Abstract
The biological impact of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) is becoming an important aspect of investigation, which may contribute to the understanding of the complex pathobiology of the disease whilst also providing novel potential therapeutic targets. Herein, we investigated the expression pattern and the biological significance of the lncRNA ST3 beta-galactoside alpha-2,3 sialyltransferase 6 antisense RNA 1 (ST3GAL6-AS1) in MM. We documented a high ST3GAL6-AS1 expression level in MM compared to normal plasma cells (PCs) or other hematological malignancies. Transcriptome analyses of MM PCs from patients included in the CoMMpass database indicated a potential involvement of ST3GAL6-AS1 in MAPK signaling and ubiquitin-mediated proteolysis pathways. ST3GAL6-AS1 silencing by LNA-gapmeR antisense oligonucleotides inhibits cell proliferation and triggers apoptosis in MM cell line. Notably, ST3GAL6-AS1 silencing in vitro displayed the down-regulation of the MAPK pathway and protein ubiquitination. These data suggest that ST3GAL6-AS1 deregulation may play a pathogenetic role in MM by affecting both proliferation pathways and circuits fundamental for PC survival. However, ST3GAL6-AS1 expression levels seem not to be significantly associated with clinical outcome and its targeting appears to exert antagonistic effects with proteasome inhibitors used in MM. These findings strongly urge the need for further studies investigating the relevance of ST3GAL6-AS1 in MM.
Highlights
Multiple myeloma (MM) is a malignant proliferation of bone marrow plasma cells (PCs) characterized by a heterogeneous clinical course, ranging from the pre-malignant condition called monoclonal gammopathy of undetermined significance (MGUS), to smoldering MM, truly overt and symptomatic MM, and extra-medullary myeloma/plasma cell leukemia (PCL)
With the aim of identifying long non-coding RNAs (lncRNAs) deregulated in MM, we investigated their expression pattern in a proprietary database (#GSE116294) recently reported by us [14], including four normal controls, 50 MM patients at diagnosis and six secondary PCL profiled on the GeneChip® Human Gene
We have focused on ST3GAL6-AS1, a lncRNA that we found as the most to be significantly upregulated in smoldering MM (sMM) and further increases its expression level in secondary PCL (sPCL), significantly upregulated in MM as compared to normal bone marrow PCs
Summary
Multiple myeloma (MM) is a malignant proliferation of bone marrow plasma cells (PCs) characterized by a heterogeneous clinical course, ranging from the pre-malignant condition called monoclonal gammopathy of undetermined significance (MGUS), to smoldering MM (sMM), truly overt and symptomatic MM, and extra-medullary myeloma/plasma cell leukemia (PCL). Cancers 2020, 12, 782 characterized by a highly heterogeneous genetic background with both structural chromosomal aberrations and specific gene mutations [1]. LncRNAs are involved in many biological processes, such as cell proliferation, apoptosis, cellular differentiation, tumorigenesis and metastasis [2,3]. Several lncRNAs have been reported to be putatively involved in MM tumor biology and our knowledge of their function is progressively expanding [5,6,7,8,9]; at the moment only a few of them have been functionally investigated, including MALAT1 [10,11,12], NEAT1 [13,14], CCAT1 [15]
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