Biochemical and Biophysical Research Communications
miR-186 inhibits cell proliferation in multiple myeloma by repressing Jagged1
Introduction
Multiple myeloma (MM) is a plasma cell disorder with a relatively high incidence rate among hematological malignancies [1]. The disease is characterized by clonal proliferation of malignant plasma cells in the bone marrow, monoclonal paraprotein in blood/urine, and related organ dysfunction [2]. Despite significant progress in elucidation of the biology and treatment options over the past few decades, myeloma remains incurable [3], highlighting an urgent requirement for the development of novel and more effective therapies [4], [5], [6], [7]. The emerging role of microRNAs (miRNAs) in numerous human cancer types has prompted the hypothesis that this group of non-coding genes may be involved in MM pathogenesis.
miRNAs are a class of small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level by directly binding to the 3′ untranslated region (3′ UTR) of target mRNAs [8], [9]. A single miRNA can target multiple proteins and consequently regulate various physiological and pathological processes [10], [11], [12]. Aberrant miRNA expression is frequently observed in various human tumors, including MM, indicative of critical roles in tumorigenesis [13], [14], [15], [16]. Previous studies have shown that miR-186 acts as a tumor suppressor and is downregulated in many tumors, such as lung adenocarcinoma, esophageal and colorectal cancers, endometrial, prostate, and bladder cancers [17], [18], [19], [20], [21], [22]. However, the expression patterns and specific function of miR-186 in MM remain unclear.
In our experiments, miR-186 expression was significantly decreased in both patient MM cells and MM cell lines. Overexpression of miR-186 inhibited MM cell growth, both in vitro and in vivo, and induced cell cycle arrest at the G0/G1 phase. Furthermore, Jagged1, a ligand of Notch, was identified as a target of miR-186 in MM. Restoration of Jagged1 reversed the inhibitory effects of miR-186 to a significant extent, suggesting that miR-186 exerts tumor suppressor activity in MM via negative regulation of Jagged1.
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Patient samples and cell lines
Thirty MM and eighteen healthy control samples were collected from April 2012 to January 2014 at the Affiliated Hospital of Binzhou Medical College. Plasma cells were isolated from bone marrow samples as described previously [23]. The study was approved by the Ethics Committee of the Affiliated Hospital of Binzhou Medical University and performed in accordance with the Declaration of Helsinki (2000). Written informed consent obtained from all patients. Human MM cell lines (MM.1S, OPM-2,
miR-186 expression is decreased in MM
We evaluated miR-186 expression via qRT-PCR in MM.1S, OPM-2, NCI-H929, U266 and RPMI-8226 MM cell lines, compared to normal healthy bone marrow-derived plasma cells (nPCs). As shown in Fig. 1A, miR-186 was downregulated in all the MM cell lines, with the lowest levels in U266 and RPMI-8226. Consistent with these data, miR-186 levels were downregulated in patient MM cells, compared to plasma cells from healthy donors (Fig. 1B). Our results support a potential role of miR-186 as a tumor
Discussion
miRNAs are reported to play essential roles in carcinogenesis and tumor progression [26], [27]. Acting as either tumor suppressors or oncogenes, miRNAs are involved in several aspects of cancer biology, including cell proliferation, apoptosis, migration and invasion [28], [29]. Due to their important functions in cancer, miRNAs present an attractive therapeutic target. Therapeutic modulation of miRNAs may therefore be successfully applied to achieve clinical benefits. In this study, we
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
This work was supported by the Science and Technology Plan of Binzhou Medical University (No. BY2013KJ24) and Binzhou Science and Technology Development Plan (No. 2014ZC0114).
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These authors contributed equally to this work.