Exosomes, extracellular vesicles with diameters ranging from 30 to 150 nm, are widely present in various body fluids. Recently, microRNAs (miRNAs) have been identified in exosomes, the biogenesis, release, and uptake of which may involve the endosomal sorting complex required for transport (ESCRT complex) and relevant proteins. After release, exosomes are taken up by neighboring or distant cells, and the miRNAs contained within modulate such processes as interfering with tumor immunity and the microenvironment, possibly facilitating tumor growth, invasion, metastasis, angiogenesis and drug resistance. Therefore, exosomal miRNAs have a significant function in regulating cancer progression. Here, we briefly review recent findings regarding tumor-derived exosomes, including RNA sorting and delivering mechanism. We then describe the intercommunication occurring between different cells via exosomal miRNAs in tumor microenvironmnt, with impacts on tumor proliferation, vascularization, metastasis and other biological characteristics. Finally, we highlight the potential role of these molecules as biomarkers in cancer diagnosis and prognosis and tumor resistance to therapeutics.

/pdf/effect-of-exosomal-mirna-on-cancer-biology-and-clinical-3n544kgn3v.pdf

Effect of exosomal miRNA on cancer biology and clinical applications.

Leukemia is known as a progressive malignant disease, which destroys the blood-forming organs and results in adverse effects on the proliferation and development of leukocytes and their precursors in the blood and bone marrow. There are four main classes of leukemia including acute leukemia, chronic leukemia, myelogenous leukemia, and lymphocytic leukemia. Given that a variety of internal and external factors could be associated with the initiation and progression of different types of leukemia. One of the important factors is epigenetic regulators such as microRNAs (miRNAs) and long noncoding RNAs (ncRNA). MiRNAs are short ncRNAs which act as tumor suppressor (i.e., miR-15, miR-16, let-7, and miR-127) or oncogene (i.e., miR-155, miR-17-92, miR-21, miR-125b, miR-93, miR-143-p3, miR-196b, and miR-223) in leukemia. It has been shown that deregulation of these molecules are associated with the initiation and progression of leukemia. Hence, miRNAs could be used as potential therapeutic candidates in the treatment of patients with leukemia. Moreover, increasing evidence revealed that miRNAs could be used as diagnostic and prognostic biomarkers in monitoring patients in early stages of disease or after received chemotherapy regimen. It seems that identification and development of new miRNAs could pave to the way to the development new therapeutic platforms for patients with leukemia. Here, we summarized various miRNAs as tumor suppressor and oncogene which could be introduced as therapeutic targets in treatment of leukemia.

MicroRNA in leukemia: Tumor suppressors and oncogenes with prognostic potential.

Myelodysplastic syndromes (MDS), heterogeneous diseases of hematopoietic stem cells, exhibit a significant risk of progression to secondary acute myeloid leukemia (sAML) that are typically accompanied by MDS-related changes and therefore significantly differ to de novo acute myeloid leukemia (AML). Within these disorders, the spectrum of cytogenetic alterations and oncogenic mutations, the extent of a predisposing defective osteohematopoietic niche, and the irregularity of the tumor microenvironment is highly diverse. However, the exact underlying pathophysiological mechanisms resulting in hematopoietic failure in patients with MDS and sAML remain elusive. There is recent evidence that the post-transcriptional control of gene expression mediated by microRNAs (miRNAs), long noncoding RNAs, and/or RNA-binding proteins (RBPs) are key components in the pathogenic events of both diseases. In addition, an interplay between RBPs and miRNAs has been postulated in MDS and sAML. Although a plethora of miRNAs is aberrantly expressed in MDS and sAML, their expression pattern significantly depends on the cell type and on the molecular make-up of the sample, including chromosomal alterations and single nucleotide polymorphisms, which also reflects their role in disease progression and prediction. Decreased expression levels of miRNAs or RBPs preventing the maturation or inhibiting translation of genes involved in pathogenesis of both diseases were found. Therefore, this review will summarize the current knowledge regarding the heterogeneity of expression, function, and clinical relevance of miRNAs, its link to molecular abnormalities in MDS and sAML with specific focus on the interplay with RBPs, and the current treatment options. This information might improve the use of miRNAs and/or RBPs as prognostic markers and therapeutic targets for both malignancies.

https://www.mdpi.com/1422-0067/21/19/7140/pdf

Expression, Regulation and Function of microRNA as Important Players in the Transition of MDS to Secondary AML and Their Cross Talk to RNA-Binding Proteins.

Multiple myeloma (MM) is a heterogeneous haematological disease that remains clinically challenging Increased activity of the epigenetic silencer EZH2 is a common feature in patients with poor prognosis Previous findings have demonstrated that metabolic profiles can be sensitive markers for response to treatment in cancer While EZH2 inhibition (EZH2i) has proven efficient in inducing cell death in a number of human MM cell lines, we hereby identified a subset of cell lines that despite a global loss of H3K27me3, remains viable after EZH2i By coupling liquid chromatography-mass spectrometry with gene and miRNA expression profiling, we found that sensitivity to EZH2i correlated with distinct metabolic signatures resulting from a dysregulation of genes involved in methionine cycling Specifically, EZH2i resulted in a miRNA-mediated downregulation of methionine cycling-associated genes in responsive cells This induced metabolite accumulation and DNA damage, leading to G2 arrest and apoptosis Altogether, we unveiled that sensitivity to EZH2i in human MM cell lines is associated with a specific metabolic and gene expression profile post-treatment

/pdf/a-distinct-metabolic-response-characterizes-sensitivity-to-1cyqv5w2ec.pdf

A distinct metabolic response characterizes sensitivity to EZH2 inhibition in multiple myeloma.

Anticancer drug resistance is a significant impediment in current cancer treatment. Extracellular vesicles (EVs) derived from cancer cells were recently acknowledged as a critical mechanism of drug resistance, tumor progression, and metastasis. EVs are enveloped vesicles comprising a lipid bilayer that transfers various cargo, including proteins, nucleic acids, lipids, and metabolites, from an originating cell to a recipient cell. Investigating the mechanisms whereby EVs confer drug resistance is still in the early stages. In this review, I analyze the roles of EVs derived from triple-negative breast cancer cells (TNBC-EVs) in anticancer drug resistance and discuss strategies to overcome TNBC-EV-mediated drug resistance.

https://www.mdpi.com/1422-0067/24/4/3704/pdf?version=1677032010

Therapeutic Implications of the Drug Resistance Conferred by Extracellular Vesicles Derived from Triple-Negative Breast Cancer Cells

The relapse and resistance to cytarabine (Ara-C) therapy is still a dominating obstacle to the successful clinical treatment of acute myeloid leukemia (AML). Recent studies have shown that dysregulation of miRNAs might modulate the resistance of cancer cells to anticancer drugs; yet, the mechanism is not fully understood. In this study, we showed a significant downregulation of miR-134 in human multidrug-resistant leukemia cells and relapsed/refractory AML patient samples. Overexpression of miR-134 sensitized K562/A02 and HL-60/ADM cells to Ara-C, inhibited cell colony formation, and enhanced the ability of Ara-C to induce apoptosis. Mechanistic analyses revealed that Mnks was a putative target of miR-134, which was inversely correlated with miR-134 expression in human multidrug-resistant leukemia cells and relapsed/refractory AML patient samples. Further investigation showed that miR-134 increased the anti-tumor effects of Ara-C through inhibiting phosphorylation of eukaryotic initiation factor 4E and downregulating Mcl-1 and bcl2, which was independent of p38 and Erk1/2 activation. Taken together, our results demonstrate that miR-134 plays a pivotal role in AML Ara-C resistance through increasing cell sensitivity to Ara-C and promoting apoptosis by targeting Mnks.

/pdf/mir-134-increases-the-antitumor-effects-of-cytarabine-by-4d4fgwwio3.pdf

miR-134 increases the antitumor effects of cytarabine by targeting Mnks in acute myeloid leukemia cells.

Objective: This study investigated the efficacy and safety of low-dose lenalidomide combined with dexamethasone in elderly patients with relapsed and refractory multiple myeloma (MM).Methods: Thirty-two elderly patients with refractory and recurrent MM (median age: 64 years) were treated with low-dose lenalidomide (LD-R) combined with dexamethasone (D). LD-R (10 mg/d) was administered orally for 21 days and D (40 mg/d) was administered twice a day on days 1–4, 9–12, and 17–20. The treatment lasted 2–8 28-day cycles.Results: After two cycles, the complete, very good partial, and partial remission rates were 12.5% (4/32), 25.0% (8/32), and 34.4% (11/32), respectively. The overall response rate was 71.9% (23/32). After a 24-month follow-up, 23 patients responded to therapy, three were in complete remission, four were stable, and 16 exhibited disease progression. In addition, median time-to-progression was 13 months. Observed side effects were hypodynamia, gastrointestinal reaction, peripheral neuriti...

https://www.tandfonline.com/doi/pdf/10.1080/10245332.2016.1234186

Low-dose lenalidomide and dexamethasone combination treatment in elderly patients with relapsed and refractory multiple myeloma

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miR-134 increases the antitumor effects of cytarabine by targeting Mnks in acute myeloid leukemia cells.

Low-dose lenalidomide and dexamethasone combination treatment in elderly patients with relapsed and refractory multiple myeloma