[Show abstract][Hide abstract] ABSTRACT: Human breast cancers include cancer stem cell populations as well as non-tumorigenic cancer cells. Breast cancer stem cells have self-renewal capability and are resistant to conventional chemotherapy. MicroRNAs (miRNAs) regulate the expression of many target genes; therefore, dysregulation of miRNAs have 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 miR-34 family are reportedly tumor-suppressor miRNAs and are associated with various human cancers. Our results confirm that miR-34a 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 miR-34a were suppressed by treatment with p53 RNAi or the dominant negative p53 mutant in MCF7 cells. Ectopic miR-34a expression reduced cancer stem cell properties and increased sensitivity to doxorubicin treatment, by directly targeting NOTCH1. Furthermore, tumors from nude mice treated with miR-34a were significantly smaller compared to those of mice treated with control lentivirus. Our research suggests that the ectopic expression of miR-34a represents a novel therapeutic approach in chemoresistant breast cancer treatment.
[Show abstract][Hide abstract] ABSTRACT: In nature, there exist a wide repertoire of dsRNA-binding proteins that have different binding modes for siRNA as well as structural differences, and some of these proteins have the potential as the effective siRNA delivery carriers. For delivering siRNA into cancer cells, a dsRNA-binding 2b protein derived from Tomato aspermy virus was genetically modified by fusing the integrin-targeting RGD peptide to its C-terminus, and biosynthesized. The resulting 2b-RGD protein possesses distinct characteristics favorable to biomedical applications of siRNA: (1) high affinity for siRNA, (2) siRNA protection against RNases in serum, (3) low cytotoxicity compared to the polycationic polymers often employed in the conventional siRNA carriers, (4) specific binding to integrins on cancer cells, and passing through the cell membrane via endocytosis, (5) ability to facilitate cytosolic release of siRNA. Here, we demonstrate the 2b-RGD/siRNA complexes have the high potential as a tumor-targeting siRNA delivery carrier and suggest their possible therapeutic applications for cancer treatment.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate urinary metabolomic profiles associated with cadmium (Cd)-induced nephrotoxicity and their potential mechanisms. Metabolomic profiles were measured by high-resolution (1)H-nuclear magnetic resonance (NMR) spectroscopy in the urine of rats after oral exposure to CdCl2 (1, 5, or 25 mg/kg) for 6 wk. The spectral data were further analyzed by a multivariate analysis to identify specific urinary metabolites. Urinary excretion levels of protein biomarkers were also measured and CdCl2 accumulated dose-dependently in the kidney. High-dose (25 mg/kg) CdCl2 exposure significantly increased serum blood urea nitrogen (BUN), but serum creatinine (sCr) levels were unchanged. High-dose CdCl2 (25 mg/kg) exposure also significantly elevated protein-based urinary biomarkers including osteopontin, monocyte chemoattractant protein-1 (MCP-1), kidney injury molecules-1 (Kim-1), and selenium-binding protein 1 (SBP1) in rat urine. Under these conditions, six urinary metabolites (citrate, serine, 3-hydroxyisovalerate, 4-hydroxyphenyllactate, dimethylamine, and betaine) were involved in mitochondrial energy metabolism. In addition, a few number of amino acids such as glycine, glutamate, tyrosine, proline, or phenylalanine and carbohydrate (glucose) were altered in urine after CdCl2 exposure. In particular, the metabolites involved in the glutathione biosynthesis pathway, including cysteine, serine, methionine, and glutamate, were markedly decreased compared to the control. Thus, these metabolites are potential biomarkers for detection of Cd-induced nephrotoxicity. Our results further indicate that redox metabolomics pathways may be associated with Cd-mediated chronic kidney injury. These findings provide a biochemical pathway for better understanding of cellular mechanism underlying Cd-induced renal injury in humans.
Journal of Toxicology and Environmental Health Part A 10/2014; 77(22-24):1384-98. · 1.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of the study was to investigate significant psychosocial needs of low-income people with cancer in Korea and the extent to which these needs are unmet and which factors influence them.
European journal of oncology nursing: the official journal of European Oncology Nursing Society 10/2014; · 1.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Excessive reactive oxygen species (ROS) production plays a crucial role in causing various diseases, including inflammatory disorders. The activation of mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-κB) signaling is implicated in stimulating inflammatory response and cytokines. Peroxiredoxin 2 (Prx2) is a 2-cysteine (Cys) peroxiredoxin capable of removing endogenous hydrogen peroxide (H2O2). PEP-1 peptide, a protein transduction domain, consists of three domains which are used to transduce exogenous therapeutic proteins into cells. The correlation between effectively transduced PEP-1-Prx2 and ROS-mediated inflammatory response is not clear. In the present study, we investigated the protective effects of cell permeable PEP-1-Prx2 on oxidative stress-induced inflammatory activity in Raw 264.7 cells and in a mouse ear edema model after exposure to lipopolysaccharides (LPS) or 12-O-tetradecanoylphorbol-13-actate (TPA). Transduced PEP-1-Prx2 suppressed intracellular ROS accumulation and inhibited the activity of MAPKs and NF-κB signaling that led to the suppression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and cytokines in LPS-induced Raw 264.7 cells and TPA-induced mouse ear edema model. Given these results, we propose that PEP-1-Prx2 has therapeutic potential in the prevention of inflammatory disorders.
International Immunopharmacology 09/2014; · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aims of the present study were to assess the prevalence of perceived risk for cancer; to explore associations between sociodemographics and family history of cancer and perceived cancer risk; to identify perceived cause of cancer risk; and to examine the associations between sociodemographics and family history of cancer and perceived cause of cancer risk.
This cross-sectional study was conducted among 1,009 participants aged 30-69 years, selected from a population-based database in October 2009 through multiple-stratified random sampling. Information was collected about the participants' perceived cancer risk and perceived cause of cancer risk.
Overall, 59.5% of the respondents thought they had the chance of developing cancer. Female sex, younger age, lower income, and family history of cancer were positively associated with perceived cancer risk. The most important perceived cause of cancer risk was stress. There was a difference between sociodemographics and family history of cancer and perceived cause of cancer risk.
Factors affecting perceptions of cancer risk and cause of cancer risk need to be addressed in risk communications. The results provide important directions for the development of educational strategies to promote awareness and self-appraisal of cancer risk and risk factors.
Cancer Research and Treatment 09/2014; · 2.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Porphyrias are inherited metabolic disorders resulting from a specific enzyme defect in the heme biosynthetic pathway. Porphyrias are induced by various precipitants. Clinical features include abdominal pain, neurologic manifestations, autonomic neuropathy, and mental disturbance. Diagnosis may be delayed because of variable symptoms that mimic other diseases and because of the rarity of of porphyrias. Although most patients with known porphyria can complete anesthesia and surgery safely, undiagnosed porphyric patients are in danger of porphyric crisis due to inadvertent exposure to precipitating drugs and environment. We report a case of a patient who experienced delayed emergence with neurological disturbance after general anesthesia, ultimately diagnosed as acute intermittent porphyria.
Korean journal of anesthesiology 09/2014; 67(3):217-20.
[Show abstract][Hide abstract] ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by abnormal proliferation of renal tubular epithelial cells resulting in loss of renal function. Despite identification of the genes responsible for ADPKD, few effective drugs are currently available for the disease. Thus, finding additional effective drug targets is necessary. The functions of MRP3 have been reported only in the field of drug-resistance, and the renal functions of multidrug-resistance associated protein 3 (MRP) are mostly unknown. In this study, we found that MRP3 was significantly downregulated in kidneys of human patients with ADPKD and polycystic kidney disease (PKD) mouse models. Our results suggest that downregulated MRP3 stimulated renal epithelial cell proliferation through the B-Raf/MEK/ERK signaling pathway. In contrast, we found that restoring MRP3 reduced cell proliferation and cystogenesis in vitro. These results suggest that the renal function of MRP3 is related to renal cell proliferation and cyst formation and that restoring MRP3 may be an effective therapeutic approach for PKD.
American journal of physiology. Renal physiology 08/2014; · 3.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The recent proliferation of data on large collections of well-characterized cancer cell lines linked to therapeutic drug responses has made it possible to identify lineage- and mutation-specific transcriptional markers that can help optimize implementation of anticancer agents. Here we leverage these resources, to systematically investigate the presence of mutation-specific transcription markers in a wide variety of cancer lineages and genotypes. Sensitivity and specificity of potential transcriptional biomarkers were simultaneously analyzed in 19 cell lineages grouped into 228 categories based on the mutational genotypes of 12 cancer-related genes. Among a total of 1,455 category-specific expression patterns, the expression of cAMP phosphodiesterase-4D (PDE4D) with 11 isoforms, one of the PDE4(A-D) sub-families, was predicted to be regulated by a mutant form of Serine/threonine kinase 11 (STK11)/liver kinase B1 (LKB1) present in lung cancer. STK11/LKB1 is the primary upstream kinase of adenine monophosphate-activated protein kinase (AMPK). Subsequently, we found that the knockdown of PDE4D gene expression inhibited proliferation of STK11-mutated lung cancer lines. Furthermore, challenge with a panel of PDE4 specific inhibitors was shown to selectively reduce the growth of STK11-mutated lung cancer lines. Thus we show that multidimensional analysis of a well-characterized large-scale panel of cancer cell lines provides unprecedented opportunities for identification of unexpected oncogenic mechanisms and mutation-specific drug targets.
Molecular Cancer Therapeutics 08/2014; · 5.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epithelial-mesenchymal transition (EMT) is associated with tumor hypoxia. EMT is regulated, in part, by the action of TWIST, which inhibits of E-cadherin expression and may interfere with the p53 tumor-suppressor pathway.
The Korean Journal of Pathology 08/2014; 48(4):283-91. · 0.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Soft tissue sarcomas (STS) are rare. We evaluated the WT1 protein expression level in various types of STS and elucidated the value of WT1 as a prognostic factor and a possible therapeutic target.
World Journal of Surgical Oncology 07/2014; 12(1):214. · 1.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We assessed the extent to which self-reported exposure to SHS underestimates the actual exposure to SHS and what factors are associated with a tolerance for SHS exposure in the Korean setting where the smoke-free policy is incomplete.
[Show abstract][Hide abstract] ABSTRACT: As it is known that FK506 binding proteins (FK506BPs) play an important role regulating a variety of biological processes for cell survival, this study was designed to examined the protective effects of FK506 binding protein 12 (FK506BP) on low humidity air flow induced dry eye in a rat model using transduced PEP-1-FK506BP. After the topically application of PEP-1-FK506BP tear volumes were markedly increased and cornea damage was significantly prevented compared with dry eye rats. Further, immunohistochemical analysis demonstrated that PEP-1-FK506BP markedly prevented damage to the cornea, the bulbar conjunctiva, and the palpebral conjunctiva epithelial lining compared with dry eye rats. Also this decreased caspase-3 and PARP expression levels. These results demonstrated that topically applied PEP-1-FK506BP significantly ameliorates dry eye injury in an animal model. Thus, we suggest that PEP-1-FK506BP can be developed as a new ophthalmic drop to treat dry eye diseases.
[Show abstract][Hide abstract] ABSTRACT: This study compares the digital literacy of people with and without disabilities in Korea, using data from the 2011 Information Divide Index Data of the National Information Society Agency (NIA). We extracted Internet and smart device users from the NIA samples and examined the main effects of disability, gender and age, as well as their interaction effects on Internet and smart device use and production literacy. Of the 1500 public individuals examined, 1190 (79.3%) were Internet users and 535 (35.7%) were smart device users. Of the 5300 with disabilities, 2110 (63.9%) were Internet users and 324 (8.8%) were smart device users. Generalized linear modelling showed significant main effects of disability, gender, age and education on Internet use and production literacy. The disability × age and disability × education interaction effects on Internet use literacy were statistically significant. We also observed a significant disability × age interaction effect on Internet production literacy. However, the main and interaction effects of disability, gender and education on smart device use and production literacy were not significant.
[Show abstract][Hide abstract] ABSTRACT: To develop effective intervention programmes to control Clonorchis sinensis infection, three interventions were evaluated in a clonorchiasis-endemic area of Korea.
Tropical Medicine & International Health 05/2014; · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AimAutosomal dominant polycystic kidney disease (ADPKD) is a highly prevalent inherited disorder and results in the progressive development of cysts in both kidneys. In recent studies, several cytokines and growth factors secreted by the cyst-lining epithelia were identified to be up-regulated and promote cyst growth. According to our previous study, chemokines with a similar amino acid sequence as human IL-8 are highly expressed in a rodent model with renal cysts. Therefore, in this study, we focused on whether IL-8 signaling is associated with renal cyst formation, and tested the possibility of IL-8 as a new therapeutic target for ADPKD.Methods
Expression of IL-8 and its receptor were screened either by ELISA or western blot. Inhibited IL-8 signaling by antagonist for IL-8 receptor or gene silencing was tested in molecular levels, mainly through Western blot. And cell proliferation was measured by XTT assays. Finally, a three-dimensional culture was performed to understand how IL-8 affected cyst formation, in vitro.ResultsIL-8 secretion and expression of its receptor highly increased in 2 different human ADPKD cell lines (WT9-7 and WT9-12), compared to normal human renal cortical epithelial cell line. Cell proliferation which is mediated by IL-8 signal was inhibited either by an antagonist or siRNA targeting for IL-8 receptor. Finally, a three-dimensional culture showed an alleviation of cystogenesis in vitro, after blocking the IL-8 receptor signals.Conclusion
These results suggest that IL-8 and its signaling molecules could be new biomarkers and a therapeutic target of ADPKD.
[Show abstract][Hide abstract] ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorder. Although a myriad of research groups have attempted to identify a new therapeutic target for ADPKD, no drug has worked well in clinical trials. Our research group has focused on the receptor for advanced glycation end products (RAGE) gene as a novel target for ADPKD. This gene is involved in inflammation and cell proliferation. We have already confirmed that blocking RAGE function attenuates cyst growth in vitro. Based on this previous investigation, our group examined the effect of RAGE on cyst enlargement in vivo. PC2R mice, a severe ADPKD mouse model that we generated, were utilized. An adenovirus containing anti-RAGE shRNA was injected intravenously into this model. We observed that RAGE gene knockdown resulted in loss of kidney weight and volume. Additionally, the cystic area that originated from different nephron segments decreased in size due to downregulation of the RAGE gene. Blood urea nitrogen and creatinine values tended to be lower after inhibiting RAGE. Based on these results, we confirmed that the RAGE gene could be an effective target for ADPKD treatment.
Journal of Biological Chemistry 02/2014; · 4.60 Impact Factor