Myeloma cells regulate miRNA transfer from fibroblast‐derived exosomes by expression of lncRNAs

Abstract

Multiple myeloma (MM) progression and drug resistance depend on the crosstalk between MM cells and bone marrow (BM) fibroblasts (FBs). During monoclonal gammopathy of undetermined significance (MGUS) to MM transition, MM cell-derived exosomes (EXOs) reprogram the miRNA (miR) profile of FBs, inducing the overexpression miR-23b-3p, miR-27b-3p, miR-125b-5p, miR-214-3p, and miR-5100. Here, we demonstrate that the miR content of MM FB-derived EXOs (FB-EXOs) overlaps the miR profile of parental FBs by overexpressing comparable levels of miR-23b-3p, miR-27b-3p, miR-125b-5p, miR-214-3p, and miR-5100. Recipient MM cells co-cultured with MM FB-EXOs selectively overexpress only miR-214-3p and miR-5100 but not miR-23b-3p, miR-27b-3p, and miR-125b-5p, suggesting a putative selective transfer. MM cells express HOTAIR, TOB1-AS1, and MALAT1 lncRNAs. Transient transfection of MM cells with lncÁsiRNAs demonstrates that HOTAIR, TOB1-AS1, and MALAT1 lncRNAs are sponges for miR-23b-3p, miR-27b-3p, and miR-125b-5p. Indeed, lncRNA knockdown significantly increased miR levels in U266 MM cells co-cultured with MM FB-EXOs. Selective miR-214-3p and miR-5100 overexpression modulates MAPK, PI3K/AKT/mTOR, and p53 pathways in MM cells. Interrogation using the DIANA tools algorithm and transient overexpression using miR mimic probes confirmed the involvement of miR-214-3p and miR-5100 and their target genes, PTEN and DUSP16, respectively, in the modulation of these intracellular pathways. Finally, the uptake of EXOs as well as miR-214-3p and miR-5100 overexpression increase MM cell proliferation and resistance to bortezomib-induced apoptosis by switching the balance between pro-/anti-apoptotic proteins. Overall, these data show that MM cells are not simply a container into which EXOs empty their cargo. On the contrary, tumour cells finely neutralize exosomal miRs via lncRNA expression to ensure their survival.

Metabolic changes underlying drug resistance in the multiple myeloma tumor microenvironment

“…MM resides in a complex permissive niche of heterogeneous cells, forming the TME ( 78 , 79 ), which is composed of cellular and non-cellular components ( 1 , 20 , 80 ) and plays a pivotal role in promoting tumorigenesis and drug resistance ( 81 – 84 ). Within the MM TME, bone-marrow stromal cells (BMSCs) are thought to be crucial in promoting MM drug resistance, which has been described to be induced through direct cell adhesion ( 84 – 90 ) and soluble factors ( 79 , 91 – 94 ), as well as via different signaling pathways. BMSCs, especially fibroblasts, can be activated by soluble factors and turn into cancer-associated fibroblasts (CAFs).…”

Exosomes in multiple myeloma: from bench to bedside

“…MM BMSC exosomes also contained miR-23b-3p, miR-27b-3p, miR-125b-5p, miR-214-3p and miR-5100. However, MM cells only incorporated miR-214-3p and miR-5100, which induced MM cell proliferation and DR via downregulation of PTEN 56 . Moreover, LINC00461, present in BM MSC exosomes, was discovered to be a sponge for miR-15a/16 after transfer into MM cells, thereby releasing BCL-2, leading to enhanced MM survival 57 .…”

Small biomarkers with massive impacts: PI3K/AKT/mTOR signalling and microRNA crosstalk regulate nasopharyngeal carcinoma

“…Long noncoding RNAs (lncRNAs) are important noncoding RNAs that can indirectly regulate the PI3K/AKT/mTOR signalling pathway by targeting and adsorbing miRNAs. Some studies have found that tumour cells can regulate exosomal transfer of miRNA from fibroblasts by expressing lncRNAs, and the miRNAs can further regulate PI3K/AKT/mTOR signalling to affect the tumour microenvironment [ 109 , 110 ]. In addition, other studies have found that lncRNAs can regulate PI3K/AKT/mTOR signalling through targeted adsorption of miRNAs, thereby affecting the growth and proliferation of a variety of tumour cells, including pharyngeal squamous cell carcinoma cells [ 111 , 112 ].…”