BackgroundMultiple myeloma (MM) accounts for 10% of all hematological malignancies. Dysregulation of microRNAs (miRNAs) or long non-coding RNAs (lncRNAs) has important impacts on progression of MM. Circular RNAs (circRNAs) are correlated with malignancy in the modulation of tumor progression. This study aims to investigate the effect of circ_0000190 on regulating the progression of MM.MethodMicroscopic examination via single molecule fluorescent in situ hybridization indicates the location of circ_0000190. qRT-PCR and Western blot were used to evaluate the expression of RNAs and proteins. Potential target of circ_0000190 was searched as miRNA, and examined by luciferase reporter assay. A computational screen was also conducted to search the potential target of miRNA. In vitro cell viability, proliferation, apoptosis assays and flow cytometric were performed to assess the effects of circ_0000190 and its target on MM. Mice model of human MM was established with subcutaneous xenograft tumor, qRT-PCR and western blot were performed to detect the underlying mechanisms of circ_0000190 on MM.ResultsCirc_0000190 was located in the cytoplasm, and down-regulated in both bone marrow tissue and peripheral blood, while the target of circ_0000190, miR-767-5p, was up-regulated, suggesting a negative correlation between them. The binding ability between circ_0000190 and miR-767-5p was confirmed by luciferase reporter assay. Moreover, circ_0000190 inhibited cell viability, proliferation and induced apoptosis of MM thus inhibiting cell progression, which is partially through the negative regulation of miR-767-5p. Mitogen-activated protein kinase 4 (MAPK4) is a direct target of miR-767-5p. In addition, over-expression of miR-767-5p promoted cell progression by directly targeting and regulating MAPK4. The MM model mice with administration of circ_0000190 suppressed tumor growth and progression.ConclusionOur results revealed that the ability of circ_0000190 to protect against MM was inherited through repression of miR-767-5p, and miR-767-5p might be a tumor drive through targeting MAPK4. Therefore, a novel role of circ_0000190 on regulating the progression of MM was found, and the clinical application of circRNAs might represent a strategy in MM.Electronic supplementary materialThe online version of this article (10.1186/s13046-019-1071-9) contains supplementary material, which is available to authorized users.

The chemoresistance is one of the major challenges for acute myeloid leukemia (AML) treatment. We found that the expression of histone deacetylase 8 (HDAC8) was increased in daunorubicin (DNR) resistant AML cells, while targeted inhibition of HDAC8 by its specific siRNA or inhibitor can restore sensitivity of DNR treatment . Further, targeted inhibition of HDAC8 can suppress expression of interleukin 6 (IL-6) and IL-8. While recombinant IL-6 (rIL-6) and rIL-8 can reverse si-HDAC8-resored DNR sensitivity of AML cells. Mechanistical study revealed that HDAC8 increased the expression of p65, one of key components of NF-κB complex, to promote the expression of IL-6 and IL-8. It might be due to that HDAC8 can directly bind with the promoter of p65 to increase its transcription and expression. Collectively, our data suggested that HDAC8 promotes DNR resistance of human AML cells via regulation of IL-6 and IL-8.

Introduction Acute myeloid leukemia (AML) is a predominant blood malignancy with high mortality and severe morbidity. AML is affected by microRNAs (miRNAs) loaded in exosomes derived from bone marrow mesenchymal stem cells (BM-MSCs). MiR-425-5p has been reported to participate in different cancer models. However, the function of BM-MSCs-derived exosomal miR-425-5p in AML is unclear. Methods The expression of miR-425-5p was measured by qRT-PCR in clinical AML samples. The immunophenotype of BM-MSCs was analyzed using antibodies against CD44, CD90, and CD105. The exosome was isolated from BM-MSCs. The effect of BM-MSCs-derived exosomal miR-425-5p on AML was analyzed by CCK-8 assay, Edu assay, transwell assay, flow cytometry in AML cells. qRT-PCR, luciferase reporter gene assay and Western blot analysis were also conducted in AML cells. Results The expression levels of miR-425-5p were decreased in CD34 + CD38-AML cells from primary AML patients compared to that from the bone marrow of healthy cases, and were reduced in exosomes from AML patients compared that from healthy cases. Similarly, miR-425-5p was also down-regulated in AML cell lines compared with BM-MSCs. MiR-425-5p was able to express in exosomes from BM-MSCs. CCK-8, Edu, transwell assay and flow cytometry analysis revealed that BM-MSCs-derived exosomal miR-425-5p significantly inhibited cell viability, Edu positive cells, invasion and migration, and induced apoptosis of AML cells. Meanwhile, the expression levels of cleaved PARP and cleaved caspase3 were increased by BM-MSCs-derived exosomal miR-425-5p in cells. MiR-425-5p inhibited the expression of Wilms tumor 1-associated protein (WTAP). Moreover, overexpression of WTAP could reverse the miR-425-5p-induced inhibition effect on AML cell proliferation, apoptosis, migration and invasion. Conclusion BM-MSCs-derived exosomal miR-425-5p inhibits proliferation, invasion and migration of AML cells and induced apoptosis of AML cells by targeting WTAP. Therapeutically, BM-MSCs-derived exosomal miR-425-5p may serve as a potential target for AML therapy.

No abstract

Acute myeloid leukemia (AML) is associated with a poor prognosis in elderly adults and currently lacks optimal treatment strategies. MicroRNAs (miRNAs or miRs) have increasingly been reported to be associated with AML progression; however, the mechanisms of action of miR-93 in AML with the involvement of disabled 2 (DAB2) are currently unknown. In the present study, miR-93 expression was assessed in patients with AML and in AML cell lines. The association between miR-93 expression and the pathological characteristics of patients with AML was analyzed. AML cells were then transfected to knockdown or overexpress miR-93 in order to elucidate its function in AML progression. The target gene of miR-93 was assessed using a dual-luciferase reporter gene assay. The expression levels of miR-93, DAB2 and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway-related proteins were measured and in vivo experiments were conducted to confirm the results. It was observed that miR-93 was highly expressed in patients with AML and in AML cells. The knockdown of miR-93 in HL-60 cells inhibited AML cell proliferation and resistance to apoptosis, while the overexpression of miR-93 in THP-1 cells led to contrasting results. Moreover, miR-93 targeted DAB2 to inactivate the PI3K/AKT pathway, and the overexpression of DAB2 reversed the effects of miR-93 on THP-1 cell growth. Tumor volume, tumor weight, and the positive expression of Ki67, survivin and p53 were increased in THP-1 cells overexpressing miR-93. On the whole, the present study demonstrates that miR-93 is highly expressed in AML cells, and that the suppression of miR-93 inhibits AML cell growth by targeting DAB2 and inhibiting the PI3K/AKT pathway.