MicroRNA miR-188-5p as a mediator of long non-coding RNA MALAT1 regulates cell proliferation and apoptosis in multiple myeloma

Multiple myeloma (MM), a malignancy of plasma cells mainly derived from the bone marrow, has remained incurable generally. LncRNA MALAT1 has been reported to be upregulated in the MM cells and knockdown of MALAT1 inhibited MM cell cycle progression and enhanced cell apoptosis. Online target prediction showed that two target sites for MALAT1 existed in miR-188-5p, which has been identified as a tumor suppressor in other types of cancers. However, the role of miR-188-5p in the MM and whether miR-188-5p mediates the MM tumor progression regulated by MALAT1 are still unknown. Herein, four main MM cell lines were adopted to investigate the effects of miR-188-5p on cell proliferation and apoptosis via transfection with miR-188-5p mimic/inhibitor and co-transfection with miR-188-5p inhibitor and MALAT1-shRNA plasmids. Xenograft tumor model was also established to study these effects in vivo. Overexpression of miR-188-5p inhibited cell viability, cell proliferation as well as tumor growth and arrested cell cycle at G1 to S transition, but miR-188-5p knockdown showed opposite effects on the MM cells in vitro and in vivo. Moreover, MALAT1 was shown to be inversely correlated with miR-188-5p expression through direct binding to miR-188-5p, and in turn, miR-188-5p could mediate the MM cell proliferation and apoptosis regulated by MALAT1. These findings indicate that miR-188-5p serves as a tumor suppressor in the progression of the MM and is directly involved in MM cell proliferation and apoptosis regulated by MALAT1, which may provide a potential therapeutic target or prognostic indictor for MM clinical treatment.多发性骨髓瘤（Multiple myeloma, MM）是一种主要起源于骨髓的浆细胞恶性肿瘤，目前仍普遍无法治愈。长链非编码RNA MALAT1（LncRNA MALAT1）已被报道在多发性骨髓瘤细胞中呈高表达，而敲低MALAT1可抑制骨髓瘤细胞的周期进程并促进细胞凋亡。在线靶基因预测结果显示，微小RNA-188-5p（miR-188-5p）中存在两个MALAT1的结合位点；而miR-188-5p在其他多种癌症中已被证实为抑癌基因。然而，miR-188-5p在多发性骨髓瘤中的作用，以及其是否介导MALAT1调控的骨髓瘤肿瘤进展，目前仍不明晰。本研究采用4种主流多发性骨髓瘤细胞系，通过转染miR-188-5p模拟物/抑制剂，以及共转染miR-188-5p抑制剂与MALAT1短发夹RNA（shRNA）质粒，探究miR-188-5p对细胞增殖与凋亡的影响。本研究同时构建异种移植瘤模型，以在体内探究上述效应。过表达miR-188-5p可抑制细胞活力、细胞增殖及肿瘤生长，并将细胞周期阻滞于G1到S期转换阶段；而敲低miR-188-5p则在体外与体内实验中对骨髓瘤细胞产生相反的效应。此外，研究证实MALAT1可通过直接结合miR-188-5p，与后者的表达呈负相关；而miR-188-5p可介导MALAT1调控的多发性骨髓瘤细胞增殖与凋亡过程。上述研究结果表明，miR-188-5p在多发性骨髓瘤的进展中发挥抑癌基因的作用，并直接参与MALAT1调控的骨髓瘤细胞增殖与凋亡过程，这可为多发性骨髓瘤的临床治疗提供潜在的治疗靶点或预后指标。