Seon Yong Lee

IRF7 promotes glioma cell invasion by inhibiting AGO2 expression

Interferon regulatory factor 7 (IRF7) is the master transcription factor that plays a pivotal role in the transcriptional activation of type I interferon genes in the inflammatory response. Our previous study revealed that IRF7 is an important regulator of tumor progression via the expression of inflammatory cytokines in glioma. Here, we report that IRF7 promotes glioma invasion and confers resistance to both chemotherapy and radiotherapy by inhibiting expression of argonaute 2 (AGO2), a regulator of microRNA biogenesis. We found that IRF7 and AGO2 expression levels were negatively correlated in patients with glioblastoma multiforme. Ectopic IRF7 expression led to a reduction in AGO2 expression, while depletion of IRF7 resulted in increased AGO2 expression in the LN-229 glioma cell line. In an in vitro invasion assay, IRF7 overexpression enhanced glioma cell invasion. Furthermore, reconstitution of AGO2 expression in IRF7-overexpressing cells led to decreased cell invasion, whereas the reduced invasion due to IRF7 depletion was rescued by AGO2 depletion. In addition, IRF7 induced chemoresistance and radioresistance of glioma cells by diminishing AGO2 expression. Finally, AGO2 depletion alone was sufficient to accelerate glioma cell invasion in vitro and in vivo, indicating that AGO2 regulates cancer cell invasion. Taken together, our results indicate that IRF7 promotes glioma cell invasion and both chemoresistance and radioresistance through AGO2 inhibition.

Inhibition of ID1–BMPR2 intrinsic signaling sensitizes glioma stem cells to differentiation therapy

Purpose: Normal stem cells tightly control self-renewal and differentiation during development, but their neoplastic counterparts, cancer stem cells (CSCs), sustain tumorigenicity both through aberrant activation of stemness and evasion of differentiation. Although regulation of CSC stemness has been extensively studied, the molecular mechanisms suppressing differentiation remain unclear. Experimental Design: We performed in silico screening and in vitro validation studies through Western blotting, qRT-PCR for treatment of WNT and SHH signaling inhibitors, and BMP signaling inducer with control and ID1-overexpressing cells. We also performed in vivo drug treatment assays with Balb/c nude mice. Results: Inhibitor of differentiation 1 (ID1) abrogated differentiation signals from bone morphogenetic protein receptor (BMPR) signaling in glioblastoma stem cells (GSCs) to promote self-renewal. ID1 inhibited BMPR2 expression through miRNAs, miR-17 and miR-20a, which are transcriptional targets of MYC. ID1 increases MYC expression by activating WNT and SHH signaling. Combined pharmacologic blockade of WNT and SHH signaling with BMP treatment significantly suppressed GSC self-renewal and extended survival of tumor-bearing mice. Conclusions: Collectively, our results suggested that ID1 simultaneously regulates stemness through WNT and SHH signaling and differentiation through BMPR-mediated differentiation signaling in GSCs, informing a novel therapeutic strategy of combinatorial targeting of stemness and differentiation. Clin Cancer Res; 24(2); 383–94. ©2017 AACR.

CD133 regulates IL-1β signaling and neutrophil recruitment in glioblastoma

CD133, a pentaspan transmembrane glycoprotein, is generally used as a cancer stem cell marker in various human malignancies, but its biological function in cancer cells, especially in glioma cells, is largely unknown. Here, we demonstrated that forced expression of CD133 increases the expression of IL-1β and its downstream chemokines, namely, CCL3, CXCL3 and CXCL5, in U87MG glioma cells. Although there were no apparent changes in cell growth and sphere formation in vitro and tumor growth in vivo, in vitro trans-well studies and in vivo tumor xenograft assays showed that neutrophil recruitment was markedly increased by the ectopic expression of CD133. In addition, the clinical relevance between CD133 expression and IL-1β gene signature was established in patients with malignant gliomas. Thus, these results imply that glioma cells expressing CD133 are capable of modulating tumor microenvironment through the IL-1β signaling pathway.

TP53 gain-of-function mutation promotes inflammation in glioblastoma

Glioblastoma (GBM), the most severe and common brain tumor in adults, is characterized by multiple somatic mutations and aberrant activation of inflammatory responses. Immune cell infiltration and subsequent inflammation cause tumor growth and resistance to therapy. Somatic loss-of-function mutations in the gene encoding tumor suppressor protein p53 (TP53) are frequently observed in various cancers. However, numerous studies suggest that TP53 regulates malignant phenotypes by gain-of-function (GOF) mutations. Here we demonstrate that a TP53 GOF mutation promotes inflammation in GBM. Ectopic expression of a TP53 GOF mutant induced transcriptomic changes, which resulted in enrichment of gene signatures related to inflammation and chemotaxis. Bioinformatics analyses revealed that a gene signature, upregulated by the TP53 GOF mutation, is associated with progression and shorter overall survival in GBM. We also observed significant correlations between the TP53 GOF mutation signature and inflammation in the clinical database of GBM and other cancers. The TP53 GOF mutant showed upregulated C–C motif chemokine ligand 2 (CCL2) and tumor necrosis factor alpha (TNFA) expression via nuclear factor kappa B (NFκB) signaling, consequently increasing microglia and monocyte-derived immune cell infiltration. Additionally, TP53 GOF mutation and CCL2 and TNFA expression correlated positively with tumor-associated immunity in patients with GBM. Taken together, our findings suggest that the TP53 GOF mutation plays a crucial role in inflammatory responses, thereby deteriorating prognostic outcomes in patients with GBM.

Facile one-pot hydrothermal synthesis of cubic spinel-type manganese ferrite/biochar composites for environmental remediation of heavy metals from aqueous solutions

This study reports the facile synthesis of cubic spinel-type manganese ferrite (MnFe2O4)/biochar (MF/BC) composites via a one-pot hydrothermal technique. Multiple characterizations demonstrated that the MnFe2O4 spinel nanoparticles were successfully grown on the biochar, which provides magnetic separability with superparamagnetic behavior and effective adsorption performance for heavy metals (Pb(II), Cu(II), and Cd(II)). The adsorption kinetics and isotherms can be well described with a pseudo-second-order and Sips isotherm models, respectively. Comparative adsorption in multi-heavy metal systems (binary and ternary) indicated that the adsorption affinity of MF/BC composites toward heavy metals followed the sequence of Pb(II) > Cu(II) > Cd(II), which followed the order of their covalent indexes. Thermodynamic analysis revealed that the adsorption process was endothermic and primarily governed by physisorption. This study provides a feasible and simple approach for the preparation of high-performance materials for the remediation of heavy metal-contaminated wastewater in a cost-effective manner.

Hydrothermal synthesis of hierarchically structured birnessite-type MnO 2 /biochar composites for the adsorptive removal of Cu(II) from aqueous media

In this study, hierarchical birnessite-type MnO2/biochar composites (δ-MnO2/BCs) were synthesized by a hydrothermal technique, and their Cu(II) removal performance was examined in aqueous solution. Morphological characterization confirmed that a three-dimensional flower-like structure of δ-MnO2 was formed, which results in effective adsorption affinity towards Cu(II). The effects of solution pH, adsorbent dosage, and ionic strength on the adsorption behavior of the prepared materials were systemically investigated. The adsorption kinetics indicated that Cu(II) adsorption onto δ-MnO2/BCs follows a pseudo-second-order model. Analysis of possible adsorption/diffusion mechanisms suggested that the adsorption process is controlled by both film and pore diffusion. The adsorption isotherms fit closely to the Sips isotherm model, and the theoretical maximum adsorption capacities of Cu(II) on the synthesized δ-MnO2/BCs are approximately 124, 154, 199, and 230 mg/g at 15, 25, 35, and 45 °C, respectively. Adsorption-desorption studies demonstrated the recyclability of the δ-MnO2/BCs for the removal of Cu(II) from aqueous solutions.

SV40 Large T Antigen Disrupts Embryogenesis of Canine and Porcine Somatic Cell Nuclear Transfer Embryo

BackgroundSomatic cell nuclear transfer (SCNT) is a useful biotechnological tool for transgenic animal production using genetically modified somatic cells (GMSCs). However, there are several limitations preventing successful transgenic animal generation by SCNT, such as obtaining proper somatic donor cells with a sufficiently long life span and proliferative capacity for generating GMSCs. Here, we established simian virus 40 large T antigen (SV40LT)-mediated lifespan-extended canine fibroblast cells (SV40LT-K9 cells) and evaluated their potential as nuclei donors for SCNT, based on cellular integrity and SCNT embryo development.ResultsSV40LT did not cause canine cell transformation, based on cell morphology and proliferation rate. No anchorage-independent growth in vitro and tumorigenicity in vivo were observed. After SCNT with SV40LT-K9 cells, embryos were transferred into surrogate dogs. All dogs failed to become pregnant. Most embryos did not proceed past the 8-cell stage and only one surrogate showed an implantation trace in its oviduct, indicating that the cells rarely developed into blastocysts. Because of the absence of an in vitro maturation method for canine embryos, we performed identical experiments using porcine fibroblast cells. Similarly, SV40LT did not transform porcine fibroblast cells (SV40LT-Pig cells). During in vitro development of SV40LT-Pig cell-driven SCNT embryos, their blastocyst formation rate was clearly lower than those of normal cells. Karyotyping analysis revealed that both SV40LT-K9 and SV40LT-Pig cells had aberrant chromosomal statuses.ConclusionsAlthough lifespan-extended canine and porcine cells via SV40LT exhibit no apparent transforming changes, they are inappropriate for use as nuclei donors for SCNT because of their aneuploidy.

Characterization of Mineralogical and Physicochemical Properties of Soils Contaminated with Metals at Gahak Mine

ABSTRACT Soil samples collected in an area of Gahak Mine were investigated for the characterization of mineralogical andphysicochemical properties of contaminants in soils. It is found that soils in the study area are contaminated by lead (Pb),copper (Cu), zinc (Zn), cadmium (Cd), in which their concentrations are 595.3 mg/kg, 184.9 mg/kg, 712.8 mg/kg, and10.64 mg/kg, respectively. All the concentrations exceed the concern criteria of Korean standard. Upon distributionpatterns of metals identified by the sequential extraction procedure, our results show that more than 50% of metals arefound as a residual type, and 30% are accounted for the association of Fe/Mn oxides. Interestingly, XRD results show thatminium (Pb 3 O 4 ) and cuprite (Cu 2 O) are identified in the soil samples, suggesting that the sources of the contaminants forPb and Cu are these minerals. In SEM images, tens of µm of Pb oxides and Pb silicate-minerals are observed. We,therefore, note that the contamination of metals in the study area results from the direct influx and disturbance of tailings. Ourfindings indicate that the characterization of physicochemical and mineralogical properties of contaminated soils is a criticalfactor and plays an important role in optimizing recovery treatments of soils contaminated in mine development areas.Key words : Mineralogical properties, Contaminant speciation, Tailings, heavy metals, Soil contamination