Abstract
Noncoding RNA (ncRNA) is involved in the occurrence, development, metastasis, and drug resistance of tumors and involves a variety of biological functions. In addition, miRNA can regulate proliferation and migration and even regulate epigenetics to promote the development of multiple myeloma (MM). However, the mechanism of ncRNA involved in MM is still unclear, and there are many unknown ncRNAs to be explored. This research is aimed at discovering the unknown lncRNA in MM through high-throughput sequencing and to study the mechanism and role of competitive endogenous RNA (ceRNA) involved in the pathogenesis of MM for the development of novel molecular markers and potential new targeted drugs. We screened out 262 new lncRNAs with statistical differences by RNA sequencing and selected the lncRNA MSTRG.29039.1 according to the expression and function of lncRNAs and their target genes in MM. We verified that MSTRG.29039.1 and its target gene OSMR were highly expressed in MM. After knockdown of MSTRG.29039.1 in MM cell lines, the expression of OSMR was decreased, and the expression of hsa-miR-12119 was upregulated which can also promote cell apoptosis and inhibit proliferation. Then, we knocked down hsa-miR-12119 and MSTRG.29039.1, we found that apoptosis of MM cells was reduced, and cell proliferation was increased compared with just knocking down hsa-miR-12119. We further verified the direct binding relationship between MSTRG.29039.1 and OSMR by the dual-luciferase reporter assay system. Thus, MSTRG.29039.1 can competitively bind with miRNA to counteract the inhibitory effect of miRNA on OSMR, which regulates cell proliferation and apoptosis through the JAK2/STAT3 pathway. In a conclusion, lncRNA MSTRG.29039.1 could promote proliferation by sponging hsa-miR-12119 via the JAK2/STAT3 pathway in multiple myeloma. This may be a molecular marker and a potential therapeutic target for MM.
Highlights
Multiple myeloma (MM) is a plasma cell disease characterized by biological heterogeneity whose clinical features are clonal hyperplasia of bone marrow plasma cells and accompanied by excessive production of monoclonal immunoglobulins, leading to a series of damages such as abnormal kidney function, hypercalcemia, anemia, and bone disease [1]
We based on P < 0:05 and fold change > 2 to elect the differentially expressed genes and detected 285 differential genes that were statistically different, 92 were upregulated, and 193 downregulated (Figures 1(b) and 1(c)); we used the same method to screen out 262 unknown Long noncoding RNA (lncRNA) with statistical differences, of which 203 were upregulated, and 59 were downregulated (Figures 1(d)–1(f))
From the upregulated 203 lncRNAs, we selected 63 lncRNAs that were highly expressed in 8 myeloma patients and submitted them for testing to predict their target genes and the Gene Ontology (GO) function of the target genes and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway enrichment analysis (Figures 2(a)–2(d), Supplementary Table 1)
Summary
Multiple myeloma (MM) is a plasma cell disease characterized by biological heterogeneity whose clinical features are clonal hyperplasia of bone marrow plasma cells and accompanied by excessive production of monoclonal immunoglobulins, leading to a series of damages such as abnormal kidney function, hypercalcemia, anemia, and bone disease [1]. Increasing experiments have proved that the content and activity of ceRNAs are dysregulated in tumors [14, 15], and artificial miRNA sponges containing multiple MREs have been used to inhibit oncogenic miRNAs and have shown tumor suppression functions [16, 17]. In this experiment, we further studied the biological function of ncRNA in MM and its pathogenic mechanism through high-throughput sequencing, and we predicted the interaction pathway of lncRNA-miRNA mRNA. These observations may provide support for the potential treatment and novel molecular markers of MM
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