MicroRNA-21 plays an oncogenic role by targeting FOXO1 and activating the PI3K/AKT pathway in diffuse large B-cell lymphoma (original) (raw)
Related papers
The Impact of Serum MicroRNA-21 on Outcome of Diffuse Large B-Cell Lymphoma Patients
Background: The emerging role of circulating microRNAs (miRNAs) as diagnostic and predictive tools has become fundamental and promising scope of cancer research. The link between the aberrant expressions of various miRNAs and the pathogenesis of Diffuse Large B-Cell Lymphoma (DLBCL) has been revealed by numerous studies. Aim of Study: This study was planned to analyze the relative expression levels of serum miRNA-21 and to elucidate its potential prognostic significance in DLBCL patients who had received cyclophosphamide, doxorubicin, vincristine, prednisone plus rituximab (R-CHOP) regimen. Patients and Methods: Serum miRNA-21 relative expression levels were analyzed by Polymerase Chain Reaction (PCR) based technique in 65 DLBCL patients prior to immunochemotherapy in comparison with 35 healthy individuals. Receiver operating characteristic curve analysis was used to determine the ideal miRNA-21 cutoff and Kaplan-Meier method was used to calculate the overall survival of DLBCL patients. Results: MiRNA-21 expression levels were significantly up-regulated in DLBCL patients compared to healthy controls (p<0.001). MiRNA-21 expression levels were closely associated disease stage, response to therapy, (3 2 microglobulin, Lactate Dehydrogenase (LDH) and C-Reactive Protein (CRP) (p<0.001; p=0.042; p<0.001; p=0.003; p=0.02 respectively). However, there was no relationship with other characteristics such as age, gender, extranodal site involvement, B symptoms, and International Prognostic Index (IPI) (all ps>0.05). Overall survival was significantly worse in patients with high miRNA-21 expression levels compared to those with low expression levels (p=0.01). Conclusion: Serum miRNA-21 may be employed as valuable non-invasive prognostic marker in DLBCL patients treated with R-CHOP regimen.
Applied Immunohistochemistry & Molecular Morphology, 2014
OncomiRs miR-21 and miR-155 have been linked to lymphomagenesis, but information on their implication in diffuse large B-cell lymphoma (DLBCL) is limited. Here, we used locked nucleic acid-based in situ hybridization (ISH) detection techniques on formalin-fixed paraffin-embedded DLBCL tissue samples to identify miR-155 and miR-21 at the cellular level in 56 patients diagnosed with DLBCL, and compared them to miR array data. miR-155 was observed in tumor cells in 19/56 (33.9%) of the samples evaluated by ISH. miR-21 was localized to the stromal compartment in 41/56 (73.2%). A subset of these, 16/56 (28.6%), also showed labeling in tumor cells. When comparing ISH-scores and miR array data, miR-155 in tumor cells, identified by ISH, was associated with miR-155 expression in miR array data (P = 0.030). Equally, miR-21 expression by miR array data were highly associated with miR-21 ISH-scores in the stromal cells (P = 0.002), whereas no association between miR array data and ISH of miR-21 in tumor cells was observed (P = 0.673). We found no association of miR-155 and miR-21 with overall survival or germinal center B-cell-like (GCB) versus non-GCB-like subtypes of DLBCL. In conclusion, miR-ISH added to the biological interpretation of miR expression in DLBCL compared with miR array data, but miR-155 and miR-21 ISH did not add prognostic information in this series.
Blood, 2016
• miR-181a regulates the NF-kB signaling pathway by targeting CARD11, NFKBIA, NFKB1, RELA/P65, and REL. • miR-181a represses NF-kB signaling and decreases cell proliferation and survival most potently in the NF-kB dependent ABC-DLBCL subgroup. Distinct subgroups of diffuse large B-cell lymphoma (DLBCL) genetically resemble specific mature B-cell populations that are blocked at different stages of the immune response in germinal centers (GCs). The activated B-cell (ABC)-like subgroup resembles post-GC plasmablasts undergoing constitutive survival signaling, yet knowledge of the mechanisms that negatively regulate this oncogenic signaling remains incomplete. In this study, we report that microRNA (miR)-181a is a negative regulator of nuclear factor k-light-chain enhancer of activated B-cells (NF-kB) signaling. miR-181a overexpression significantly decreases the expression and activity of key NF-kB signaling components. Moreover, miR-181a decreases DLBCL tumor cell proliferation and survival, and anti-miR-181a abrogates these effects. Remarkably, these effects are augmented in the NF-kB dependent ABC-like subgroup compared with the GC B-cell (GCB)-like DLBCL subgroup. Concordantly, in vivo analyses of miR-181a induction in xenografts results in slower tumor growth rate and prolonged survival in the ABC-like DLBCL xenografts compared with the GCB-like DLBCL. We link these outcomes to relatively lower endogenous miR-181a expression and to NF-kB signaling dependency in the ABC-like DLBCL subgroup. Our findings indicate that miR-181a inhibits NF-kB activity, and that manipulation of miR-181a expression in the ABC-like DLBCL genetic background may result in a significant change in the proliferation and survival phenotype of this malignancy.
MicroRNA-17∼92 plays a causative role in lymphomagenesis by coordinating multiple oncogenic pathways
The EMBO Journal, 2013
MicroRNAs (miRNAs) have been broadly implicated in cancer, but their exact function and mechanism in carcinogenesis remain poorly understood. Elevated miR-17B92 expression is frequently found in human cancers, mainly due to gene amplification and Myc-mediated transcriptional upregulation. Here we show that B cell-specific miR-17B92 transgenic mice developed lymphomas with high penetrance and that, conversely, Myc-driven lymphomagenesis stringently requires two intact alleles of miR-17B92. We experimentally identified miR-17B92 target genes by PAR-CLIP and validated select target genes in miR-17B92 transgenic mice. These analyses demonstrate that miR-17B92 drives lymphomagenesis by suppressing the expression of multiple negative regulators of the PI3K and NFjB pathways and by inhibiting the mitochondrial apoptosis pathway. Accordingly, miR-17B92-driven lymphoma cells exhibited constitutive activation of the PI3K and NFjB pathways and chemical inhibition of either pathway reduced tumour size and prolonged the survival of lymphoma-bearing mice. These findings establish miR-17B92 as a powerful cancer driver that coordinates the activation of multiple oncogenic pathways, and demonstrate for the first time that chemical inhibition of miRNA downstream pathways has therapeutic value in treating cancers caused by miRNA dysregulation.
Molecular Biology Reports
MicroRNAs (miRNAs) have major roles in nearly all cellular process including gene expression, and may behave as oncogene or tumor suppressor gene by binding to complementary sequences in the target mRNA. The circulating microRNA-15a (miRNA-15a) and microRNA-16-1 (miRNA-16-1) of 15 healthy adults and of 40 untreated patients diagnosed with diffuse large B-cell lymphoma (DLBC) were recruited to investigate the expression levels. The expression levels of miRNA-15a, and miRNA-16-1 genes of the untreated DLBCL patients, and healthy individuals with matched age, sex and ethnicity were examined. MicroRNA expression profiles obtained from peripheral blood were investigated. The samples were collected from 40 patients diagnosed with DLBC patients, and from 15 healthy controls. Two miRNAs were selected, and expression profile was examined using a quantitative real-time polymerase chain reaction (qPCR) based on the previous studies. Statistically significant expression level differences (p < 0.05) were detected for miRNA-16-1 in DLBCL patients and healthy control groups. miRNA-16-1 gene expression level was found approximately ninefold higher in the patient group compared to the controls; however, no statistical difference was detected in the expression profile of miRNA-15a between the both groups. On the other hand, the decreased gene expression in miRNA16-1 was observed in 88.3% of DLBCL patients. These results suggested that there was no statistically significant decrease in the miRNA-15a gene expression in DLBCL patients (p > 0.05). On the contrary to the literature, miRNA-16-1 expression level was suppressed in DLBCL group in our study, however no whole gene silencing was performed. MicroRNA-16-1 might be suggested to behave as a tumor suppressor in DLBCL in our study.
Journal of experimental & clinical cancer research : CR, 2018
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of tumors, with aggressive clinical course that renders prognostication and choice of treatment strategy difficult. Chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) is the current first-line treatment. MicroRNAs (miRNAs) are under investigation as novel diagnostic and prognostic biomarkers in several malignancies, including malignant lymphomas. While tissue miRNAs in DLBCL patients have been extensively studied as biomarkers, only few reports to date have evaluated the role of circulating/serum miRNAs as potential prognostic factors. Here circulating/serum miRNAs, including miR-22, were investigated as potential non-invasive biomarkers, with the aim of a better prognostic stratification of DLBCL patients. MiRNAs were selected by global expression profile of serum miRNAs of DLBCL patients, The Cancer Genome Atlas (TCGA) analysis and literature research. Serum and tissues ...
Investigating the Expression of Oncogenic and Tumor Suppressive MicroRNA in DLBCL
Journal of the Association of Genetic Technologists, 2013
Diffuse Large B-cell Lymphoma (DLBCL) is the most common form of lymphoma, accounting for 40 percent of newly diagnosed cases each year. DLBCL is an aggressive abnormal growth of tissue characterized by the accumulation of abnormal B-lymphocytes in the lymphatics of affected individuals. The goal of this study was to analyze microRNA (miRNA) as an alternative method of diagnosis and treatment for patients affected with the observed cancer. MiRNAs are small, non-coding, endogenous RNA that control gene expression at the post-transcriptional level. Emerging evidence suggests that miRNA-mediated gene regulation has a functional role in cancer and could prove to be crucial targets for therapeutic intervention. Here, we provide a quantitative study on the expression of a diverse class of oncogenic and tumor suppressive miRNA that have shown to regulate oncoproteins involved in differentiation, proliferation, and/or apoptosis.
Journal of Investigative Dermatology, 2015
The oncogenic microRNA (miR) 17-92 cluster has a causative role in the lymphomagenesis of nodal B-cell lymphomas, by activating proliferation and inhibiting apoptosis. Here we analyzed primary cutaneous B-cell lymphomas for the miR-17-92 cluster and its paralogs miR-106a-363 and miR-106b-25. In 22 primary cutaneous diffuse large B-cell lymphomas, leg type (PCLBCL-LT) compared with 22 primary cutaneous follicle center lymphomas (PCFCLs), we found that miR-20a and miR-106a were overexpressed. Multivariate Cox analysis showed that higher miR-20a and miR-20b expression levels were associated with shorter disease-free and overall survival, independently from histological type. Gene expression profiling also showed a downregulation of 8 candidate target genes of miR-20a, miR-20b, and miR-106a in PCLBCL-LT compared with PCFCL. Among the candidate target genes, PTEN, NCOA3, and CAPRIN2 were confirmed to be underexpressed in PCLBCL-LT using quantitative reverse transcriptase-PCR on CD20-positive laser-microdissected tumor cells. In multivariate Cox analysis, lower PTEN mRNA expression level was associated with shorter disease-free survival (DFS), independently from the histological type. Altogether, this molecular and bioinformatic study of 44 patient skin biopsy samples showed that the oncogenic miR-17-92 cluster and its paralogs were involved in cutaneous B-cell lymphoma progression, and that the downregulation of the target gene PTEN was associated with shorter DFS.
Network analysis of microRNAs, genes and their regulation in diffuse and follicular B-cell lymphomas
MicroRNAs (miRs) are short non-coding regulatory RNAs that control gene expression at the post-transcriptional level and play an important role in cancer development and progression, acting either as oncogenes or as tumor suppressors. Identification of aberrantly expressed miRs in patients with hematological malignancies as compared to healthy individuals has suggested that these molecules may serve as novel clinical diagnostic and prognostic biomarkers. We conducted a systematic literature review of articles published between 2007 and 2017 and re-analyzed experimentally-validated human miR expression signatures in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) from various biological sources (tumor tissue, peripheral blood, bone marrow and cell lines). A unique miR expression pattern was observed for each disease. Compared to healthy individuals, 61 miRs were aberrantly expressed in DLBCL and 85 in FL; 20-30% of aberrantly expressed miRs overlapped between the two lymphoma subtypes. Analysis of integrative positive and negative miRNA-mRNA relationships using the Ingenuity Pathway Analysis (IPA) system revealed 970 miR-mRNA pairs for DLBCL and 90 for FL. Through gene ontology analysis, we found potential regulatory pathways that are deregulated in DLBCL and FL due to improper expression of miR target genes. By comparing the expression level of the aberrantly expressed miRs in DLBCL to their expression levels in other malignancies, we identified seven miRs that are aberrantly expressed in DLBCL tumor tissues (miR-15a, miR-16, miR-17, miR-106, miR-21, miR-155 and miR-34a-5p). This specific expression pattern may be a potential diagnostic tool for DLBCL.