Erythropoiesis is a multistep process regulated at the molecular level by intrinsic and extrinsic factors including microRNAs (miRNAs). We previously identified aberrant expression of miR-451 and miR-150 in polycythemia vera (PV) erythroid differentiating cells. To address the functional relevance of these miRNAs in erythroid differentiation, we employed synthetic mimics and inhibitors of miR-451 and miR-150 in erythroid differentiating K562 cells. We observed that miR-451 up-regulation and miR-150 down-regulation are associated with progression of erythroid maturation in K562 cells. Further, enforced expression of miR-451 promoted erythroid differentiation. Inhibition of miR-150 reduced hemoglobinization of K562 cells. Microarray data suggested potential targets regulated by miR-451: UBE2H, ARPP-19; and by miR-150: MS4A3, AGA, PTPRR. Our results demonstrate that miR-451 is involved in the regulation of erythroid differentiation and functions as an enhancer of differentiation. These data support the concept that aberrant expression of miRNAs may contribute to abnormal erythropoiesis such as that of PV.
- MeSH
- akutní erytroblastická leukemie genetika patologie MeSH
- buněčná diferenciace účinky léků genetika MeSH
- buňky K562 MeSH
- erytroidní buňky účinky léků patologie MeSH
- erytropoéza účinky léků genetika MeSH
- hemin farmakologie MeSH
- lidé MeSH
- mikro RNA genetika fyziologie MeSH
- nádorové buněčné linie MeSH
- regulace genové exprese u leukemie účinky léků MeSH
- sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
- stanovení celkové genové exprese MeSH
- transfekce MeSH
- upregulace účinky léků fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- MeSH
- hemin farmakologie MeSH
- histony biosyntéza krev MeSH
- krevní buňky metabolismus účinky léků MeSH
- lidé MeSH
- nádorové buňky kultivované MeSH
- proteiny s vysokou pohyblivostí biosyntéza krev MeSH
- tetradekanoylforbolacetát farmakologie MeSH
- tretinoin farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
Neovascularization and hemorrhage are common features of malignant tumors. We wondered whether hemoglobin derived from extravasated RBC deposits heme-derived iron into the tumor, which could modulate the sensitivity of cancer cells to oxidant-mediated injury. A brief exposure (1 h) of 51Cr-radiolabeled breast cancer cells (BT-20) but not colon cancer cells (Caco-2) to hemin (10 microM) or FeSO4 (10 microM) significantly enhances cytotoxicity mediated by 0.5 mM hydrogen peroxide (H2O2). Associated with Caco-2 resistance, these cells were found to be enriched in the endogenous iron chelator, ferritin. If cellular ferritin is even further increased through 1 h incubation (24 h prior to H2O2 exposure) of both cell types with hemin, FeSO4, or exogenous spleen apoferritin itself (24 h), marked resistance to H2O2-mediated cytotoxicity is manifest. Under several conditions, the sensitivity of tumor cells to oxidant-mediated lysis is inversely proportional to their ferritin content. Pretreatment of BT-20 and Caco-2 cells with hemin or FeSO4 rapidly increases H-ferritin mRNA but only slightly increases L-ferritin mRNA; nevertheless, large increases in overall ferritin content of iron-exposed cells result. Data analogous to those with H2O2-mediated cytotoxicity were obtained in studies of bleomycin-engendered DNA strand breakage and cell damage, i.e., brief treatment of BT-20 cells with both hemin or FeSO4 significantly increases their sensitivity to bleomycin (100 micrograms/ml), whereas treatment followed by 24 h incubation with media alone significantly protects against bleomycin toxicity. We speculate that acute exposure of tumors to iron (e.g., derived from heme-proteins in hemorrhagic cancerous lesions) may increase sensitivity of some cancer cells, particularly those relatively low in endogenous ferritin, to oxidant-mediated lysis. In contrast, repeated, more chronic, exposure effector cells or chemotherapeutic agents, an effect derived from their increased synthesis and accumulation of the intracellular iron scavenger, ferritin.
- MeSH
- biologický transport MeSH
- cévní endotel cytologie metabolismus účinky léků MeSH
- ferritiny * biosyntéza MeSH
- hemin * farmakologie metabolismus MeSH
- kinetika MeSH
- kultivované buňky MeSH
- lidé MeSH
- messenger RNA analýza metabolismus MeSH
- nádorové buňky kultivované MeSH
- nádory prsu MeSH
- nádory tračníku MeSH
- oxidancia * toxicita MeSH
- peroxid vodíku * toxicita MeSH
- poškození DNA * MeSH
- protinádorové látky * farmakologie terapeutické užití MeSH
- venae umbilicales MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- železnaté sloučeniny farmakologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
