Hyun Woo Lee

Targeting of miR34a–NOTCH1 Axis Reduced Breast Cancer Stemness and Chemoresistance

Human breast cancers include cancer stem cell populations as well as nontumorigenic cancer cells. Breast cancer stem cells have self-renewal capability and are resistant to conventional chemotherapy. miRNAs regulate the expression of many target genes; therefore, dysregulation of miRNAs has been associated with the pathogenesis of human diseases, including cancer. However, a role for miRNA dysregulation in stemness and drug resistance has yet to be identified. Members of the miR34 family are reportedly tumor-suppressor miRNAs and are associated with various human cancers. Our results confirm that miR34a expression was downregulated in MCF7/ADR cells compared with MCF7 cells. We hypothesized that this reduction was due to the p53 (TP53) mutation in MCF7/ADR cells. In this study, we found that primary and mature miR34a were suppressed by treatment with p53 RNAi or the dominant-negative p53 mutant in MCF7 cells. Ectopic miR34a expression reduced cancer stem cell properties and increased sensitivity to doxorubicin treatment by directly targeting NOTCH1. Furthermore, tumors from nude mice treated with miR34a were significantly smaller compared with those of mice treated with control lentivirus. Our research suggests that the ectopic expression of miR34a represents a novel therapeutic approach in chemoresistant breast cancer treatment.

Boron-Doped Peroxo-Zirconium Oxide Dielectric for High-Performance, Low-Temperature, Solution-Processed Indium Oxide Thin-Film Transistor

We developed a solution-processed indium oxide (In2O3) thin-film transistor (TFT) with a boron-doped peroxo-zirconium (ZrO2:B) dielectric on silicon as well as polyimide substrate at 200 °C, using water as the solvent for the In2O3 precursor. The formation of In2O3 and ZrO2:B films were intensively studied by thermogravimetric differential thermal analysis (TG-DTA), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FT IR), high-resolution X-ray diffraction (HR-XRD), and X-ray photoelectron spectroscopy (XPS). Boron was selected as a dopant to make a denser ZrO2 film. The ZrO2:B film effectively blocked the leakage current at 200 °C with high breakdown strength. To evaluate the ZrO2:B film as a gate dielectric, we fabricated In2O3 TFTs on the ZrO2:B dielectrics with silicon substrates and annealed the resulting samples at 200 and 250 °C. The resulting mobilities were 1.25 and 39.3 cm(2)/(V s), respectively. Finally, we realized a flexible In2O3 TFT with the ZrO2:B dielectric on a polyimide substrate at 200 °C, and it successfully operated a switching device with a mobility of 4.01 cm(2)/(V s). Our results suggest that aqueous solution-processed In2O3 TFTs on ZrO2:B dielectrics could potentially be used for low-cost, low-temperature, and high-performance flexible devices.

Solution-processed high-k HfO2 gate dielectric processed under softening temperature of polymer substrates

A low-temperature, solution-processed high-k HfO2 gate dielectric was demonstrated. To decompose a hafnium precursor at a temperature lower than 200 °C, an aqueous solution of HfCl4 was used because the strongly hydrated hafnium precursor was decomposed at a much lower temperature than anhydrous or partially hydrated hafnium chloride. No hazardous organic material was required in the low-temperature HfO2 coating process. Thus this precursor solution is environmentally safe and it is preferable to use this solution for gate dielectric coating on flexible substrates. The fabricated HfO2 gate dielectric shows reliable breakdown characteristics and high dielectric constant. We fabricated a thin film transistor (TFT) device with this gate dielectric and a maximum processing temperature of 150 °C for all the components of the TFT. The ZnO TFT on the HfO2 gate dielectric shows field-effect mobility of 1.17 cm2 V−1 s−1 and threshold voltage of 5.87 V. These results demonstrate the potential of our HfO2 thin film for flexible electronic device fabrication.

Galectin-3 increases the motility of mouse melanoma cells by regulating matrix metalloproteinase-1 expression

Although mounting evidence indicates the involvement of galectin-3 in cancer progression and metastasis, the underlying molecular mechanisms remain largely unknown. In this study, we investigated the effect and possible mechanism of galectin-3 on the migration and invasion of B16F10, a metastatic melanoma cell line, in which galectin-3 and matrix metalloproteinase-1 (MMP-1) were both found to be highly expressed. Knockdown of galectin-3 with specific siRNA reduced migration and invasion, which was associated with reduced expression of MMP-1. To further investigate the underlying mechanism, we examined the effect of galectin-3 knockdown on the activity of AP-1, a transcriptional factor regulating MMP-1 expression. We found that galectin-3 directly interacted with AP-1 and facilitated the binding of this complex to the MMP-1 promoter that drives MMP-1 transcription. Moreover, silencing of galectin-3 inhibited binding of fra-1 and c-Jun to promoter sites of MMP-1 gene. Consistent with these in vitro findings, our in vivo study demonstrated that galectin-3 shRNA treatment significantly reduced the total number of mouse lung metastatic nodules. Taken together, galectin-3 facilitates cell migration and invasion in melanoma in vitro and can induce metastasis in vivo, in part through, regulating the transcription activity of AP-1 and thereby up-regulating MMP-1 expression.

Celastrol inhibits gastric cancer growth by induction of apoptosis and autophagy

Recently, the interest in natural products for the treatment of cancer is increasing because they are the pre-screened candidates. In the present study, we demonstrate the therapeutic effect of celastrol, a triterpene extracted from the root bark of Chinese medicine on gastric cancer. The proliferation of AGS and YCC-2 cells were most sensitively decreased in six kinds of gastric cancer cell lines after the treatment with celastrol. Celastrol inhibited the cell migration and increased G1 arrest in cell-cycle populations in both cell lines. The treatment with celastrol significantly induced autophagy and apoptosis and increased the expression of autophagy and apoptosis-related proteins. We also found an increase in phosphorylated AMPK following a decrease in all phosphorylated forms of AKT, mTOR and S6K after the treatment with celastrol. Moreover, gastric tumor burdens were reduced in a dose-dependent manner by celastrol administration in a xenografted mice model. Taken together, celastrol distinctly inhibits the gastric cancer cell proliferation and induces autophagy and apoptosis. [BMB Reports 2014; 47(12): 697-702]

PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis

The activity of the phosphatase and tensin homologue (PTEN) is known to be suppressed via post-translational modification. However, the mechanism and physiological significance by which post-translational modifications lead to PTEN suppression remain unclear. Here we demonstrate that PTEN destabilization is induced by EGFR- or oncogenic PI3K mutation-mediated AKT activation in cervical cancer. EGFR/PI3K/AKT-mediated ubiquitination and degradation of PTEN are dependent on the MKRN1 E3 ligase. These processes require the stabilization of MKRN1 via AKT-mediated phosphorylation. In cervical cancer patients with high levels of pAKT and MKRN1 expression, PTEN protein levels are low and correlate with a low 5-year survival rate. Taken together, our results demonstrate that PI3K/AKT signals enforce positive-feedback regulation by suppressing PTEN function.

Highly efficient inverted polymer solar cells with reduced graphene-oxide-zinc-oxide nanocomposites buffer layer

In this study, we reported a 36% improvement in the performance of inverted solar cells as a result of increased short-circuit current (JSC) obtained using a composition of zinc oxide (ZnO) and reduced graphene oxide (RGO) as an n-type buffer layer. RGO-ZnO nanocomposites show higher electron conductivity than intrinsic ZnO; moreover, they show reduced contact resistance at the interface between the active layer and n-type buffer layer. These factors prevent carrier loss resulting from defects and recombinations in the device, thereby significantly increasing the JSC value for the device. Thus, an efficiency of 4.15% was achieved for inverted solar cells with a controlled RGO-ZnO nanocomposites layer.

Galectin-3 activates PPARγ and supports white adipose tissue formation and high-fat diet-induced obesity

Galectin-3, a β-galactoside-binding lectin, is elevated in obesity and type 2 diabetes mellitus, and metformin treatment reduces these galectin-3 levels. However, the role of galectin-3 in adipogenesis remains controversial. We found that 17-month-old galectin-3-deficient (lgals3(-/-)) mice had decreased body size and epididymal white adipose tissue (eWAT) without related inflammatory diseases when fed normal chow. Galectin-3 knockdown significantly reduced adipocyte differentiation in 3T3-L1 cells and also decreased the expression of peroxisome proliferator-activated receptor (PPAR)-γ, ccaat-enhancer-binding protein α, and ccaat-enhancer-binding protein β. Endogenous galectin-3 directly interacted with PPARγ, and galectin-3 ablation reduced the nuclear accumulation and transcriptional activation of PPARγ. After a 12-week high-fat diet (60% fat), lgals3(-/-) mice had lower body weight and eWAT mass than lgals3(+/+) mice. Moreover, the expression of PPARγ and other lipogenic genes was drastically decreased in the eWAT and liver of lgals3(-/-) mice. We suggest that galectin-3 directly activates PPARγ and leads to adipocyte differentiation in vitro and in vivo. Furthermore, galectin-3 might be a potential therapeutic target in metabolic syndromes as a PPARγ regulator.

Enhanced Air Stability of Polymer Solar Cells with a Nanofibril-Based Photoactive Layer

In spite of the rapid increase in the power conversion efficiency (PCE) of polymer solar cells (PSCs), the poor stability of the photoactive layer in air under sunlight is a critical problem blocking commercialization of PSCs. This study investigates the photo-oxidation behavior of a bulk-heterojunction (BHJ) photoactive film made of single-crystalline poly(3-hexlythiophene) (P3HT) nanofibrils and fullerene derivatives [phenyl-C61-butyric methyl ester (PCBM), indene-C 60 bisadduct (ICBA)]. Because the single-crystalline P3HT nanofibrils had tightly packed π-π stacking, the permeation of oxygen and water into the nanofibrils was significantly reduced. Chemical changes in P3HT were not apparent in the nanofibrils, and hence the air stability of the nanofibril-based BHJ film was considerably enhanced as compared with conventional BHJ films. The chemical changes were monitored by Fourier-transform infrared (FT-IR) spectroscopy, Raman spectroscopy, and UV-vis absorbance. Inverted PSCs made of the nanofibril-based BHJ layer also showed significantly enhanced air stability under sunlight. The nanofibril-based solar cell maintained more than 80% of its initial PCE after 30 days of continuous exposure to sunlight (AM 1.5G, 100 mW/cm(2)), whereas the PCE of the conventional BHJ solar cell decreased to 20% of its initial PCE under the same experimental conditions.

Targeting Notch signaling by γ-secretase inhibitor I enhances the cytotoxic effect of 5-FU in gastric cancer

Abstract Current medication for gastric cancer patients has a low success rate and the patients develop rapid tolerance to these drugs. Therefore, the development of new regimens is desired. In this study, we determined that Notch-signaling-related genes were overexpressed and activated in gastric cancer patients and gastric cancer cell lines. According to recent studies, γ-secretase inhibitors (GSIs), which function as Notch signaling inhibitors, could be used as therapeutic drugs in cancer. We demonstrated that GSI I (cbz-IL-CHO) is the most effective GSI in gastric cancer cells. We also determined the cell survival signaling-related proteins that were affected by GSI I. The levels of phosphorylated AKT were significantly decreased upon GSI I treatment, and constitutively activated myristoylated AKT completely blocked GSI I-induced apoptosis and cell survival, suggesting that inhibition of AKT signaling is critical for GSI I-mediated effects in gastric cancer cells. In order to maximize the effects and safety of GSI I, a combination treatment with GSI I and 5-FU was performed. Inhibition of gastric cancer cell proliferation with the combination treatment was significantly better than that with the single treatment. All phosphorylated forms of AKT, p44/42, JNK, and p38 were drastically changed by the combination treatment. Orthotopically transplanted gastric tumor burdens in mice were reduced using the combined treatment. The outcomes of this study clearly demonstrated the therapeutic potential of GSI I in gastric cancer, as well as the greater efficacy of the combined treatment of GSI I with 5-FU. Therefore, we suggest that further clinical trials examining the potential of combined GSI I and 5-FU treatment in gastric cancer patients be undertaken.