippets

Cell culture

The human leukemia cell line HL-60 was obtained from Academy of Military Medical Science (Beijing, China). Human vincristine (VCR)-resistant leukemia cell line HL-60/VCR was obtained from Memorial Sloan-Kettering Cancer Center (NY, USA). All cells were routinely cultured in RPMI 1640 medium (Life Technologies Inc., Gaithersburg, MD) supplemented with 10% fetal calf serum in a 37 °C humidified incubator with a mixture of 95% air and 5% CO₂. For HL-60/VCR cells, the medium additionally contained

Expression of miR-138 in leukemia cell lines

The expression of miR-138 in HL-60/VCR and HL-60 cells was detected by northern blot and real-time quantitative RT-PCR. Fig. 1 shows that the expression of miR-138 was less in HL-60/VCR than in HL-60 cells, indicating that miR-138 might be related to drug-resistant phenotype of leukemia cells.

In vitro drug sensitivity assay

HL-60/VCR cells were transfected with either the mimics of miR-138 or control RNA (Fig. 1), then MTT assay was performed. As shown in Table 1, the IC₅₀ values of HL-60-miR-138 cells for VCR, ADR and 5-flu

Discussion

MiRNAs were critical regulators of transcriptional and post-transcriptional gene silencing, which were involved in multiple developmental processes in many organisms. The highly conserved miRNA, miR-138, might help establish discrete domains of gene expression required for normal cardiac morphogenesis and did so by directly repressing multiple members of a common pathway involving retinoic acid synthesis [12]. Down-regulation of miR-138 had been previously observed in SCC of the tongue and

Conclusions

In conclusion, miR-138 might mediate drug resistance at least in part through regulation of MDR1 and apoptosis. Further analysis of the mechanism of biological actions of miR-138 in MDR might help to further understand the mechanisms of MDR in leukemia and generate a new approach to reverse MDR.

Conflict of interest

None.

Acknowledgements

This study was supported in part by grants from the National Scientific Foundation of China (30770641).

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miR-138 might reverse multidrug resistance of leukemia cells

Abstract

Introduction

Section snippets

Cell culture

Expression of miR-138 in leukemia cell lines

In vitro drug sensitivity assay

Discussion

Conclusions

Conflict of interest

Acknowledgements

Cancer Cell

Cell Biol Int

Biochem Pharmacol

Biochem Biophys Res Commun

Cancer Lett

Chronic myeloid leukemia in Asia

Int J Hematol

Potential uses of microRNA in lung cancer diagnosis, prognosis, and therapy

Curr Cancer Drug Targets

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Curr Opin Mol Ther

MicroRNA polymorphisms: the future of pharmacogenomics, molecular epidemiology and individualized medicine

Pharmacogenomics