Homo sapiens
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PROVIDER: PRJNA317575 | ENA |
REPOSITORIES: ENA
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Project description:MiR-196b is epigenetically silenced during the pre-malignant stage of lung carcinogenesis
| PRJNA317578 | ENA
Project description:MicroRNA silencing by promoter hypermethylation may represent a mechanism by which lung cancer develops and progresses, but the microRNAs involved during malignant transformation are unknown. We previously established a model of pre-malignant lung cancer wherein we treated human bronchial epithelial cells (HBEC) with low doses of tobacco carcinogens. Here, we demonstrate that next-generation sequencing of carcinogen-transformed HBECs treated with the demethylating agent 5-aza-2'deoxycytidine revealed miR-196b and miR-34c-5p to be epigenetic targets. Bisulfite sequencing confirmed dense promoter hypermethylation indicative of silencing in multiple malignant cell lines and primary tumors. Chromatin immunoprecipitation studies further demonstrated an enrichment in repressive histone marks on the miR-196b promoter during HBEC transformation. Restoration of miR-196b expression by transfecting transformed HBECs with specific mimics led to cell cycle arrest mediated in part through transcriptional regulation of the FOS oncogene, and miR-196b re-expression also significantly reduced the growth of tumor xenografts. Luciferase assays demonstrated that forced expression of miR-196b inhibited the FOS promoter and AP-1 reporter activity. Finally, a case-control study revealed that methylation of miR-196b in sputum was strongly associated with lung cancer (OR = 4.7, p<0.001). Collectively, these studies highlight miR-196b as a tumor suppressor whose silencing early in lung carcinogenesis may provide a selective growth advantage to pre-malignant cells. Targeted delivery of miR-196b could therefore serve as a preventive or therapeutic strategy for the management of lung cancer.
2016-09-09 | GSE79982 | GEO
Project description:MicroRNA silencing by promoter hypermethylation may represent a mechanism by which lung cancer develops and progresses, but the microRNAs involved during malignant transformation are unknown. We previously established a model of pre-malignant lung cancer wherein we treated human bronchial epithelial cells (HBEC) with low doses of tobacco carcinogens. Here, we demonstrate that next-generation sequencing of carcinogen-transformed HBECs treated with the demethylating agent 5-aza-2'deoxycytidine revealed miR-196b and miR-34c-5p to be epigenetic targets. Bisulfite sequencing confirmed dense promoter hypermethylation indicative of silencing in multiple malignant cell lines and primary tumors. Chromatin immunoprecipitation studies further demonstrated an enrichment in repressive histone marks on the miR-196b promoter during HBEC transformation. Restoration of miR-196b expression by transfecting transformed HBECs with specific mimics led to cell cycle arrest mediated in part through transcriptional regulation of the FOS oncogene, and miR-196b re-expression also significantly reduced the growth of tumor xenografts. Luciferase assays demonstrated that forced expression of miR-196b inhibited the FOS promoter and AP-1 reporter activity. Finally, a case-control study revealed that methylation of miR-196b in sputum was strongly associated with lung cancer (OR = 4.7, p<0.001). Collectively, these studies highlight miR-196b as a tumor suppressor whose silencing early in lung carcinogenesis may provide a selective growth advantage to pre-malignant cells. Targeted delivery of miR-196b could therefore serve as a preventive or therapeutic strategy for the management of lung cancer. HBEC2MBT and H1975 were transiently transfected with a miR-196b mimic and subjected to array-based genome-wide gene expression profiling 48 hours post transfection.
2016-09-09 | GSE79987 | GEO
Project description:Background: MicroRNA-196b-5p (miR-196b-5p) has been previously involved in carcinogenesis, though its role in colorectal cancer (CRC) patients and biology remains controversially. In our current study, we systematically explored the clinical significance and biological relevance of miR-196b-5p, as well as the underlying molecular mechanisms regulated by miR-196b-5p in colorectal cancer. Methods: In this study, we measured miR-196b-5p expression by quantitative RT-PCR and explored its prognostic value in two independent patient cohorts of 292 CRC patients. In a panel of CRC cell lines, using transient and stable gain and loss of function experiments, we evaluated the impact on in vitro proliferation, chemo-sensitivity and migration/invasion as well as in vivo metastases-formation. The molecular mode of action was characterized by mRNA transcriptome profiling, target prediction tools, luciferase-interaction assays, and pheno-copy gene knock-down experiments for potential target genes. Results: Our clinical data indicate that low levels of miR-196b-5p in CRC are significantly associated with metastatic disease and poor patient outcome in both independent cohorts (p<0.05). A loss of function of miR-196b-5p led to increased cancer cell migration/invasion and metastases formation, which can be partly explained by direct interaction with HOXB7 and GalNT5 mRNA, which both of them influence CRC cell migration. Conclusion: In conclusion, our data suggest that low levels of miR-196b-5p are associated with poor prognosis in CRC. MiR-196b-5p has an effect on CRC progression through genes important for cancer cell migration and metastases.
2017-01-01 | GSE86575 | GEO
Project description:microRNA are aberrantly expressed in acute myeloid leukemia (AML), and clinically may have diagnostic, prognostic, and therapeutic value. We identify one such microRNA, miR-196b, is essential for MLL-AF9 leukemia initiation and maintenance. To discover how miR-196b contributes to leukemogenesis, we utilized multiple unbiased approaches that identified and functionally screened miR-196b target activity in AML. Our studies resolved how conflicting networks of miRNA-regulated targets are integrated during leukemogenesis. This work uncovered two miR-196b direct targets, the cell cycle regulator Cdkn1b (p27Kip1) and Polycomb group member Phc2, that independently cooperate with MLL-AF9 to promote leukemogenesis by regulating stem cell transcriptional programs. Finally, we found that therapeutic disruption of miR-196b direct targeting of Cdkn1b suppresses leukemogenesis.
2018-06-29 | GSE75841 | GEO
Project description:microRNA are aberrantly expressed in acute myeloid leukemia (AML), and clinically may have diagnostic, prognostic, and therapeutic value. We identify one such microRNA, miR-196b, is essential for MLL-AF9 leukemia initiation and maintenance. To discover how miR-196b contributes to leukemogenesis, we utilized multiple unbiased approaches that identified and functionally screened miR-196b target activity in AML. Our studies resolved how conflicting networks of miRNA-regulated targets are integrated during leukemogenesis. This work uncovered two miR-196b direct targets, the cell cycle regulator Cdkn1b (p27Kip1) and Polycomb group member Phc2, that independently cooperate with MLL-AF9 to promote leukemogenesis by regulating stem cell transcriptional programs. Finally, we found that therapeutic disruption of miR-196b direct targeting of Cdkn1b suppresses leukemogenesis.
2018-06-29 | GSE75842 | GEO
Project description:<p>We show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway and re-expression of epigenetically silenced endogenous retrovirus. In melanoma patients treated with an immune checkpoint therapy, high viral defense signature expression in tumors significantly associates with durable clinical response and DNMTi treatment sensitizes to anti-CTLA4 therapy in a pre-clinical melanoma model.</p>
| phs001038 | dbGaP
Project description:To identify such targets of leukemia-related miRNAs such as miR-196b, we conducted Affymetrix gene arrays of leukemic BM samples from 24 mice including 9 primary (including 3 each of negative control, MLL-AF9, and miR-196b+MLL-AF9) and 15 secondary (including 3 negative control, 6 MLL-AF9, and 6 miR-196b+MLL-AF9) recipient mice A total of 24 mouse bone marrow samples including 9 primary (including 3 each of negative control, MLL-AF9, and miR-196b+MLL-AF9) and 15 secondary (including 3 negative control, 6 MLL-AF9, and 6 miR-196b+MLL-AF9) obtained from the in vivo mouse bone marrow reconstitution assays were analyzed by use of Affymetrix GeneChip Mouse Gene 1.0 ST Array (Affymetirx, Santa Clara, CA)
2012-08-09 | E-GEOD-34185 | biostudies-arrayexpress
Project description:To identify such targets of leukemia-related miRNAs such as miR-196b, we conducted Affymetrix gene arrays of leukemic BM samples from 24 mice including 9 primary (including 3 each of negative control, MLL-AF9, and miR-196b+MLL-AF9) and 15 secondary (including 3 negative control, 6 MLL-AF9, and 6 miR-196b+MLL-AF9) recipient mice
2012-08-10 | GSE34185 | GEO
Project description:Ocular Sebaceous Carcinoma (OSC) is a rare malignant tumor for which initial clinical and pathological diagnosis is often incorrect. OSC can mimic Squamous Cell Carcinoma of the Conjunctiva (SCCC). Aim of this study was to find microRNA biomarkers to distinguish OSC and SCCC from normal tissue and from each other. Clinical OSC and SCCC case files and corresponding histopathological slides were collected and reviewed. Microdissected formalin-fixed paraffin-embedded tumor and control tissue were sub-jected to semi-high throughput microRNA profiling. MicroRNA expression distinguishes OSC and SCCC from corresponding control tissues. Selected differentially expressed miRNAs were validated using single RT-PCR assays. No prognostic miRNAs could be identified that reliable predict SCCC metastasis or OSC recurrence. A com-parison between OSC (n=14) and SCCC (n=18) revealed 38 differentially expressed microRNAs (p<0.05). Differentially expressed miRNAs were selected for validation in the discovery cohort and an independent validation cohort (OSC, n=11; SCCC, n=12). At least two miRNAs miR-196b-5p (p ≤ 0.05) and miR-107 (p ≤ 0.001) displayed a statistically significant differential expression between OSC and SCCC with miR-196b-5p upregulated in SCCC and miR-107 up-regulated in OSC. In the validation cohort microRNA miR-493-3p also showed significant up-regulation in SCCC when compared to OSC (p ≤ 0.05). ROC analyses indicated that the com-bined miR-196b-5p and miR-107 expression levels predicted OSC with 90.0% sensitivity and 83.3% specificity. In conclusion, combined testing of miR-196b-5p and miR-107, can be of additional use in routine diagnostics to discriminate OSC from SCCC.
2022-04-26 | GSE201490 | GEO