Downregulation of miRNA‑15a and miRNA‑16 promote tumor proliferation in multiple myeloma by increasing CABIN1 expression

Abstract

Abstract. Multiple myeloma (MM) is a malignant disorder characterized by the neoplastic growth of plasma cells in the bone marrow. MicroRNAs (miRNAs/miRs) modulate key regulatory cell pathways via their influence on target genes, and may serve a crucial function in tumorigenesis. Previous studies have indicated that the downregulation of miR-15a and miR-16 contributes to MM pathogenesis. However, the functional mechanisms of miR-15a and miR-16 in MM remain unclear. In the present study, potential target sites for miR-15a and miR-16 were identified on the calcineurin-binding protein 1 (CABIN1) mRNA sequence from analyses of previously published crosslinking, ligation and sequencing of hybrids data. Again-of-function study was also performed, which determined that miR-15a/16 directly targeted CABIN1 mRNA and negatively regulated the expression of CABIN1 at the mRNA and protein level in MM cells. A cell proliferation assay demonstrated that the upregulation of miR-15a and miR-16 inhibited the proliferation of MM cells via targeting CABIN1. miR-15a and miR-16 were significantly decreased in MM specimens, compared with in normal specimens, whereas CABIN1 mRNA levels were significantly higher in MM samples compared with in normal samples. CABIN1 mRNA levels were negatively correlated with miR-15a and miR-16 expression levels in MM tissues, as determined using Pearson's correlation coefficient analysis. The results of the present study indicate that the downregulation of miR-15a and miR-16 promotes tumor proliferation in MM by increasing CABIN1 expression. The present study may aid elucidation of the functions of miR-15a and miR-16 and their function in MM carcinogenesis.

Monosomic Loss of MIR15A/MIR16-1 Is a Driver of Multiple Myeloma Proliferation and Disease Progression

“…S6). Bcl2, Vegfa, Tab3, and Cabin1, previously reported to be direct miR15-a/16-1 targets in multiple myeloma or CLL, were not differentially expressed in MYCxMIR tumors (17,(32)(33)(34). However, Bcl2 was not generally expressed in Vk*MYC tumors, with appreciable expression in 3 of 45 de novo Vk*MYC compared with 3 of 16 transplant and 3 of 18 Vk*MYCxMIR and Vk*MYCxMDR tumors, where the expression levels were 2-to 4-fold higher.…”

<p>LncRNA MORT Inhibits Cancer Cell Proliferation and Promotes Apoptosis in Mantle Cell Lymphoma by Upregulating miRNA-16</p>

“…Downregulation of miRNA-16 has been observed in oral squamous carcinoma and multiple myeloma. 9,10 Overexpression of miRNA-16 inhibited tumor growth in oral squamous carcinoma by targeting Wnt/β-catenin signaling pathway. In addition to the direct roles in cancer development and progression, miRNA-16 also participates in the development of drug resistance of cancer treatment.…”

“…We reported that MORT was also downregulated in MCL and its overexpression inhibited MCL cell proliferation and promoted MCL cell apoptosis possibly by upregulating miRNA-16, which is a wellestablished tumor suppressor miRNA in different types of cancers. 9,10…”

MicroRNAs and exosomes: Small molecules with big actions in multiple myeloma pathogenesis

“…Moreover, only the miR-17-92 cluster and miR-32 were up-regulated in MM cell lines and MM samples in comparison with MGUS or normal PCs, which suggest their possible implication in malignant transformation of MGUS to MM. 62 Furthermore, it was demonstrated that miRNAs could affect crucial cellular pathways of MM cells: miR-19b/20a regulates proliferation, migration, and apoptosis 59 ; miR-20a regulates the proliferation and migration by modulating the PTEN/PI3K/AKT signaling pathway 68 ; miR-410 promotes cell proliferation, cell cycle progression, and inhibits apoptosis, 69 over expression of miR-1271 inhibited proliferation and promoted apoptosis 26 ; miR-29b controls the methylation profile 26 ; miR-29b leads to induction of SOCS-1 expression by promoter demethylation and negatively regulates the migration 31 ; overexpression of miR33b decreased MM cell viability, migration, colony formation, and increased apoptosis and sensitivity to MLN2238 treatment 41 ; upregulation of miR-15a and miR-16 inhibits the proliferation 43 ; miR-22 inhibits LIG3-dependent DNA repair inducing DNA damage and apoptosis 63 ; miR-324-5p regulates stemness, pathogenesis, and sensitivity to bortezomib. 40 To avoid being degraded, extracellular miRNAs bind to proteins in urine, saliva, plasma, serum, and other body fluids, or are protected by apoptosis bodies, particles, exosomes, and tiny vesicles.…”

“…Furthermore, it was demonstrated that miRNAs could affect crucial cellular pathways of MM cells: miR‐19b/20a regulates proliferation, migration, and apoptosis; miR‐20a regulates the proliferation and migration by modulating the PTEN/PI3K/AKT signaling pathway; miR‐410 promotes cell proliferation, cell cycle progression, and inhibits apoptosis, over expression of miR‐1271 inhibited proliferation and promoted apoptosis; miR‐29b controls the methylation profile; miR‐29b leads to induction of SOCS‐1 expression by promoter demethylation and negatively regulates the migration; overexpression of miR33b decreased MM cell viability, migration, colony formation, and increased apoptosis and sensitivity to MLN2238 treatment; upregulation of miR‐15a and miR‐16 inhibits the proliferation; miR‐22 inhibits LIG3‐dependent DNA repair inducing DNA damage and apoptosis; miR‐324‐5p regulates stemness, pathogenesis, and sensitivity to bortezomib …”