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ABSTRACT: INTRODUCTION: Liver kinase 1 (LKB1) plays a critical barrier role in lung tumorigenesis by controlling initiation, differentiation and metastasis. We searched for genetic and epigenetic alterations of the LKB1 gene in Korean non-small cell lung cancers (NSCLCs) and correlated the results with clinicopathological features. We also investigated the relationship between genetic and epigenetic alterations of LKB1 and mutations in the TP53 gene and epidermal growth factor receptor (EGFR) pathway genes. METHODS: A total of 159 NSCLCs were analyzed for loss of heterozygosity (LOH) at microsatellite loci D19S886, and D19S878. Mutations and methylation status of LKB1 were examined by direct sequencing and a methylation-specific polymerase chain reaction, respectively. RESULTS: A somatic mutation was found in one of the 159 tumors. LOH and promoter methylation was detected in 19.5% (31/159) and 13.2% (21/159) of the tumors, respectively. Four of the 159 tumors had concomitant LOH and methylation of LKB1. In total, 30.2% of the 159 NSCLCs harbored LKB1 LOH or promoter methylation, which were correlated with down-regulation of gene expression. LKB1 LOH was more frequent in males, smokers, and tumors with a TP53 mutation than in females, never-smokers, and tumors without a TP53 mutation, respectively. However, no significant correlation between LKB1 alterations and mutations in EGFR pathway genes was found. CONCLUSION: These results suggest that the prevalence of LKB1 genetic and epigenetic alterations in NSCLCs vary depending on patient ethnicity. Our results show that LKB1 alterations often occur simultaneously with mutations in EGFR pathway genes.
Lung cancer (Amsterdam, Netherlands) 05/2013; · 3.14 Impact Factor
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ABSTRACT: Lung cancer is the leading cause of cancer-related deaths worldwide and is usually associated with a late diagnosis and a
poor prognosis. Thymosin β10 (TMSB10) is a monomeric actin sequestering protein that regulates actin cytoskeleton organization. The aberrant TMSB10 expression has been implicated in the pathogenesis of human cancers. However, its role in carcinogenesis is still controversial.
To better understand the role of TMSB10 in lung tumorigenesis and its regulatory mechanism, we examined the methylation status and expression of the TMSB10 gene in non-small cell lung cancers (NSCLCs) using methylation-specific PCR (MSP) and immunohistochemistry (IHC), respectively.
MSP analysis showed that the TMSB10 promoter was already unmethylated in most tumor tissues and became demethylated in 20 (14.4%) of the 139 NSCLCs. TMSB10 hypomethylation was not significantly correlated with the clinicopathological features. IHC showed that the TMSB10 protein
was strongly expressed in the cytoplasm of malignant cells and its overexpression was detected in 50.0% of the tumor tissues
compared to normal tissues. TMSB10 overexpression was frequently observed in sqaumous cell carcinomas compared to adenocarcinomas
with border line significance (P = 0.072). However, TMSB10 methylation status was not linked to its overexpression. Collectively, these results suggest that TMSB10 hypomethylation may be a frequent event in NSCLCs, but it may not be a common mechanism underlying TMSB10 overexpression. However, further studies with large numbers of patients are needed to confirm our findings.
Keywordshypomethylation–immunohistochemistry–methylation-specific PCR–non-small cell lung cancer–thymosin β10
Molecules and Cells 04/2012; 32(4):343-348. · 2.18 Impact Factor
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ABSTRACT: Renal mass reduction, such as unilateral nephrectomy induces a compensatory hypertrophy of remaining renal mass in response to overload induced by reduction of functional renal parenchyma. In our recent study, we observed that the recovery of ischemic injured kidney following transient unilateral renal ischemia took longer time than that following transient bilateral renal ischemia, indicating that non-damaged kidney may affect the damaged kidney and vice versa. Here, we investigated whether transient and partial renal parenchymal injury by transient unilateral renal ischemia (UI) results in the hypertrophy of its contralateral kidney (CLK) and reactive oxygen species is associated with the hypertrophy. Thirty minutes of UI resulted in gradual increase in CLK weight over time. UI increased superoxide formation, but not lipid peroxidation in the CLK. After UI, a significant increase in the number of NADPH oxidase 2 (Nox2)-expressing cells and the level of Nox2 expression in the CLK was observed. In parallel with the increases in Nox2-expressing cells in CLKs, infiltration of bone marrow-derived cells (BMDC) increased in CLK. Treatments with Mn(III) Tetrakis(1-methyl-4-pyridyl) porphyrin (MnTMPyP, a superoxide dismutase (SOD) mimetic) and apocynin (a putative NADPH oxidase inhibitor) inhibited UI-induced hypertrophy of CLK along with reduction in Nox2-positive cell, BMDC, amount of Nox2 expression and superoxide formation. In conclusion, transient and partial renal mass reduction by UI resulted in the hypertrophy of CLK through increased ROS formation by infiltrated cells into the interstitium of CLK.
Free radical research 04/2012; 46(7):903-11. · 2.22 Impact Factor
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ABSTRACT: Inhibitory and excitatory synaptic inputs onto trigeminal motoneurons play an important role in coordinating jaw movements. Previously, we reported that the phenotype of the inhibitory boutons apposing the somata of jaw-closing (JC) motoneurons changes from -aminobutyric acid (GABA)-positive (GABA+) to predominantly glycine-positive (Gly+) during development. In the present study, we investigated the development of inhibitory and excitatory boutons apposing antagonistic jaw-opening (JO) motoneurons (anterior digastric motoneurons) at postnatal day 2 (P2), P11, and P31 in the rat. JO motoneurons were retrogradely labeled with horseradish peroxidase. Postembedding immunogold staining with antisera against GABA, Gly, and glutamate (Glut) was performed and followed by quantitative ultrastructural analysis. The size of both small and large JO motoneurons increased during development. The number of excitatory (Glut+) and inhibitory (GABA+, Gly+, and GABA+/Gly+) boutons per JO motoneuron increased significantly from P2 to P11 and then remained unchanged until P31. The time course of inhibitory synapse formation differed between JO and JC motoneurons, whereas that of excitatory synapse formation was similar between the two neuronal populations. The fraction of GABA+ boutons decreased by 86% and the fraction of GABA+/Gly+ boutons increased by 200% from P11 to P31, suggesting a switch from GABA+ to GABA+/Gly+ phenotype. The fraction of Gly+ boutons remained unchanged. These results indicate that inhibitory synapses onto somata of JO motoneurons exhibit a developmental pattern distinct from that of synapses onto JC motoneurons, which may reflect distinctive maturation of oral motor system. J. Comp. Neurol. 520:1212–1226, 2012. © 2011 Wiley Periodicals, Inc.
The Journal of Comparative Neurology 02/2012; 520(6):1212 - 1226. · 3.81 Impact Factor
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ABSTRACT: Lung cancer is the leading cause of cancer-related deaths worldwide and is usually associated with a late diagnosis and a poor prognosis. Thymosin β(10) (TMSB10) is a monomeric actin sequestering protein that regulates actin cytoskeleton organization. The aberrant TMSB10 expression has been implicated in the pathogenesis of human cancers. However, its role in carcinogenesis is still controversial. To better understand the role of TMSB10 in lung tumorigenesis and its regulatory mechanism, we examined the methylation status and expression of the TMSB10 gene in non-small cell lung cancers (NSCLCs) using methylation-specific PCR (MSP) and immunohistochemistry (IHC), respectively. MSP analysis showed that the TMSB10 promoter was already unmethylated in most tumor tissues and became demethylated in 20 (14.4%) of the 139 NSCLCs. TMSB10 hypomethylation was not significantly correlated with the clinicopathological features. IHC showed that the TMSB10 protein was strongly expressed in the cytoplasm of malignant cells and its overexpression was detected in 50.0% of the tumor tissues compared to normal tissues. TMSB10 overexpression was frequently observed in sqaumous cell carcinomas compared to adenocarcinomas with border line significance (P = 0.072). However, TMSB10 methylation status was not linked to its overexpression. Collectively, these results suggest that TMSB10 hypomethylation may be a frequent event in NSCLCs, but it may not be a common mechanism underlying TMSB10 overexpression. However, further studies with large numbers of patients are needed to confirm our findings.
Molecules and Cells 10/2011; 32(4):343-8. · 2.18 Impact Factor
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ABSTRACT: Renal epithelial cells damaged by ischemia/reperfusion (I/R) can be restored by timely and appropriate treatment. Recent studies have reported that intra renal adult kidney stem cells contribute to the restoration of tubules damaged by I/R. Here, we determined the role of adult tubular cells in the restoration of damaged tubules. We labeled slow cell-cycle cells (SCCs) with 5-bromo-2'-deoxyuridine (BrdU) and investigated their location in the kidneys as well as their contribution to the restoration of tubular cells damaged by I/R injury in mice. Thirty minutes of bilateral ischemia resulted in severe disruption of tubular epithelial cells along with a decline in renal function. The post-ischemic disruption of tubular epithelial cells was most severe in the S3 segment of the outer stripe of the outer medulla. Damaged tubules demonstrated gradual recovery of renal function over time. BrdU-labeled SCCs were mainly observed in tubules located at the junction of cortex and outer medulla, as well as in the inner medulla. The tubular SCCs expressed functional tubule cell markers such as Na/K-ATPase, Na-K-Cl cotransporter-2, and aquaporin 1 and 2. BrdU-labeled SCCs survived I/R injury and proliferated. These results demonstrate that SCCs present in tubules contribute to the restoration of tubular epithelial cells injured by I/R.
Anatomy & cell biology 09/2011; 44(3):186-93.
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ABSTRACT: The growth arrest DNA-damage-inducible protein 45 (GADD45) can serve as a key coordinator of the stress response by regulating cell cycle progression, genomic stability, DNA repair, and other stress-related responses. Although deregulation of GADD45 expression has been reported in several types of human tumors, its role in lung cancer is still unknown. DNA hypermethylation of promoter CpG islands is known to be a major mechanism for epigenetic inactivation of tumor suppressor genes. We investigated the methylation status of GADD45 family genes (GADD45A, B, and G) in 139 patients with non-small cell lung cancer (NSCLC) using methylation-specific PCR (MSP) and correlated the results with clinicopathologic features of the patients. Methylation frequencies in tumors were 1.4% for GADD45A, 7.2% for GADD45B, and 31.6% for GADD45G. RT-PCR and MSP analysis showed that promoter methylation of the GADD45G gene resulted in downregulation of its mRNA expression. GADD45G methylation was significantly more frequent in female patients than male patients (P = 0.035). This finding suggests that methylation-associated down-regulation of the GADD45G gene may be involved in lung tumorigenesis.
Molecules and Cells 07/2010; 30(1):89-92. · 2.18 Impact Factor
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Dong-Sun Kim,
Min-Jin Kim,
Ji-Yun Lee,
Su-Man Lee,
Jun-Young Choi,
Ghil-Suk Yoon, Yeon-Kyung Na,
Hae-Sook Hong,
Sang-Geol Kim,
Jin-Eun Choi,
Shin-Yeop Lee,
Jae-Yong Park
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ABSTRACT: Promoter methylation is an important mechanism in gene silencing and is a key epigenetic event in cancer development. Homeobox A5 (HOXA5) is a master regulator of the morphogenesis and cell differentiation to be implicated as a tumor suppressor gene in breast cancer, but its role in lung cancer is still unknown. In this study, we have investigated the methylation status of the promoter region of the HOXA5 gene in nonsmall cell lung cancers (NSCLCs) using nested and standard methylation-specific PCR (MSP) and correlated the methylation status with clinicopathological features. With standard MSP analysis, HOXA5 methylation were found in 113 (81.3%) of 139 NSCLCs and 72 (51.8%) in their corresponding nonmalignant lung tissues. RT-PCR and immunohistochemical analysis showed that HOXA5 methylation correlates with gene expression. Moreover, in the patients with stage I disease, HOXA5 methylation was more frequent in smokers than in never-smokes (P = 0.01). There was no influence of HOXA5 methylation on survival in all NSCLCs or at stages II-IV. However, in the patients with stage I disease, HOXA5 methylation was associated with a borderline significantly worse survival (P = 0.09). These findings suggest that downregulation of the HOXA5 gene by aberrant promoter methylation occurs in the vast majority of NSCLCs and that it may play a role in the pathogenesis of NSCLC. Additional studies with larger sample sizes are required to evaluate the prognostic value of HOXA5 methylation in patients with stage I NSCLC.
Molecular Carcinogenesis 07/2009; 48(12):1109-15. · 3.16 Impact Factor
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ABSTRACT: The purpose of this study was to examine the effects of the ulmus root-bark dressing on tissue regeneration in experimentally-induced pressure ulcers in rats.
A randomized pretest/post-test control group time-series study design was used. Thirty-three male Sprague-Dawley rats were used in this study. The rats were anesthetized with 100 mg/kg of ketamine. Pressure ulcers were induced at 140 mmHg for three hours using a personally-designed pressing apparatus. For four weeks, the ulmus root-bark dressing was applied every other day in the experimental group (n=18) and a wet gauze dressing in the control group (n=15). For data analysis, the statistical program SPSS WIN 12 was used. The wounds were examined by light microscopy and electron microscopy.
There were significant statistical differences in the size of the pressure ulcers as time went by (p=0.006). It should be noted that there were no significant statistical differences in the number of capillaries. Using light microscopy the inflammatory infiltration and neovascularization in the dermis in the experimental group emerged densely in the early stages, but recovered rapidly at the latter stages. In addition, the reepithelization of the epidermis occurred earlier than in the control group. By electron microscopy, the cell organelles of the capillary endothelial cells and the basal lamina of capillaries in the experimental group showed a more rapid maturation during the latter stages, compared with the control group.
According to this study, it can be concluded that the ulmus root-bark dressing is effective regarding the healing of pressure ulcers.
Taehan Kanho Hakhoe chi 07/2006; 36(3):523-31.
