miR-186 inhibits cell proliferation in multiple myeloma by repressing Jagged1

Highlights

• miR-186 expression is decreased in MM.

• miR-186 inhibits MM cell proliferation in vitro and in vivo.

• Jagged1 is regulated by miR-186.

• Overexpression of Jagged1 reverses the effects of miR-186.

Abstract

MicroRNAs (miRNAs) are small, noncoding ribonucleic acids that regulate gene expression by targeting mRNAs for translational repression and degradation. Accumulating experimental evidence supports a causal role of miRNAs in hematology tumorigenesis. However, the specific functions of miRNAs in the pathogenesis of multiple myeloma (MM) remain to be established. In this study, we demonstrated that miR-186 is commonly downregulated in MM cell lines and patient MM cells. Ectopic expression of miR-186 significantly inhibited cell growth, both in vitro and in vivo, and induced cell cycle G₀/G₁ arrest. Furthermore, miR-186 induced downregulation of Jagged1 protein expression by directly targeting its 3′-untranslated region (3′-UTR). Conversely, overexpression of Jagged1 rescued cells from miR-186-induced growth inhibition. Our collective results clearly indicate that miR-186 functions as a tumor suppressor in MM, supporting its potential as a therapeutic target for the disease.

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.