miR-150 Suppresses the Proliferation and Tumorigenicity of Leukemia Stem Cells by Targeting the Nanog Signaling Pathway

Abstract

Proliferation, a key feature of cancer cells, accounts for the majority of cancer-related diseases resulting in mortality. MicroRNAs (miRNAs) plays important post-transcriptional modulation roles by acting on multiple signaling pathways, but the underlying mechanism in proliferation and tumorigenicity is unclear. Here, we identified the role of miR-150 in proliferation and tumorigenicity in leukemia stem cells (LSCs; CD34+CD38- cells). miR-150 expression was significantly down-regulated in LSCs from leukemia cell lines and clinical samples. Functional assays demonstrated that increased miR-150 expression inhibited proliferation and clonal and clonogenic growth, enhanced chemosensitivity, and attenuated tumorigenic activity of LSCs in vitro. Transplantation animal studies revealed that miR-150 overexpression progressively abrogates tumor growth. Immunohistochemistry assays demonstrated that miR-150 overexpression enhanced caspase-3 level and reduced Ki-67 level. Moreover, luciferase reporter assays indicated Nanog is a direct and functional target of miR-150. Nanog silencing using small interfering RNA recapitulated anti-proliferation and tumorigenicity inhibition effects. Furthermore, miR-150 directly down-regulated the expression of other cancer stem cell factors including Notch2 and CTNNB1. These results provide insights into the specific biological behavior of miR-150 in regulating LSC proliferation and tumorigenicity. Targeting this miR-150/Nanog axis would be a helpful therapeutic strategy to treat acute myeloid leukemia.

MiR-196b affects the progression and prognosis of human LSCC through targeting PCDH-17

“…To characterize the mechanism of miR-196b on the biological features of LSCC via targeting PCDH-17, we selected the LSCC Hep-2 cell lines to design further functional in-vitro experiments with the transfection of miR-196b inhibitors or PCDH17 CRISPR activation plasmid. As we know, miRNAs, includingmiR-196b, could mediate the target mRNAs to involve in several biological behaviors of tumors [43,44]. While, PCDH-17, as a member of protocadherin family, could encode a kind of Ca 2+ -dependent transmembrane protein [45], which was mainly participated in cell develop- ment, cytoskeleton formation, intercellular signaling transduction, intercellular adhesion and migration [46].…”

Downregulation of TLR4 by miR-181a Provides Negative Feedback Regulation to Lipopolysaccharide-Induced Inflammation

“…MicroRNAs (miRNAs) are a class of evolutionarily conserved, single strand and small non-coding RNA molecules, approximately 20–25 nucleotides (nts), which mainly regulate gene expression in a post-transcriptional level ( Chen and Rajewsky, 2007 ; Leuenberger et al, 2016 ). Once in their mature form, miRNAs interact specifically with the 3′-untranslated regions (3′-UTRs) of target mRNAs, resulting in silencing of their functions through mRNA degradation or translational inhibition ( Griffiths-Jones et al, 2006 ; Xu et al, 2016 ). A number of miRNAs have been demonstrated to have a notable impact on the magnitude of the inflammatory response by targeting signal transduction proteins or directly targeting mRNAs that encode pro-inflammatory cytokines following pathogenic microbes infection ( O’Connell et al, 2012 ).…”

MicroRNAs as New Biomarkers for Diagnosis and Prognosis, and as Potential Therapeutic Targets in Acute Myeloid Leukemia

“…To summarized these concepts, we have illustrated in Table 2 the most important miRNAs found to play a role in AML, specifying for each miRNA the altered expression (up or downregulation), the mechanisms of dysregulation, their targets, and their functional effects in AML pathogenesis [ 23 , 28 , 31 , 32 , 33 , 41 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , …”