Exosomal miR-182 derived from bone marrow mesenchymal stem cells drives carfilzomib resistance of multiple myeloma cells by targeting SOX6.

BACKGROUND: Multiple myeloma (MM) is a common hematological malignancy. Drug resistance remains to be a major clinical challenge in MM therapy. In this study, we aim to investigate the functional roles of bone marrow mesenchymal stem cells (BMSC)-derived exosomal miR-182 on the carfilzomib resistance of MM and its underlying mechanism. METHODS: qRT-PCR and Western blot methods were utilized to confirm the gene or protein expressions. CCK-8 and transwell assays were performed to measure the capabilities of proliferation, migration, and invasion. The molecular interactions were validated through ChIP and Dual luciferase assay. RESULTS: Our findings indicated that miR-182 expression was upregulated in serum, BMSCs and BMSC-derived exosomes from MM patients. Hypoxia-inducible factor-1α (HIF-1α), a key transcriptional factor in tumor microenvironment, could boost miR-182 expression by directly binding to its promoter, thus favoring exosomal secretion. Moreover, exosomal miR-182 from BMSCs could be transferred to MM cells and was able to promote malignant proliferation, metastasis, and invasion, as well as decrease the sensitivity of MM cells against carfilzomib. Additionally, SOX6 was identified as a downstream target of miR-182 in MM cells, and its expression was negatively regulated by miR-182. Rescue experiments proved that loss of SOX6 in MM cells dramatically reversed the promoting roles of BMSC-secreted exosomal miR-182 on proliferation, metastasis, and carfilzomib resistance in MM cells. CONCLUSION: Collectively, our findings indicated that exosomal miR-182 derived from BMSCs contributed to the metastasis and carfilzomib resistance of MM cells by targeting SOX6. This study sheds light on the pathogenesis of the BMSC-derived exosome containing miR-182 in the malignant behaviors of MM cells and carfzomib resistance.

MicroRNA-765 is pregulated in multiple myeloma and serves an oncogenic role by directly targeting SOX6.

Increasing evidence has revealed that microRNAs (miRNAs) are closely associated with multiple myeloma (MM) pathogenesis and progression. Therefore, an in-depth understanding of the biological functions of miRNAs in MM may be helpful for the identification of promising therapeutic techniques for patients with MM. miRNA-765 (miR-765) has been reported to be dysregulated in many types of human cancer. However, the expression pattern, specific roles and underlying mechanisms of miR-765 in MM remain largely unknown. In the present study, plasma miR-765 significantly increased in patients with MM and cell lines. The downregulation of miR-765 in MM cells attenuated proliferation and promoted apoptosis. Bioinformatics analysis predicted that SRY-Box 6 (SOX6) was a putative target of miR-765. This was experimentally verified using a luciferase reporter assay, reverse transcription-quantitative PCR and western blot analysis. Furthermore, plasma SOX6 was downregulated in patients with MM and the downregulation of SOX6 was inversely correlated with that of miR-765 expression. Furthermore, SOX6 knockdown markedly abrogated the effects of miR-765 underexpression on cell proliferation and apoptosis in MM. The current study demonstrated that miR-765 serves an oncogenic role in MM progression by directly targeting SOX6, suggesting that miR-765 may be a potential therapeutic target for MM prevention and treatment.