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According to the expression of miRNA in pathological processes, miRNAs can be divided into oncogenes or tumor suppressors. Prediction of the regulation relations between miRNAs and small molecules (SMs) becomes a vital goal for miRNA-target therapy. But traditional biological approaches are laborious and expensive. Thus, there is an urgent need to develop a computational model. In this study, we proposed a computational model to predict whether the regulatory relationship between miRNAs and SMs is up-regulated or down-regulated. Specifically, we first use the Large-scale Information Network Embedding (LINE) algorithm to construct the node features from the self-similarity networks, then use the General Attributed Multiplex Heterogeneous Network Embedding (GATNE) algorithm to extract the topological information from the attribute network, and finally utilize the Light Gradient Boosting Machine (LightGBM) algorithm to predict the regulatory relationship between miRNAs and SMs. In the fivefold cross-validation experiment, the average accuracies of the proposed model on the SM2miR dataset reached 79.59% and 80.37% for up-regulation pairs and down-regulation pairs, respectively. In addition, we compared our model with another published model. Moreover, in the case study for 5-FU, 7 of 10 candidate miRNAs are confirmed by related literature. Therefore, we believe that our model can promote the research of miRNA-targeted therapy. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) produces clonal plasma cells and aberrant monoclonal antibody accumulation in patients' bone marrow (BM). Around 1% of all cancers and 13% of hematological malignancies are caused by MM, making it one of the most common types of cancer. Diagnostic and therapeutic methods for managing MM are currently undergoing extensive research. MicroRNAs (miRNAs) are short noncoding RNAs that reduce or inhibit the translation of their target mRNA after transcription. Because miRNAs play an influential role in how myeloma develops, resources, and becomes resistant to drugs, miRNA signatures may be used to diagnose, do prognosis, and treat the myeloma response. Consequently, researchers have investigated the levels of miRNA in plasma cells from MM patients and developed tools to test whether they directly impacted tumor growth. This review discusses the latest discoveries in miRNA science and their role in the development of MM. We also emphasize the potential applications of miRNAs to diagnose, prognosticate, and treat MM in the future. [ABSTRACT FROM AUTHOR]

Non-coding RNA (ncRNA) species, mainly long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been currently imputed for lesser or greater involvement in human erythropoiesis. These RNA subsets operate within a complex circuit with other epigenetic components and transcription factors (TF) affecting chromatin remodeling during cell differentiation. Lymphoma/leukemia-related (LRF) TF exerts higher occupancy on DNA CpG rich sites and is implicated in several differentiation cell pathways and erythropoiesis among them and also directs the epigenetic regulation of hemoglobin transversion from fetal (HbF) to adult (HbA) form by intervening in the γ-globin gene repression. We intended to investigate LRF activity in the evolving landscape of cells' commitment to the erythroid lineage and specifically during HbF to HbA transversion, to qualify this TF as potential repressor of lncRNAs and miRNAs. Transgenic human erythroleukemia cells, overexpressing LRF and further induced to erythropoiesis, were subjected to expression analysis in high LRF occupancy genetic loci-producing lncRNAs. LRF abundance in genetic loci transcribing for studied lncRNAs was determined by ChIP-Seq data analysis. qPCRs were performed to examine lncRNA expression status. Differentially expressed miRNA pre- and post-erythropoiesis induction were assessed by next-generation sequencing (NGS), and their promoter regions were charted. Expression levels of lncRNAs were correlated with DNA methylation status of flanked CpG islands, and contingent co-regulation of hosted miRNAs was considered. LRF-binding sites were overrepresented in LRF overexpressing cell clones during erythropoiesis induction and exerted a significant suppressive effect towards lncRNAs and miRNA collections. Based on present data interpretation, LRF's multiplied binding capacity across genome is suggested to be transient and associated with higher levels of DNA methylation. Key messages: During erythropoiesis, LRF displays extensive occupancy across genetic loci. LRF significantly represses subsets of lncRNAs and miRNAs during erythropoiesis. Promoter region CpG islands' methylation levels affect lncRNA expression. MiRNAs embedded within lncRNA loci show differential regulation of expression. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a malignancy of plasma cells in the bone marrow and is characterized by the clonal proliferation of B-cells producing defective monoclonal immunoglobulins. Despite the latest developments in treatment, drug resistance remains one of the major challenges in the therapy of MM. The crosstalk between MM cells and other components within the bone marrow microenvironment (BME) is the major determinant of disease phenotypes. Exosomes have emerged as the critical drivers of this crosstalk by allowing the delivery of informational cargo comprising multiple components from miniature peptides to nucleic acids. Such material transfers have now been shown to perpetuate drug-resistance development and disease progression in MM. MicroRNAs(miRNAs) specifically play a crucial role in this communication considering their small size that allows them to be readily packed within the exosomes and widespread potency that impacts the developmental trajectory of the disease inside the tumor microenvironment (TME). In this review, we aim to provide an overview of the current understanding of the role of exosomal miRNAs in the epigenetic modifications inside the TME and its pathogenic influence on the developmental phenotypes and prognosis of MM. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is the second most common hematological malignancy. Despite the huge therapeutic progress thanks to the introduction of novel therapies, MM remains an incurable disease. Extensive research is currently ongoing to find new options. MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression at a post-transcriptional level. Aberrant expression of miRNAs in MM is common. Depending on their role in MM development, miRNAs have been reported as oncogenes and tumor suppressors. It was demonstrated that specific miRNA alterations using miRNA mimics or antagomirs can normalize the gene regulatory network and signaling pathways in the microenvironment and MM cells. These properties make miRNAs attractive targets in anti-myeloma therapy. However, only a few miRNA-based drugs have been entered into clinical trials. In this review, we discuss the role of the miRNAs in the pathogenesis of MM, their current status in preclinical/clinical trials, and the mechanisms by which miRNAs can theoretically achieve therapeutic benefit in MM treatment. [ABSTRACT FROM AUTHOR]

Osteoclast-mediated bone resorption is responsible for bone metabolic diseases, negatively impacting people's health and life. It has been demonstrated that microRNA influences the differentiation of osteoclasts by regulating the signaling pathways during osteoclast-mediated bone resorption. So far, the involved mechanisms have not been fully elucidated. This review introduced the pathways involved in osteoclastogenesis and summarized the related microRNAs binding to their specific targets to mediate the downstream pathways in osteoclast-mediated bone resorption. We also discuss the clinical potential of targeting microRNAs to treat osteoclast-mediated bone resorption as well as the challenges of avoiding potential side effects and producing efficient delivery methods. [ABSTRACT FROM AUTHOR]

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 lnc·siRNAs 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. © 2021 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC), a common malignancy of the human digestive system, represents the second leading cause of cancer-related deaths worldwide. Early detection of GC has a significant impact on clinical outcomes. The aim of this study was to identify potential GC biomarkers. Methods: In this study, we conducted a multi-step analysis of expression profiles in GC clinical samples downloaded from TCGA database to identify differentially expressed miRNAs (DEMs) and differentially expressed mRNAs (DEGs). Potential prognostic biomarkers from the available DEMs were then established using the Cox regression method. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to investigate the biological role of the predicted target genes of the miRNA biomarkers. Then, the prognostic DEM-mediated regulatory network was constructed based on transcription factor (TF)–miRNA–target interaction. Subsequently, the consensus genes were further determined based on the overlap between DEGs and these target genes of DEMs. Besides, expression profile, co-expression analysis, immunity, and prognostic values of these prognostic genes were also investigated to further explore the roles in the mechanism of GC tumorigenesis. Results: We got five miRNAs, including miR-23b, miR-100, miR-143, miR-145, and miR-409, which are associated with the overall survival of GC patients. Subsequently, enrichment analysis of the target genes of the miRNA biomarkers shown that the GO biological process terms were mainly enriched in mRNA catabolic process, nuclear chromatin, and RNA binding. In addition, the KEGG pathways were significantly enriched in fatty acid metabolism, extracellular matrix (ECM) receptor interaction, and proteoglycans in cancer pathways. The transcriptional regulatory network consisting of 68 TFs, 4 DEMs, and 58 targets was constructed based on the interaction of TFs, miRNAs, and targets. The downstream gene ETS1 of miR-23b and TCF4 regulated by ETS1 were obtained by the regulatory network construction and co-expression analysis. High expression of ETS1 and TCF4 indicated poor prognosis in GC patients, particularly in the advanced stages. The expression of ETS1 and TCF4 was correlated with CD4+ T cells, CD8+ T cells, and B cells. Conclusions: miR-23b, ETS1, and TCF4 were identified as the prognostic biomarkers. ETS1 and TCF4 had potential immune function in GC, which provided a theoretical basis for molecular-targeted combined immunotherapy in the future. [ABSTRACT FROM AUTHOR]

MicroRNAs (MiRNAs) are small endogenous non-coding RNAs that bind to the 3′-untranslated region of target genes and promote their degradation or inhibit translation, thereby regulating gene expression. MiRNAs are ubiquitous in biology and are involved in many biological processes, playing an important role in a variety of physiological and pathological processes. MiRNA-21 (miR-21) is one of them. In recent years, miR-21 has received a lot of attention from researchers as an emerging player in orthopedic diseases. MiR-21 is closely associated with the occurrence, development, treatment, and prevention of orthopedic diseases through a variety of mechanisms. This review summarizes its effects on osteoblasts, osteoclasts and their relationship with osteoporosis, fracture, osteoarthritis (OA), osteonecrosis, providing a new way of thinking for the diagnosis, treatment and prevention of these bone diseases. [ABSTRACT FROM AUTHOR]

Despite the administration of new effective drugs in recent years, relapse and drug resistance are still the main obstacles in multiple myeloma (MM) treatment, making MM an incurable disease. To overcome drug resistance in MM, it is critical to understand the underlying mechanisms of malfunctioning gene expression and develop novel targeted therapies. During the past few decades, with the discovery and characterization of noncoding RNAs (ncRNAs), the landscape of dysregulated ncRNAs of cancers as well as their biological and pathobiological functions in tumorigenesis and drug resistance have been recognized. Studies about ncRNAs improved the understanding of variations of drug response among individuals at a level distinguished from genetic polymorphism, and provided with new orientations for targeted therapies. In this review, we will summarize the emerging impact and underlying molecular mechanisms of the most relevant classes of ncRNAs in drug resistance of MM, and discuss the potential as well as strategies of treating ncRNAs as therapeutic targets. [ABSTRACT FROM AUTHOR]

Periodontal accelerate osteogenesis orthodontics (PAOO) is an extension of described techniques that surgically alter the alveolar bone; however, the specific mechanism underlying the technique is not completely understood. The aim of the present study was to evaluate the roles of microRNA (miR)-21 during PAOO. Sprague-Dawley rats were divided into the following four groups: i) Group tooth movement (TM), underwent TM and were administered normal saline (NS); ii) Group PAOO, underwent PAOO + TM and were administered NS; iii) Group agomiR-21, underwent PAOO + TM and were administered agomiR-21; and iv) Group antagomiR-21, underwent PAOO + TM and were administered antagomiR-21. To validate the rat model of PAOO, morphological analyses were performed and measurements were collected. Reverse transcription-quantitative PCR, western blotting and immunohistochemical staining were performed to examine the expression levels of programmed cell death 4 (PDCD4), activin A receptor type 2B (ACVR2b), receptor activator of NF-κΒ ligand (RANKL) and C-Fos. Dual-luciferase reporter assays were performed to validate PDCD4 as a target of miR-21 in vitro. Following 7 days of treatment, the TM distance of group PAOO was longer compared with groups TM and antagomiR-21 (P<0.05), but shorter compared with group agomiR-21 (P<0.05). Tartrate-resistant acid phosphatase staining indicated that following treatment with agomiR-21, osteoclast activity was notably increased, whereas the mRNA and protein expression levels of PDCD4 were notably decreased compared with group PAOO. The mRNA and protein expression levels of RANKL and C-Fos in group agomiR-21 were notably increased compared with group PAOO, whereas group antagomiR-21 displayed the opposite pattern (P<0.05). With regard to ACVR2b, no significant differences were observed among the group agomiR-21 and antagomiR-21 compared with group PAOO. Bioinformatics analysis predicted that PDCD4 was a potential target gene of miR-21, and dual-luciferase reporter assays demonstrated that miR-21 directly targeted PDCD4. In conclusion, the present study demonstrated that miR-21 serves an important role during PAOO-mediated orthodontic TM. [ABSTRACT FROM AUTHOR]

Osteocytes play a critical role in mediating cell–cell communication and regulating bone homeostasis, and osteocyte apoptosis is associated with increased bone resorption. miR21, an oncogenic microRNA, regulates bone metabolism by acting directly on osteoblasts and osteoclasts, but its role in osteocytes is not clear. Here, we show that osteocytic miR21 deletion has sex‐divergent effects in bone. In females, miR21 deletion reduces osteocyte viability, but suppresses bone turnover. Conversely, in males, miR21 deletion increases osteocyte viability, but stimulates bone turnover and enhances bone structure. Further, miR21 deletion differentially alters osteocyte cytokine production in the two sexes. Interestingly, despite these changes, miR21 deletion increases bone mechanical properties in both sexes, albeit to a greater extent in males. Collectively, our findings suggest that miR21 exerts both sex‐divergent and sex‐equivalent roles in osteocytes, regulating osteocyte viability and altering bone metabolism through paracrine actions on osteoblasts and osteoclasts differentially in males vs females, whereas, influencing bone mechanical properties independent of sex. [ABSTRACT FROM AUTHOR]

Objectives: The present study was designed to investigate the effects of microRNA‐21 (miR‐21) on orthodontic tooth movement. Methods: The orthodontic tooth movement model was established in C57BL/6 and miR‐21−/− mice with or without implantation of activated T cells. Histological and histomorphometrical analyses were performed by hematoxylin–eosin staining. Tartrate‐resistant acid phosphate staining was used to analyze the osteoclast numbers during tooth movement. Enzyme‐linked immunosorbent assay, reverse transcription polymerase chain reaction, and immunohistochemistry analysis were used to examine the expression of RANKL and OPG. Results: In miR‐21−/− mice, the distance of tooth movement was retarded, the osteoclast number was decreased, and serum RANKL expression was strongly reduced. MiR‐21 promoted the secretion of RANKL from activated T cells. Furthermore, activated T cells could partially rescue the decreased orthodontic tooth movement distance in miR‐21−/− mice. MiR‐21 was shown to promote orthodontic tooth movement by modulating the RANKL/OPG balance in T cells. Conclusions: The impact of miR‐21 on tooth movement was better elucidated, furthering our understanding of its role and clinical applications in orthodontics. [ABSTRACT FROM AUTHOR]

The study of cancer prognosis serves as an important part of cancer research. Large-scale cancer studies have identified numerous genes and microRNAs (miRNAs) associated with prognosis. These informative genes and miRNAs represent potential biomarkers to predict survival and to elucidate the molecular mechanism of tumour progression. MiRNAs and transcription factors (TFs) can work cooperatively as essential mediators of gene expression, and their dysregulation affects cancer prognosis. A panoramic view of cancer prognosis at the system level, considering the co-regulation roles of miRNA and TF, remains elusive. Here, we establish 12 prognosis-related miRNA-TF co-regulatory networks. The characteristics of prognostic target genes and their regulators in the network are depicted. Although the target genes and co-regulatory patterns exhibit cancer-specific properties, some miRNAs and TFs are highly conserved across cancers. We illustrate and interpret the roles of these conserved regulators by building a model associated with cancer hallmarks, functional enrichment analysis, network community detection, and exhaustive literature research. The elaborated system-level prognostic miRNA-TF co-regulation landscape, including the highlighted roles of conserved regulators, provides a novel and powerful insights into further biological and medical discoveries. [ABSTRACT FROM AUTHOR]

Intensive research has been undertaken during the last decade to identify the implication of microRNAs (miRNAs) in the pathogenesis of multiple myeloma (MM). The expression profiling of miRNAs in MM has provided relevant information, demonstrating different patterns of miRNA expression depending on the genetic abnormalities of MM and a key role of some miRNAs regulating critical genes associated with MM pathogenesis. However, the underlying causes of abnormal expression of miRNAs in myeloma cells remain mainly elusive. The final expression of the mature miRNAs is subject to multiple regulation mechanisms, such as copy number alterations, CpG methylation or transcription factors, together with impairment in miRNA biogenesis and differences in availability of the mRNA target sequence. In this review, we summarize the available knowledge about the factors involved in the regulation of miRNA expression and functionality in MM. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM), accounting for ∼1% of all types of human cancer and 13% of all hematological malignancies, is characterized by the malignant proliferation of monoclonal plasma cells (PCs) in the bone marrow. MM leads to end stage organ impairment, including bone lesions, renal dysfunction, hypercalcemia and anemia. So far, the specific pathogenesis of MM remains unclear and no early-stage sensitive biomarker of MM has been well characterized. Furthermore, treating MM is difficult, as the majority of patients eventually relapse or become refractory following treatment using presently available methods. To date, a number of studies have demonstrated that microRNAs (miRNAs) may serve crucial functions in the progression of numerous cancers, including MM. During the tumorigenesis and pathogenesis of MM, there are multiple carcinogenic events that involve the pernicious transformation from normal to malignant PCs. miRNAs, as oncogenes or tumor suppressors, regulate MM progression-related signaling pathways. In the present review, the up-to-date preliminary basic studies and associated clinical works on the underlying mechanisms of aberrant miRNA profiling in MM have been summarized, including an evaluation of its value as a potential biomarker and a novel therapeutic strategy for MM. [ABSTRACT FROM AUTHOR]

The NT5E (CD73) molecule represents an ecto-5'-nucleotidase expressed on the cell surface of various cell types. Hydrolyzing extracellular adenosine monophosphate into adenosine and inorganic phosphate, NT5E performs numerous homeostatic functions in healthy organs and tissues. Importantly, NT5E can act as inhibitory immune checkpoint molecule, since free adenosine generated by NT5E inhibits cellular immune responses, thereby promoting immune escape of tumor cells. MicroRNAs (miRNAs) are small non-coding RNA molecules regulating gene expression on posttranscriptional level through binding to mRNAs, resulting in translational repression or degradation of the targeted mRNA molecule. In tumor cells, miRNA expression patterns are often altered which in turn might affect NT5E surface expression and eventually influence the efficacy of antitumor immune responses. This review describes the diverse roles of NT5E, summarizes current knowledge about transcription factors controlling NT5E expression, and highlights the significance of miRNAs involved in the posttranscriptional regulation of NT5E expression. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells and is the second most common hematological cancer. MM frequently occurs in the elderly population with the median age as the middle sixties. Over the last 10 years, the prognosis of MM has been dramatically improved by new therapeutic drugs; however, MM is still incurable. The pathogenesis of MM is still unclear, thus greater understanding of the molecular mechanisms of MM malignancy is desirable. Recently, microRNAs (miRNAs) were shown to modulate the expression of genes critical for MM pathogenesis. In addition, miRNAs are secreted via extracellular vesicles (EVs), which are released from various cell types including MM cells, and these miRNAs are involved in multiple types of cell-cell interactions, which lead to the malignancy of MM. In this review, we summarize the current knowledge regarding the role of miRNA secretion via EVs and of EVs themselves in MM development. We also discuss the potential clinical applications of EVs as promising biomarkers and new therapeutic targets for improving the outcome of MM, resulting in a brighter future for aging societies. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the molecular mechanisms of microRNA (miR)-181b in heart disease due to hypertensive disorders complicating pregnancy (HDCP) through regulating the expression of metallopeptidase inhibitor 3 (TIMP3). miR-181b expression was detected by reverse transcription-quantitative polymerase chain reaction in peripheral blood samples from patients with HDCP. These samples were analyzed for clinical pathological characteristics. The primary cardiomyocytes of rats were cultured in hypoxic conditions for 24 h, in which miR-181b expression was detected at different time points. The expression of TIMP3 was assessed in normal rat cardiomyocytes following transfection with miR-181b mimics by western blot analysis. The TIMP3 protein was also detected in cardiomyocytes following transfection with TIMP3 short interfering-RNA. The apoptosis rate of transfected cardiomyocytes was detected by flow cytometry following 24 h of culture in a hypoxic environment. Luciferase assay was applied to validate whether miR-181b binds to the 3' untranslated region of TIMP3 mRNA. miR-181b expression was significantly downregulated in the peripheral blood of patients with HDCP and the miR-181b expression was negatively associated with the grades of hypertension (P<0.05). The results of luciferase assay indicated that miR-181b directly targets TIMP3. The apoptosis rates of rat cardiomyocytes in the group transfected with miR-181b or TIMP3 siRNA was significantly lower than the normal control group (P<0.05). miR-181b may inhibit apoptosis of cardiomyocytes to protect myocardial cells through directly targeting TIMP3 genes, which serve important roles in HDCP. [ABSTRACT FROM AUTHOR]

Purpose of Review: Multiple myeloma remains an incurable disease, largely due to the tumor-supportive role of the bone marrow microenvironment. Bone marrow adipose tissue (BMAT) is one component of the fertile microenvironment which is believed to contribute to myeloma progression and drug resistance, as well as participate in a vicious cycle of osteolysis and tumor growth. Recent Findings: MicroRNAs (miRNAs) have recently emerged as instrumental regulators of cellular processes that enable the development and dissemination of cancer. This review highlights the intersection between two emerging research fields and pursues the scientific and clinical implications of miRNA transfer between BMAT and myeloma cells. Summary: This review provides a concise and provocative summary of the evidence to support exosome-mediated transfer of tumor-supportive miRNAs. The work may prompt researchers to better elucidate the mechanisms by which this novel means of genetic communication between tumor cells and their environment could someday yield targeted therapeutics. [ABSTRACT FROM AUTHOR]

Ovarian cancer is the eighth most common cancer in women worldwide, and epithelial ovarian cancer (EOC) represents 90% of cases. Nerve growth factor (NGF) and its high affinity receptor tyrosine kinase A receptor (TRKA) have been associated with the development of several types of cancer, including EOC; both NGF and TRKA levels are elevated in this pathology. EOC presents high angiogenesis and several molecules have been reported to induce this process. NGF increases angiogenesis through its TRKA receptor on endothelial cells, and by indirectly inducing vascular endothelial growth factor expression. Other molecules controlled by NGF include ciclooxigenase-2, disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) and calreticulin (CRT), proteins involved in crucial processes needed for EOC progression. These molecules could be modified through microRNA regulation, which could be regulated by NGF. MicroRNAs are the widest family of non-coding RNAs; they bind to 30-UTR of mRNAs to inhibit their translation, to deadenilate or to degraded them. In EOC, a deregulation in microRNA expression has been described, including alterations of miR-200 family, cluster-17-92, and miR-23b, among others. Since the NGF-microRNA relationship in pathologies has not been studied, this review proposes that some microRNAs could be associated with NGF/TRKA activation, modifying protein levels needed for EOC progression. [ABSTRACT FROM AUTHOR]

microRNAs could be mechanosensitive and emerge as critical posttranscriptional regulators in the bone-remodeling process. During orthodontic tooth movement (OTM), the application of mechanical force induces alveolar bone remodeling, but whether microRNAs respond to orthodontic force and contribute to OTM is unknown. microRNA-21 (miR-21) has been previously reported in vitro to mediate stretch-induced osteogenic differentiation of periodontal ligament stem cells and support osteoclast differentiation. In this study, the authors show that miR-21 responded to orthodontic force in periodontal tissue in a dose- and time-dependent manner and regulated the osteogenesis of human periodontal ligament stem cells following OTM. Using mmu-miR-21-deficient (miR-21-/-) mice, the authors discovered that mmu-miR-21 deficiency inhibited OTM and prevented force-induced maxillary bone loss. The authors found that miR-21-/- mice showed a normal skeletal phenotype in development and a similar alveolar bone formation rate to wild-type mice postnatally. During OTM, mmu-miR-21 regulated force-induced alveolar osteoblastogenesis in the tensile side, while no effects were detected in the compressive side. However, miR-21-/- mice showed inhibited alveolar osteoclastogenesis when compared with wild-type mice. During OTM, mmu-miR-21 deficiency blocked alveolar bone resorption in both the compressive and tensile sides. To dissect the mechanism by which miR-21 regulates alveolar bone remodeling, the authors screened the reported functional targets of miR-21 and found that periodontal expression of programmed cell death 4 ( Pdcd4) was inhibited following OTM. Furthermore, mmu-miR-21 deficiency removed the suppression of Pdcd4 at both the mRNA and protein levels in the periodontium, resulting in upregulation of the downstream effector C-fos. Further analysis of OTM under lipopolysaccharide-induced periodontal inflammation showed that mmu-miR-21 mediated lipopolysaccharide (LPS)-accelerated OTM and that mmu-miR-21 deficiency blocked lipopolysaccharide-induced maxillary bone loss. In summary, these findings reveal a previously unrecognized mechanism that a microRNA can modulate OTM and alveolar bone remodeling under both normal and inflammatory microenvironments in vivo. [ABSTRACT FROM AUTHOR]

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Interferon regulatory factor 4 (IRF4) is an attractive therapeutic target in multiple myeloma (MM). We here report that expression of IRF4 mRNA inversely correlates with microRNA (miR)-125b in MM patients. Moreover, we provide evidence that miR-125b is downregulated in TC2/3 molecular MM subgroups and in established cell lines. Importantly, constitutive expression of miR-125b-5p by lentiviral vectors or transfection with synthetic mimics impaired growth and survival of MM cells and overcame the protective role of bone marrow stromal cells in vitro. Apoptotic and autophagy-associated cell death were triggered in MM cells on miR-125b-5p ectopic expression. Importantly, we found that the anti-MM activity of miR-125b-5p was mediated via direct downregulation of IRF4 and its downstream effector BLIMP-1. Moreover, inhibition of IRF4 translated into downregulation of c-Myc, caspase-10 and cFlip, relevant IRF4-downstream effectors. Finally, in vivo intra-tumor or systemic delivery of formulated miR-125b-5p mimics against human MM xenografts in severe combined immunodeficient/non-obese diabetic mice induced significant anti-tumor activity and prolonged survival. Taken together, our findings provide evidence that miR-125b, differently from other hematologic malignancies, has tumor-suppressor activity in MM. Furthermore, our data provide proof-of-concept that synthetic miR-125b-5p mimics are promising anti-MM agents to be validated in early clinical trials. [ABSTRACT FROM AUTHOR]

The analysis of deregulated microRNAs (miRNAs) is emerging as a novel approach to disclose the regulation of tumor suppressor or tumor promoting pathways in tumor cells. Targeting aberrantly expressed miRNAs is therefore a promising strategy for cancer treatment. By miRNA profiling of primary plasma cells from multiple myeloma (MM) patients, we previously reported increased miR-125a-5p levels associated to specific molecular subgroups. On these premises, we aimed at investigating the biological effects triggered by miR-125a-5p modulation in MM cells. Expression of p53 pathway-related genes was down-regulated in MM cells transfected with miR-125a-5p mimics. Luciferase reporter assays confirmed specific p53 targeting at 3′UTR level by miR-125a-5p mimics. Interestingly, bone marrow stromal cells (BMSCs) affected the miR-125a-5p/p53 axis, since adhesion of MM cells to BMSCs strongly up-regulated miR-125a-5p levels, while reduced p53 expression. Moreover, ectopic miR-125a-5p reduced, while miR-125-5p inhibitors promoted, the expression of tumor suppressor miR-192 and miR-194, transcriptionally regulated by p53. Lentiviral-mediated stable inhibition of miR-125a-5p expression in wild-type p53 MM cells dampened cell growth, increased apoptosis and reduced cell migration. Importantly, inhibition of in vitro MM cell proliferation and migration was also achieved by synthetic miR-125a-5p inhibitors and was potentiated by the co-expression of miR-192 or miR-194. Taken together, our data indicate that miR-125a-5p antagonism results in the activation of p53 pathway in MM cells, underlying the crucial role of this miRNA in the biopathology of MM and providing the molecular rationale for the combinatory use of miR-125a inhibitors and miR-192 or miR-194 mimics for MM treatment. J. Cell. Physiol. 229: 2106-2116, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a disease with an adverse outcome and new therapeutic strategies are urgently awaited. A rising body of evidence supports the notion that microRNAs (miRNAs), master regulators of eukaryotic gene expression, may exert anti-MM activity. Here, we evaluated the activity of synthetic miR-34a in MM cells. We found that transfection of miR-34a mimics in MM cells induces a significant change of gene expression with relevant effects on multiple signal transduction pathways. We detected early inactivation of pro-survival and proliferative kinases Erk-2 and Akt followed at later time points by caspase-6 and -3 activation and apoptosis induction. To improve the in vivo delivery, we encapsulated miR-34a mimics in stable nucleic acid lipid particles (SNALPs). We found that SNALPs miR-34a were highly efficient in vitro in inhibiting growth of MM cells. Then, we investigated the activity of the SNALPs miR-34a against MM xenografts in SCID mice. We observed significant tumor growth inhibition (p<0.05) which translated in mice survival benefits (p = 0.0047). Analysis of miR-34a and NOTCH1 expression in tumor retrieved from animal demonstrated efficient delivery and gene modulation induced by SNALPs miR-34a in the absence of systemic toxicity. We here therefore provide evidence that SNALPs miR-34a may represent a promising tool for miRNA-therapeutics in MM. [ABSTRACT FROM AUTHOR]

MiRNA-8074 is a molecule with the potential to regulate the expression of key genes related to the pathogenesis of multiple myeloma (MM), i.e., TP53, MYC, MAPK1, and KIAA. We analyzed the predictive and prognostic value of miRNA-8074 expression in MM patients. In total, 105 newly diagnosed MM patients treated with thalidomide (n = 27), bortezomib (n = 41) and bortezomib with thalidomide (n = 37) were studied. For miRNA analysis, the column method and the Real-Time PCR technique with specific TaqMan Fast Advanced Master Mix and TaqMan probes were used. Factors that were associated with a significant reduction in progression-free survival (PFS) included: ECOG > 1, ISS stage III, low hemoglobin, thrombocytopenia, hypoalbuminemia, abnormal renal function, elevated creatinine, GFR < 60 mL/min/1.73 m2, elevated LDH, del(17p), t(11;14), the use of a single drug regimen (thalidomide or bortezomib) and high miRNA-8074 expression (HR = 2.01, 95% CI: 1.16–3.49; p = 0.0233). In addition to the known prognostic factors, such as ECOG > 1, Durie–Salmon stage III, diagnosis of light chain disease or non-secreting MM, renal failure, hypoalbuminemia, hypercalcemia, high β2-microglobulin, elevated LDH, and t(14;16), a high expression of miRNA-8074 was significantly associated with a higher risk of death (HR = 4.12, 95% CI: 2.20–7.70; p = 0.0009). In summary, miRNA-8074 may be a useful diagnostic tool to assess the prognosis in MM patients. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is a fast-progressing bone tumor with high incidence in children and adolescents. The main diagnostic methods for OS are imaging exams and biopsies. In spite of the several resources available for detecting the disease, establishing an early diagnosis is still difficult, resulting in worse prognosis and lower survival rates for patients with OS. The identification of novel biomarkers would be helpful, and recently, circulating microRNAs (miRNAs) have been pointed to as possible non-invasive biomarkers. In order to assess the effectiveness of miRNA research, we performed a systematic review to assess the potential role of circulating miRNAs as biomarkers for OS diagnosis. We performed a search in various databases—PubMed, LILACS (Literatura Latino-americana e do Caribe em Ciências da Saúde), VHL (Virtual Health Library), Elsevier, Web of Science, Gale Academic One File—using the terms: "Circulating microRNAs" OR "plasma microRNAs" OR "serum microRNAs" OR "blood microRNAs" OR "cell-free microRNAs" OR "exosome microRNAs" OR "extracellular vesicles microRNAs" OR "liquid biopsy" AND "osteosarcoma" AND "diagnostic". We found 35 eligible studies that were independently identified and had had their quality assessed according to Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) guidelines. Despite the useful number of publications on this subject and the fact that several microRNAs showed excellent diagnostic performance for OS, the lack of consistency in results suggests that additional prospective studies are needed to confirm the role of circulating miRNAs as non-invasive biomarkers in OS. [ABSTRACT FROM AUTHOR]

Powerful bioinformatics tools have provided a wealth of novel miRNA–transcription factor networks crucial in controlling gene regulation. In this review, we focus on the biological functions of miRNAs targeting ZNF521, explaining the molecular mechanisms by which the dysregulation of this axis contributes to malignancy. ZNF521 is a stem cell-associated co-transcription factor implicated in the regulation of hematopoietic, neural, and mesenchymal stem cells. The aberrant expression of ZNF521 transcripts, frequently associated with miRNA deregulation, has been detected in several tumors including pancreatic, hepatocellular, gastric, bladder transitional cell carcinomas as well as in breast and ovarian cancers. miRNA expression profiling tools are currently identifying a multitude of miRNAs, involved together with oncogenes and TFs in the regulation of oncogenesis, including ZNF521, which may be candidates for diagnostic and prognostic biomarkers of cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma (MM) is the second most common haematologic malignancy, and it remains an incurable disease despite the advances of novel therapies. It is characterised by a multistep process that arises from a pre-malignant asymptomatic status-defined monoclonal gammopathy of undetermined significance (MGUS), evolves to a middle stage named smouldering myeloma phase (SMM), and culminates in the active disease (MM). Identification of early and non-invasive markers of the disease progression is currently an active field of investigation. In this review, we discuss the role and significance of microRNAs (miRNAs) as potential diagnostic biomarkers to predict the clinical transition from MGUS/SMM status to MM. Multiple myeloma (MM) is a hematological malignancy characterised by proliferation of clonal plasma cells (PCs) within the bone marrow (BM). Myelomagenesis is a multi-step process which goes from an asymptomatic phase, defined as monoclonal gammopathy of undetermined significance (MGUS), to a smouldering myeloma (SMM) stage, to a final active MM disease, characterised by hypercalcemia, renal failure, bone lesions anemia, and higher risk of infections. Overall, microRNAs (miRNAs) have shown to significantly impact on MM tumorigenesis, as a result of miRNA-dependent modulation of genes involved in pathways known to be crucial for MM pathogenesis and disease progression. We aim to revise the literature related to the role of miRNAs as potential diagnostic and prognostic biomarkers, thus highlighting their key role as novel players within the field of MM and related premalignant conditions. [ABSTRACT FROM AUTHOR]

Normal B-cell development is a tightly regulated complex procedure, the deregulation of which can lead to lymphomagenesis. One common group of blood cancers is the B-cell non-Hodgkin lymphomas (NHLs), which can be categorized according to the proliferation and spread rate of cancer cells into indolent and aggressive ones. The most frequent indolent B-cell NHLs are follicular lymphoma and marginal zone lymphoma. MicroRNAs (miRNAs) are small non-coding RNAs that can greatly influence protein expression. Based on the multiple interactions among miRNAs and their targets, complex networks of gene expression regulation emerge, which normally are essential for proper B-cell development. Multiple miRNAs have been associated with B-cell lymphomas, as the deregulation of these complex networks can lead to such pathological states. The aim of the present review is to summarize the existing information regarding the multifaceted role of miRNAs in indolent B-cell NHLs, affecting the main B-cell subpopulations. We attempt to provide insight into their biological function, the complex miRNA-mRNA interactions, and their biomarker utility in these malignancies. Lastly, we address the limitations that hinder the investigation of the role of miRNAs in these lymphomas and discuss ways that these problems could be overcome in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer onset and progression are promoted by high deregulation of the immune system. Recently, major advances in molecular and clinical cancer immunology have been achieved, offering new agents for the treatment of common tumors, often with astonishing benefits in terms of prolonged survival and even cure. Unfortunately, most tumors are still resistant to current immune therapy approaches, and basic knowledge of the resistance mechanisms is eagerly awaited. We focused our attention on noncoding RNAs, a class of RNA that regulates many biological processes by targeting selectively crucial molecular pathways and that, recently, had their role in cancer cell immune escape and modulation of the tumor microenvironment identified, suggesting their function as promising immunotherapeutic targets. In this scenario, we point out that noncoding RNAs are progressively emerging as immunoregulators, and we depict the current information on the complex network involving the immune system and noncoding RNAs and the promising therapeutic options under investigation. Novel opportunities are emerging from noncoding-RNAs for the treatment of immune-refractory tumors. Immunotherapy is presently one of the most promising areas of investigation and development for the treatment of cancer. While immune checkpoint-blocking monoclonal antibodies and chimeric antigen receptor (CAR) T-cell-based therapy have recently provided in some cases valuable therapeutic options, the goal of cure has not yet been achieved for most malignancies and more efforts are urgently needed. Noncoding RNAs (ncRNA), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), regulate several biological processes via selective targeting of crucial molecular signaling pathways. Recently, the key roles of miRNA and lncRNAs as regulators of the immune-response in cancer have progressively emerged, since they may act (i) by shaping the intrinsic tumor cell and microenvironment (TME) properties; (ii) by regulating angiogenesis, immune-escape, epithelial-to-mesenchymal transition, invasion, and drug resistance; and (iii) by acting as potential biomarkers for prognostic assessment and prediction of response to immunotherapy. In this review, we provide an overview on the role of ncRNAs in modulating the immune response and the TME. We discuss the potential use of ncRNAs as potential biomarkers or as targets for development or clinical translation of new therapeutics. Finally, we discuss the potential combinatory approaches based on ncRNA targeting agents and tumor immune-checkpoint inhibitor antibodies or CAR-T for the experimental treatment of human cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Bone metastases cause substantial morbidity and implicate worse clinical outcomes for clear-cell renal cell carcinoma patients. MicroRNAs are small RNA molecules that modulate gene translation and are involved in the development of cancer and metastasis. We identified six microRNAs that are potentially specifically involved in metastasis to bone, of which two seem protective and four implicate a higher risk. This aids further understanding of the process of metastasizing to bone. Furthermore, these microRNA hold potential for biomarkers or therapeutic targets. Bone metastasis in clear-cell renal cell carcinoma (ccRCC) leads to substantial morbidity through skeletal related adverse events and implicates worse clinical outcomes. MicroRNAs (miRNA) are small non-protein coding RNA molecules with important regulatory functions in cancer development and metastasis. In this retrospective analysis we present dysregulated miRNA in ccRCC, which are associated with bone metastasis. In particular, miR-23a-3p, miR-27a-3p, miR-20a-5p, and miR-335-3p specifically correlated with the earlier appearance of bone metastasis, compared to metastasis in other organs. In contrast, miR-30b-3p and miR-139-3p were correlated with less occurrence of bone metastasis. These miRNAs are potential biomarkers and attractive targets for miRNA inhibitors or mimics, which could lead to novel therapeutic possibilities for bone targeted treatment in metastatic ccRCC. [ABSTRACT FROM AUTHOR]

Simple Summary: In this review, the history of RNA interference discovery and current knowledge about microRNA biogenesis and post-transcriptional regulation of gene expression is summarized, with a special focus on microRNA clusters and families. Further, strong interplay between microRNAs and basic epigenetic mechanisms, such as DNA methylation and histone modifications, are introduced and associated with deregulated expression of microRNAs during tumor development. Finally, novel strategies for epigenetic-based therapies are discussed. MicroRNAs are small non-coding single-stranded RNA molecules regulating gene expression on a post-transcriptional level based on the seed sequence similarity. They are frequently clustered; thus, they are either simultaneously transcribed into a single polycistronic transcript or they may be transcribed independently. Importantly, microRNA families that contain the same seed region and thus target related signaling proteins, may be localized in one or more clusters, which are in a close relationship. MicroRNAs are involved in basic physiological processes, and their deregulation is associated with the origin of various pathologies, including solid tumors or hematologic malignancies. Recently, the interplay between the expression of microRNA clusters and families and epigenetic machinery was described, indicating aberrant DNA methylation or histone modifications as major mechanisms responsible for microRNA deregulation during cancerogenesis. In this review, the most studied microRNA clusters and families affected by hyper- or hypomethylation as well as by histone modifications are presented with the focus on particular mechanisms. Finally, the diagnostic and prognostic potential of microRNA clusters and families is discussed together with technologies currently used for epigenetic-based cancer therapies. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a common hematological malignancy arising from terminally differentiated plasma cells. In the majority of cases, symptomatic disease is characterized by the presence of bone disease. Multiple myeloma bone disease (MMBD) is a result of an imbalance in the bone-remodeling process that leads to increased osteoclast activity and decreased osteoblast activity. The molecular background of MMBD appears intriguingly complex, as several signaling pathways and cell-to-cell interactions are implicated in the pathophysiology of MMBD. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the expression of their target mRNAs. Numerous miRNAs have been witnessed to be involved in cancer and hematological malignancies and their role has been characterized either as oncogenic or oncosuppressive. Recently, scientific research turned towards miRNAs as regulators of MMBD. Scientific data support that miRNAs finely regulate the majority of the signaling pathways implicated in MMBD. In this review, we provide concise information regarding the molecular pathways with a significant role in MMBD and the miRNAs implicated in their regulation. Moreover, we discuss their utility as molecular biomarkers and highlight the putative usage of miRNAs as novel molecular targets for targeted therapy in MMBD. [ABSTRACT FROM AUTHOR]

Despite substantial advancements have been done in the understanding of the pathogenesis of plasma cell (PC) disorders, these malignancies remain hard-to-treat. The discovery and subsequent characterization of non-coding transcripts, which include several members with diverse length and mode of action, has unraveled novel mechanisms of gene expression regulation often malfunctioning in cancer. Increasing evidence indicates that such non-coding molecules also feature in the pathobiology of PC dyscrasias, where they are endowed with strong therapeutic and/or prognostic potential. In this review, we aim to summarize the most relevant findings on the biological and clinical features of the non-coding RNA landscape of malignant PCs, with major focus on multiple myeloma. The most relevant classes of non-coding RNAs will be examined, along with the mechanisms accounting for their dysregulation and the recent strategies used for their targeting in PC dyscrasias. It is hoped these insights may lead to clinical applications of non-coding RNA molecules as biomarkers or therapeutic targets/agents in the near future. [ABSTRACT FROM AUTHOR]

Recently, attention has been drawn to the role of non-coding regions of the genome in cancer pathogenesis. MicroRNAs (miRNAs) are small non-coding RNAs with 19–25 bases of length that control gene expression by destroying messenger RNA or inhibiting its translation. In multiple myeloma (MM), the expression of several miRNAs, such as miR-15a and miR-16, is markedly decreased and their target genes upregulated, suggesting their role as tumor-suppressing miRNAs. In contrast, miRNAs such as miR-21 and miR-221 are highly expressed and function as oncogenes (oncomiRs). In addition, several miRNAs, such as those belonging to the miR-34 family, are transcriptional targets of p53 and mediate its tumor-suppressive functions. Many miRNAs are associated with drug resistance, and the modulation of their expression or activity might be explored to reverse it. Moreover, miRNA expression patterns in either MM cells or serum exosomes have been shown to be good prognostic markers. miRNA regulation mechanisms have not been fully elucidated. Many miRNAs are epigenetically controlled by DNA methylation and histone modification, and others regulate the expression of epigenetic modifiers, indicating that miRNA and other epigenetic effectors are part of a network. In this review, we outlined the roles of miRNAs in MM and their potential to predict MM prognosis and develop novel therapies. [ABSTRACT FROM AUTHOR]

Imbalanced regulation of reactive oxygen species (ROS) and antioxidant factors in cells is known as "oxidative stress (OS)". OS regulates key cellular physiological responses through signal transduction, transcription factors and noncoding RNAs (ncRNAs). Increasing evidence indicates that continued OS can cause chronic inflammation, which in turn contributes to cardiovascular and neurological diseases and cancer development. MicroRNAs (miRNAs) are small ncRNAs that produce functional 18-25-nucleotide RNA molecules that play critical roles in the regulation of target gene expression by binding to complementary regions of the mRNA and regulating mRNA degradation or inhibiting translation. Furthermore, miRNAs function as either tumor suppressors or oncogenes in cancer. Dysregulated miRNAs reportedly modulate cancer hallmarks such as metastasis, angiogenesis, apoptosis and tumor growth. Notably, miRNAs are involved in ROS production or ROS-mediated function. Accordingly, investigating the interaction between ROS and miRNAs has become an important endeavor that is expected to aid in the development of effective treatment/prevention strategies for cancer. This review provides a summary of the essential properties and functional roles of known miRNAs associated with OS in cancers. [ABSTRACT FROM AUTHOR]

Background: Osteoclasts play a critical role in bone resorption due to orthodontic tooth movement (OTM). In OTM, a force is exerted on the tooth, creating compression of the periodontal ligament (PDL) on one side of the tooth, and tension on the other side. In response to these mechanical stresses, the balance of receptor activator of nuclear-factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) shifts to stimulate osteoclastogenesis. However, the mechanism of OPG expression in PDL cells under different mechanical stresses remains unclear. We hypothesized that compression and tension induce different microRNA (miRNA) expression profiles, which account for the difference in OPG expression in PDL cells. To study miRNA expression profiles resulting from OTM, compression force (2 g/cm2) or tension force (15% elongation) was applied to immortalized human PDL (HPL) cells for 24 h, and miRNA extracted. The miRNA expression in each sample was analyzed using a human miRNA microarray, and the changes of miRNA expression were confirmed by real-time RT-PCR. In addition, miR-3198 mimic and inhibitor were transfected into HPL cells, and OPG expression and production assessed. Results: We found that certain miRNAs were expressed differentially under compression and tension. For instance, we observed that miR-572, − 663, − 575, − 3679-5p, UL70-3p, and − 3198 were upregulated only by compression. Real-time RT-PCR confirmed that compression induced miR-3198 expression, but tension reduced it, in HPL cells. Consistent with previous reports, OPG expression was reduced by compression and induced by tension, though RANKL was induced by both compression and tension. OPG expression was upregulated by miR-3198 inhibitor, and was reduced by miR-3198 mimic, in HPL cells. We observed that miR-3198 inhibitor rescued the compression-mediated downregulation of OPG. On the other hand, miR-3198 mimic reduced OPG expression under tension. However, RANKL expression was not affected by miR-3198 inhibitor or mimic. Conclusions: We conclude that miR-3198 is upregulated by compression and is downregulated by tension, suggesting that miR-3198 downregulates OPG expression in response to mechanical stress. [ABSTRACT FROM AUTHOR]

Aberrant expression of microRNAs (miRNAs) has been associated to the pathogenesis of multiple myeloma (MM). While miR-155 is considered a therapeutic target in several malignancies, its role in MM is still unclear. The analysis of miR-155 expression indicates its down-regulation in MM patient-derived as compared to healthy plasma cells, thus pointing to a tumor suppressor role in this malignancy. On this finding, we investigated miR-155 replacement as a potential anti-tumor strategy in MM. The miR-155 enforced expression triggered anti-proliferative and pro-apoptotic effects in vitro. Given the lower miR-155 levels in bortezomib-resistant as compared to sensitive MM cells, we analyzed the possible involvement of miR-155 in bortezomib resistance. Importantly, miR-155 replacement enhanced bortezomib anti-tumor activity both in vitro and in vivo in a xenograft model of human MM. In primary MM cells, we observed an inverse correlation between miR-155 and the mRNA encoding the proteasome subunit gene PSMβ5, whose dysregulation has been largely implicated in bortezomib resistance, and we validated PSMβ5 3′UTR mRNA targeting, along with reduced proteasome activity, by miR-155. Collectively, our findings demonstrate that miR-155 elicits anti-MM activity, likely via proteasome inhibition, providing the framework for miR-155-based anti-MM therapeutic strategies. [ABSTRACT FROM AUTHOR]