Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155

Abstract

The myelodysplastic syndromes (MDSs) comprise a group of disorders characterized by multistage progression from cytopenias to acute myeloid leukemia (AML). They display exaggerated apoptosis in early stages, but lose this behavior during evolution to AML. The molecular basis for loss of apoptosis is unknown. To investigate this critical event, we analyzed phosphatidylinositol (PI) 3 0 kinase signaling, implicated as a critical pathway of cell survival control in epithelial and hematological malignancies. PI 3 0 kinase activates Akt through its production of 3 0 phosphoinositides. In turn, the phosphoinositides are dephosphorylated by two lipid phosphatases, PTEN and SHIP-1, in myeloid cells. We studied primary MDS-enriched bone marrow cells and bone marrow sections by western blotting, immunohistochemistry, immunocytochemistry and quantitative PCR for components of the SHIP/PTEN/PI 3 0 kinase signaling circuit. We reported constitutively activated Akt, variable levels of PTEN and uniformly decreased SHIP-1 expression in MDS progenitor cells. Overexpression of SHIP-1, but not the phosphatase-deficient form, inhibited myeloid leukemic growth. Levels of microRNA (miR)-210 and miR-155 transcripts, which target SHIP-1, were increased in CD34 þ MDS cells compared with their normal counterparts. Direct binding of miR-210 to the 3 0 untranslated region of SHIP-1 was confirmed by luciferase reporter assay. Transfection of a myeloid cell line with miR-210 resulted in loss of SHIP-1 protein expression. These data suggest that miR-155 and miR-210/SHIP-1/Akt pathways could serve as clinical biomarkers for disease progression, and that miR-155 and miR-210 might serve as novel therapeutic targets in MDS.

MicroRNA-205-5p is upregulated in myelodysplastic syndromes and induces cell proliferation via PTEN suppression

“…PTEN has been shown to be downregulated in high-risk MDS patients [22,23]. These findings along with the results of the present study indicate that miR-205-5p may contribute to MDS via a miR-205/PTEN/Akt signaling pathway.…”

MicroRNA-155 and MicroRNA-21 Promote the Expansion of Functional Myeloid-Derived Suppressor Cells

“…PTEN is a well-known tumor suppressor gene through its phosphatase protein product action (48). SHIP-1 and PTEN have been reported previously as the targets of miR-155 (26,49) and miR-21 (20), respectively. The present study confirmed that miR-155 and miR-21 target these two essential molecules accordingly during the induction of functional MDSC.…”

A role for miR-155 in enabling tumor-infiltrating innate immune cells to mount effective antitumor responses in mice

“…12,45,47 These evidences have motivated the development of anti-miR-155 drugs as potential anticancer therapeutics. 43,[48][49][50] Our data indicate that the oncogenic activity of miR-155 is cell context dependent, and thus suggest some caution before applying anti-miR-155 treatments to cancer patients.…”