[Show abstract][Hide abstract] ABSTRACT: HOX genes not only play important roles in defining body patterning during embryonic development, but also control numerous cellular events in adult cells. Deregulated HOX gene expression in different cancers including breast cancer is now increasingly being reported. Given that human HOXA cluster is marked with several CTCF binding sites, we investigated whether the presence of CTCF is associated directly with expression of HOXA genes in breast cancer cells. Several HOX genes, such as HOXA4, HOXA5 and HOXA10, were deregulated by CTCF overexpression and knockdown in MCF-7 cells. Among these genes, HOXA10 is an emerging tumor suppressor for its role in activation of p53 and in countering tumorigenesis in breast cancer. Here we provided evidences that CTCF functions as a negative regulator of HOXA10 in breast cancer cells. The putative promoter region of HOXA10 lies between 5.3 to 6.1 kb upstream of its start codon and its promoter activity was negatively regulated by CTCF. Together with in-silico analysis and in vitro mutation assay we identified a 20 bp CTCF binding motif flanking with core promoter element of HOXA10. HOXA10 promoter region was kept inactivated by maintaining H3K27me3 inactivation marks in the presence of CTCF. Epigenetic silencing of HOXA10 by CTCF in breast cancer cells may contribute towards tumorigenesis by decreasing apoptosis and promoting metastasis.
Biochemical and Biophysical Research Communications 10/2015; DOI:10.1016/j.bbrc.2015.10.058 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: HOX transcription factors play an important role in determining body patterning and cell fate during embryogenesis. Accumulating evidence has shown that these genes act as positive and/or negative modulators in many types of cancer, including breast cancer, in a tissue-specific manner. We have previously reported that HOXB5 is aberrantly overexpressed in breast cancer tissues and cell lines. Here, we investigated the biological roles and clinical relevance of HOXB5 in breast cancer. Immunohistochemical analysis of HOXB5 on tissue microarray (TMA) including 34 normal and 67 breast cancer specimens revealed that HOXB5 was highly expressed in cancer tissues, particularly from estrogen receptor (ER)-positive breast cancer patients. An online survival analysis confirmed the correlation between HOXB5 expression and poor distant metastasis-free survival in ER-positive, but not in ER-negative, breast cancer. In vitro studies indicated that HOXB5 silencing in ER-positive cells significantly decreased cell proliferation and anchorage-independent cell growth. In contrast, overexpression of HOXB5 displayed EMT characteristics with a greater invasive ability, higher cell proliferation and colony formation in soft agar. HOXB5 knockdown or overexpression led to changes in the expression levels of RET, ERBB2, and EGFR, but not of ESR1. In conclusion, we suggest that HOXB5 acts as a positive modulator most likely by promoting cell proliferative response and invasiveness in ER-positive breast cancer. These results would help predict prognosis of breast cancer and identify a new valuable therapeutic target.
International journal of biological sciences 05/2015; 11(6):701-711. DOI:10.7150/ijbs.11431 · 4.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Retinoic acid (RA), the most potent natural form of vitamin A, is a key morphogen in vertebrate development and a potent regulator of both adult and embryonic cell differentiation. Specifically, RA regulates clustered Hox gene expression during embryogenesis and is required to establish the anteroposterior body plan. The PI3K/Akt pathway was also reported to play an essential role in the process of RA-induced cell differentiation. Therefore, we tested whether the PI3K/Akt pathway is involved in RA-induced Hox gene expression in a F9 murine embryonic teratocarcinoma cells. To examine the effect of PI3K/Akt signaling on RA-induced initiation of collinear expression of Hox genes, F9 cells were treated with RA in the presence or absence of PI3K inhibitor LY294002, and time-course gene expression profiles for all 39 Hox genes located in four different clusters—Hoxa, Hoxb, Hoxc, and Hoxd—were analyzed. Collinear expression of Hoxa and -b cluster genes was initiated earlier than that of the -c and -d clusters upon RA treatment. When LY294002 was applied along with RA, collinear expression induced by RA was delayed, suggesting that the PI3K/Akt signaling pathway somehow regulates RA-induced collinear expression of Hox genes in F9 cells. The initiation of Hox collinear expression by RA and the delayed expression following LY294002 in F9 cells would provide a good model system to decipher the yet to be answered de novo collinear expression of Hox genes during gastrulation, which make the gastrulating cells to remember their positional address along the AP body axis in the developing embryo.
Development Growth and Regeneration 09/2014; 56(7). DOI:10.1111/dgd.12152 · 2.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The evolutionarily conserved Hox genes are organized in clusters and expressed colinearly to specify body patterning during embryonic development. Previously, Akt1 has been identified as a putative Hox gene regulator through in silico analysis. Substantial upregulation of consecutive 5' Hoxc genes has been observed when Akt1 is absent in mouse embryonic fibroblast (MEF) cells. In this study, we provide evidence that Akt1 regulates the 5' Hoxc gene expression by epigenetic modifications. Enrichment of histone H3K9 acetylation and low level of H3K27me3 mark were detected at the posterior 5' Hoxc loci when Akt1 is absent. A histone deacetylase (HDAC) inhibitor de-repressed 5' Hoxc gene expression when Akt1 is present, and a DNA demethylating reagent synergistically upregulated HDAC-induced 5' Hoxc gene expression. A knockdown study revealed that HDAC6 is mediated in the Hoxc12 repression through direct binding to the transcription start site (TSS) in the presence of Akt1. Co-immunoprecipitation analysis revealed that endogenous Akt1 directly interacted with HDAC6. Furthermore, exogenous Akt1 was enriched at the promoter region of the posterior Hoxc genes such as Hoxc11 and Hoxc12, not the Akt1-independent Hoxc5 and Hoxd10 loci. The regulation of H3K27me3 mark by Ezh2 and Kdm6b at the 5' Hoxc gene promoter turned out to be Akt1 dependent. Taken together, these results suggest that Akt1 mediates the posterior 5' Hoxc gene expression through epigenetic modification such as histone methylation and acetylation, and partly through a direct binding to the promoter region of the 5' Hoxc genes and/or HDAC6 in mouse embryonic fibroblast cells.
[Show abstract][Hide abstract] ABSTRACT: Pax3 mutations result in malformed inner ears in Splotch mutant mice and hearing loss in humans with Waardenburg's syndrome type I. In the inner ear, Pax3 is thought to be involved mainly in the development of neural crest. However, recent studies have shown that Pax3-expressing cells contribute extensively to multiple inner ear structures, some of which were considered to be derived from the otic epithelium. To examine the specific functions of Pax3 during inner ear development, fate mapping of Pax3 lineage was performed in the presence or absence of functional Pax3 proteins using Pax3(Cre) knock-in mice bred to Rosa26 reporter (R26R) line. β-gal-positive cells were widely distributed in Pax3(Cre/+); R26R inner ears at embryonic day (E) 15.5, including the endolymphatic duct, common crus, cristae, maculae, cochleovestibular ganglion, and stria vascularis. In the absence of Pax3 in Pax3(Cre/Cre); R26R inner ears, β-gal-positive cells disappeared from regions with melanocytes such as the stria vascularis of the cochlea and dark cells in the vestibule. Consistently, the expression of Dct, a melanoblast marker, was also absent in the mutant inner ears. However, when examined at E11.5, β-gal positive cells were present in Pax3(Cre/Cre) mutant otocysts, whereas Dct expression was absent, suggesting that Pax3 lineage with a melanogenic fate migrated to the inner ear, yet failed to differentiate and survive without Pax3 function. Gross inner ear morphology was generally normal in Pax3(Cre/Cre) mutants, unless neural tube defects extended to the cranial region. Taken together, these results suggest that despite the extensive contribution of Pax3-expressing cells to multiple inner ear tissues, Pax3 function is required specifically for inner ear components with melanogenic fates.
Biochemical and Biophysical Research Communications 02/2014; 445(3). DOI:10.1016/j.bbrc.2014.02.047 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The evolutionarily conserved Hox genes are organized in clusters and expressed colinearly to specify body patterning during embryonic development. Previously, Akt1 has been identified as a putative Hox gene regulator through in silico analysis. Substantial upregulation of consecutive 5’ Hoxc genes has been observed when Akt1 is absent in mouse embryonic fibroblast (MEF) cells. In this study, we provide evidence that Akt1 regulates the 5’ Hoxc gene expression by epigenetic modifications. Enrichment of histone H3K9 acetylation and low level of H3K27me3 mark were detected at the posterior 5’ Hoxc loci when Akt1 is absent. A histone deacetylase (HDAC) inhibitor de-repressed 5’ Hoxc gene expression when Akt1 is present, and a DNA demethylating reagent synergistically upregulated HDAC-induced 5’ Hoxc gene expression. A knockdown study revealed that HDAC6 is mediated in the Hoxc12 repression through direct binding to the transcription start site (TSS) in the presence of Akt1. Co-immunoprecipitation analysis revealed that endogenous Akt1 directly interacted with HDAC6. Furthermore, exogenous Akt1 was enriched at the promoter region of the posterior Hoxc genes such as Hoxc11 and Hoxc12, not the Akt1-independent Hoxc5 and Hoxd10 loci. The regulation of H3K27me3 mark by Ezh2 and Kdm6b at the 5’ Hoxc gene promoter turned out to be Akt1 dependent. Taken together, these results suggest that Akt1 mediates the posterior 5’ Hoxc gene expression through epigenetic modification such as histone methylation and acetylation, and partly through a direct binding to the promoter region of the 5’ Hoxc genes and/or HDAC6 in mouse embryonic fibroblast cells.
[Show abstract][Hide abstract] ABSTRACT: The Hox genes, which are organized into clusters on different chromosomes, are key regulators of embryonic anterior-posterior (A-P) body pattern formation and are expressed at specific times and in specific positions in developing vertebrate embryos. Previously, we have shown that histone methylation patterns are closely correlated with collinear Hox gene expression patterns along the A-P axis of E14.5 mouse embryos. Since histone modification is thought to play a crucial mechanistic role in the highly coordinated pattern of collinear Hox gene expression, we examined the maintenance of the spatial collinear expression pattern of Hoxc genes and the corresponding histone modifications during embryogenesis and in early postnatal mice. Hox expression patterns and histone modifications were analyzed by semi-quantitative RT-PCR and chromatin immunoprecipitation (ChIP)-PCR analyses, respectively. The spatiotemporal expression patterns of Hoxc genes in a cluster were maintained until the early postnatal stage (from E8.5 through P5). Examination of histone modifications in E14.5 and P5 tissues revealed that level of H3K27me3 is only a weak correlation with collinear Hoxc gene expression in the trunk regions although diminished in general, however the enrichment of H3K4me3 is strongly correlated with the gene expression in both stages. In summary, the initial spatiotemporal collinear expression pattern of Hoxc genes and epigenetic modifications are maintained after birth, likely contributing to the establishment of the gene expression code for position in the anatomic body axis throughout the entire life of the organism.
International journal of biological sciences 09/2013; 9(9):960-5. DOI:10.7150/ijbs.6739 · 4.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study used data from the Korea Labor and Income Panel Survey (2001, 2003–2007) to estimate the effect of a husband's unemployment on his wife's subjective well‐being (SWB). Ordinal and pooled binary logistic regression models were estimated using 20,099 observations from a sample of 4,569 married women; a fixed‐effects logistic regression model was also estimated using 5,514 observations from a restricted sample of 1,070 wives who experienced at least 1 change in SWB over the follow‐up period. The findings indicated that a husband's unemployment was detrimental to his wife's SWB. This spillover effect appeared to be mediated in part through nonpecuniary factors (i.e., dissatisfaction with family and social relations). These findings suggest that, beyond income loss and the well‐being of unemployed individuals, the social cost of unemployment should consider the negative effects of unemployment on the family, in particular the spouse.
Journal of Marriage and Family 04/2013; 75(2). DOI:10.1111/jomf.12004 · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Over the past several years, the incidence of hepatitis A infection has been increasing rapidly in the young-adult population in Korea. We examined the effects of area-level socioeconomic status and environmental hygiene on the incidence of hepatitis A.
This study is based on the registered national population of Korea and the national health insurance data from 2004 to 2008. A total of 73 459 individuals were confirmed to have had hepatitis A. The standardized incidences of hepatitis A in 232 districts adjusted for sex and age of people were calculated for each year, and the rate ratios of the incidence rates were estimated according to area-level socioeconomic status and environmental hygiene using multiple Poisson regression models.
The incidence rates of hepatitis A infection were 15.6 (per 100 000) in 2004, 19.0 (per 100 000) in 2005, 27.2 (per 100 000) in 2006, 25.1 (per 100 000) in 2007, and 61.7 (per 100 000) in 2008. The analysis of the area-level effects showed that residential areas of the less deprived than other regions, areas with higher levels of education, and heavily populated areas were significantly associated with increased risk.
There is a very strong possibility that both area-level socioeconomic status and environmental hygiene play a role in increasing the risk of hepatitis A infection in Korea. Therefore, to reduce hepatitis A infection, we need a nationwide strategy that considers these area-level characteristics.
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to compare the validity of the International Study of Asthma and Allergies in Childhood (ISAAC) written (WQ) and audiovisual questionnaires (AVQ 3.0) in two age-groups (10-12 and 13-15 years, respectively).
The 13-15 year olds performed the self-completed the WQ and AVQ on the same day. The 10-12 year olds performed the self-completed the AVQ and the parent-completed WQ was completed by their parents. The methacholine challenge test was conducted in 10-12 year olds from one elementary school.
In 10-12 year olds, the AVQ detected a generally higher prevalence of asthma symptoms than WQ. In 13-15 year olds, this was reversed. In 10-12 year olds, poor agreement was found between the parent-completed WQ and the self-reported AVQ. In 13-15 year olds, moderate agreement was found between the self-reported WQ and AVQ. Low sensitivity was found, in predicting bronchial hyper-responsiveness (BHR) for all questions of both WQ and AVQ in 10-12 year olds. However, the AVQ had slightly higher sensitivity than WQ, with the exception of wheeze ever, although it was not statistically significant.
The ISAAC AVQ may be another effective instrument for assessing the prevalence of asthma symptoms in children aged 10-12 years, whereas the parent-reported-WQ may underestimate the prevalence of asthma symptoms in this age-group.
[Show abstract][Hide abstract] ABSTRACT: The impact on quality of life (QOL) and safety has increasingly been an important consideration for living donors after kidney transplantation. The purposes of this study were to evaluate the QOL of living kidney donors and to indentify factors for impediment of their QOL.
[Show abstract][Hide abstract] ABSTRACT: Busan is reported to have the highest mortality rate among 16 provinces in Korea, as well as considerable health inequality across its districts. This study sought to examine overall and cause-specific mortality and deprivation at the town level in Busan, thereby identifying towns and causes of deaths to be targeted for improving overall health and alleviating health inequality.
Standardized mortality ratios (SMRs) for all-cause and four specific leading causes of death were calculated at the town level in Busan for the years 2005 through 2008. To construct a deprivation index, principal components and factor analysis were adopted, using 10% sample data from the 2005 census. Geographic information system (GIS) mapping techniques were applied to compare spatial distributions between the deprivation index and SMRs. We fitted the Gaussian conditional autoregressive model (CAR) to estimate the relative risks of mortality by deprivation level, controlling for both the heterogeneity effect and spatial autocorrelation.
The SMRs of towns in Busan averaged 100.3, ranging from 70.7 to 139.8. In old inner cities and towns reclaimed for replaced households, the deprivation index and SMRs were relatively high. CAR modeling showed that gaps in SMRs for heart disease, cerebrovascular disease, and physical injury were particularly high.
Our findings indicate that more deprived towns are likely to have higher mortality, in particular from cardiovascular disease and physical injury. To improve overall health status and address health inequality, such deprived towns should be targeted.
[Show abstract][Hide abstract] ABSTRACT: Adipose-derived stem cells (ADSCs) have been shown to induce wound-healing effects. Because inflammation near the wound area induces oxygen deficiency, it is interesting to elucidate the effect of hypoxia on the function of ADSCs. In this work, we asked: (1) does hypoxia alter the wound-healing function of ADSCs? and (2) what are the major factors responsible for the alteration in the wound-healing function? Effect of hypoxia on the proliferation of ADSCs was first examined that hypoxia (2% O(2)) enhanced the proliferation of ADSCs in either the presence of serum or in the absence of serum. The conditioned medium of ADSCs harvested under hypoxia (hypoCM) significantly promoted collagen synthesis and the migration of human dermal fibroblasts, compared with that in normoxia (norCM). In the animal studies, hypoCM significantly reduced the wound area compared with norCM. Furthermore, mRNA and protein measurements showed that hypoxia up-regulated growth factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Inhibition of VEGF and bFGF using neutralizing antibodies reversed the migration of the wounded human dermal fibroblasts and the healing of wounds in animal experiment. Collectively, these results suggest that hypoxia increases the proliferation of ADSCs and enhances the wound-healing function of ADSCs, at least partly, by up-regulating the secretion of VEGF and bFGF.
[Show abstract][Hide abstract] ABSTRACT: Hoxc8 has multiple roles in normal skeletal development. In this paper, a MC3T3-E1 subclone 4 osteogenic cell differentiation model was used to examine expression of Hoxc8 at multiple stages of osteogenesis. We found that Hoxc8 expression levels do not change in the early stage but increase in the middle stage and decrease in the late stage of osteogenesis. A knockdown of Hoxc8 by small-interfering RNA transfection in C2C12 cells indicated that Hoxc8 is a negative regulator of osteogenesis. Similarly, expression of Hoxc8 in C2C12 cells decreases alkaline phosphatase levels induced by bone morphogenetic protein-2 (BMP-2). The results of this study showed that Hoxc8 is involved in BMP-2-induced osteogenesis, and osteoblast differentiation in vitro is negatively regulated by Hoxc8, suggesting that Hoxc8 regulation is essential for osteoblast differentiation.
[Show abstract][Hide abstract] ABSTRACT: Protein transduction domains (PTDs) have been shown to cross the biological cell membranes efficiently through a receptor and energy independent mechanism. Because of its ease in membrane transducing ability, PTDs could be used as a gene delivery vector. Since we already have shown that purified Hoxc8 homeoprotein has the ability to cross the cellular membrane, we analyzed the possibility of the third helix of the Hoxc8 homeodomain as a useful gene delivery vector. For that purpose, a 16-aa long synthetic oligopeptide Hoxc8 Protein Transduction Domain (HPTD) was chemically synthesized and then tested to see whether the HPTD could form a complex with DNA or not. Gel retardation analysis revealed that the HPTD interacts with plasmid DNA efficiently but failed to transfer the DNA into the cells. However, HPTD can enhance the efficiency of gene transfer in combination with Lipofectamine which doubled the gene transfer rate into COS-7 cells compared with the DNA/Lipofectamine control. An MTT assay indicated that the amount of HPTD used in the complex for the transfection did not show any cytotoxicty in COS-7 cells. The TEM studies showed compact particle formation in the presence of HPTD. These results indicate that the HPTD could be a good candidate adjuvant molecule to enhance the gene transfer efficiency of Lipofectamine in eukaryotic cells.
[Show abstract][Hide abstract] ABSTRACT: Homeobox (Hox)-containing genes have been identified as regulators which control the expression of a variety of genes involved in development and differentiation. Recent reports also suggested an involvement of Hox genes in transformation and/or tumor progression. In human prostate cancer, overexpression of HOXC8 was associated with a loss of tumor differentiation, which implies the involvement of HOXC8 in the process leading to the tumorigenicity of tumor cells. In order to investigate the role of Hoxc8 in the growth of tumor cells, Hoxc8 was designed to be expressed constitutively in B16F10 melanoma cells after stable transfection, and then a clone B16F10Shoxc8#14 overexpressing Hoxc8 was selected and analyzed further. B16F10Shoxc8#14 expressed Hoxc8 at high level and exhibited a reduced growth rate in vitro. When the cell cycle progress was analyzed, it has a decreased S phase population through upregulation of cell cycle regulators, such as p21, HDAC8 and E2F5. When the effect of Hoxc8 was analyzed on tumor growth in vivo C57BL/6 mice, the tumorigenicity as well as the growth rate was significantly decreased, indicating that the overexpression of Hoxc8 in B16F10 melanoma inhibits the tumor proliferation, probably functioning as a cell cycle regulator.
[Show abstract][Hide abstract] ABSTRACT: Osteoporosis is a major public health problem in both Western and Asian populations. Because the aged population in Korea is increasing, the number of osteoporotic fractures is thought to be also increasing. However, there has been no nationwide analysis of osteoporotic fractures in Korea. We analyzed the incidence and cost of hip fracture from 2001 to 2004 by using data from the Health Insurance Review Agency, Korea. In the over 50 years age group, the number of hip fractures in women increased from 250.9/100,000 persons in 2001 to 262.8/100,000 in 2004, a 4.7% increase. However, that in men decreased from 162.8/100,000 in 2001 to 137.5/100,000 in 2004, a 15.5% decrease. Direct medical care costs of hip fracture increased from $62,707,697 in 2001 to $65,200,035 in 2004, and the proportional cost of hip fractures in the national medical costs increased by 4.5% over 4 years (from 0.200% in 2001 to 0.209% in 2004). On analysis of the population-based data obtained from the whole country from 2001 to 2004, the incidence rate of hip fractures in women, not in men, and its cost have increased in Korea. The gender distribution of hip fractures underlines the need for aggressive intervention in osteoporosis in elderly women.
Journal of Bone and Mineral Metabolism 02/2008; 26(4):400-5. DOI:10.1007/s00774-007-0835-z · 2.46 Impact Factor