The micro-RNA 199b-5p regulatory circuit involves Hes1, CD15, and epigenetic modifications in medulloblastoma

Abstract

Micro-RNA (miR) 199b-5p targets Hes1 in medulloblastoma, one of the downstream effectors of both the canonical Notch and noncanonical Sonic Hedgehog pathways. In medulloblastoma patients, expression of miR-199b-5p is significantly decreased in metastatic cases, thus suggesting a downregulation mechanism. We studied this mechanism, which is mediated mostly by Hes1 and epigenetic promoter modifications. The miR-199b-5p promoter region was characterized, which identified a Hes1 binding site, thus demonstrating a negative feedback loop of regulation. MiR-199b-5p was shown to be downregulated in several medulloblastoma cell lines and in tumors by epigenetic methylation of a cytosine-phosphate-guanine island upstream of the miR-199b-5p promoter. Furthermore, the cluster of differention (CD) carbohydrate antigen CD15, a marker of medulloblastoma tumor-propagating cells, is an additional direct target of miR-199b-5p. Most importantly, regulation of miR-199b-5p expression in these CD15+/CD133+ tumor-propagating cells was influenced by only Hes1 expression and not by any epigenetic mechanism of regulation. Moreover, reverse-phase protein array analysis showed both the Akt and extracellular-signal-regulated kinase pathways as being mainly negatively regulated by miR-199b-5p expression in several medulloblastoma cell lines and in primary cell cultures. We present here the finely tuned regulation of miR-199b-5p in medulloblastoma, underlining its crucial role by its additional targeting of CD15.

Tigecycline Inhibits Glioma Growth by Regulating miRNA-199b-5p–HES1–AKT Pathway

“…MiR-199b-5p could regulate Notch pathway through its targeting of the transcription factor HES1 (14,15). In this study, we investigated the function of miR-199b-5p for the regulation of HES1 after tigecycline exposure in glioma cells.…”

“…Growing evidence has proved that miRNAs regulate major cellular processes involved in tumor biology, including cell proliferation, differentiation, apoptosis, and metastasis (12,13). miR-199b-5p could regulate Notch pathway through its targeting of the transcription factor HES1 (14,15). Overexpression of miR-199b-5p could inhibit AKT signaling pathway and decrease cyclin D1 expression and negatively regulated proliferation by inducing cell-cycle arrest at G 1 phase in breast cancer cells (16).…”

Impact of individual intravenous iron preparations on the differentiation of monocytes towards macrophages and dendritic cells

“…First, this comprises dysregulation of miRNAs that are linked to surface protein expression [50]. Next, IS down-regulated miR-let-7d, which has central functions in iron absorption and utilization [51], and several miRNAs that are strongly involved in inflammation, comprising miR-32, which is crucial for viral defence [26], miR-132, miR-146 and miR-155, which regulate central inflammatory pathways such as the Toll-like receptor pathway [52]. …”

CD15 Expression Does Not Identify a Phenotypically or Genetically Distinct Glioblastoma Population

“…Initial data identifying CD133/prominin 1 as a marker that enriched for TICs in GB [20][21][22] were subsequently challenged [23][24][25][26]. More recently, the cell surface marker CD15/stage-specific embryonic antigen 1 has been identified as a possible TIC marker in GB and medulloblastoma [23,[27][28][29][30]. CD15 is a carbohydrate moiety expressed by a variety of cells including neural stem and progenitor cells and is developmentally regulated in the brain, where it is thought to play a role in cell-cell interaction during neuronal development [31][32][33][34][35].…”