• Molecules and Cells
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• v.38 no.6
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• pp.528-534
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• 2015

Hypoxia-inducible factor (HIF) is a key regulator of tumor growth and angiogenesis. Recent studies have shown that, BIX01294, a G9a histone methyltransferase (HMT)-specific inhibitor, induces apoptosis and inhibits the proliferation, migration, and invasion of cancer cells. However, not many studies have investigated whether inhibition of G9a HMT can modulate HIF-$1{\alpha}$ stability and angiogenesis. Here, we show that BIX01294 dose-dependently decreases levels of HIF-$1{\alpha}$ in HepG2 human hepatocellular carcinoma cells. The half-life of HIF-$1{\alpha}$, expression of proline hydroxylase 2 (PHD2), hydroxylated HIF-$1{\alpha}$ and von Hippel-Lindau protein (pVHL) under hypoxic conditions were decreased by BIX01294. The mRNA expression and secretion of vascular endothelial growth factor (VEGF) were also significantly reduced by BIX01294 under hypoxic conditions in HepG2 cells. BIX01294 remarkably decreased angiogenic activity induced by VEGF in vitro, ex vivo, and in vivo, as demonstrated by assays using human umbilical vein endothelial cells (HUVECs), mouse aortic rings, and chick chorioallantoic membranes (CAMs), respectively. Furthermore, BIX01294 suppressed VEGF-induced matrix metalloproteinase 2 (MMP2) activity and inhibited VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR-2), focal adhesion kinase (FAK), and paxillin in HUVECs. In addition, BIX01294 inhibited VEGF-induced formation of actin cytoskeletal stress fibers. In conclusion, we demonstrated that BIX01294 inhibits HIF-$1{\alpha}$ stability and VEGF-induced angiogenesis through the VEGFR-2 signaling pathway and actin cytoskeletal remodeling, indicating a promising approach for developing novel therapeutics to stop tumor progression.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.30 no.1
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• pp.41-51
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• 2008

Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumor which compromises about 6$\sim$8% of all tumors followed by the adenoid cystic carcinoma (ACC) and adenocarcinoma. Most deaths from salivary carcinomas are caused by recurrent or metastatic lesions that are resistant to conventional therapy. Therefore, knowledge of cellular properties and tumor-host interactions that influence the vascular metastasis is important for the design of more effective therapy of salivary carcinomas. Neoangiogenesis is essential for tumor growth, which is postulated to be fundamentally dependent on the induction of stromal neovascularization. However, how neovascularization takes place in live tissue has not been fully established, especially in recruitment and differentiation of endothelial cells in the salivary gland tumors. Vascular endothelial growth factor (VEGF) is a heparin-binding, dimeric polypeptide growth factor known to exert its mitogenic activity specifically on endothelial cells. VEGF has been shown th be directly involved in angiogenesis, which in essential for the pathogenesis of many solid tumors. von Willebrand factor (vWF) is a large multimeric protein synthesized by megakaryocytes and endothelial cells that enable platelets to adhere to exposed subendothelium and, as well, to respond to changes in the blood flow. Recent studies suggest that increased levels of vWF correlate with progression of disease, metastasis, or survival time and thus may have a prognostic significance. vWF is explained as an acute phase proteins which is increased in cancer or as a result of increased endothelial cell synthesis associated with tumor-induced angiogenesis. Due to adhesive properties of vWF, its increased concentrations may also contribute metastasis of tumor. In this study, we determined the mRNA expression of VEGF and vWF in salivary ACC, MEC and pleomorphic adenoma by in situ hybridization. As a result, stronger expression of VEGF and vWF was seen in salivary ACC and MEC which has more invasive nature than the salivary benign tumor.

• Journal of Life Science
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• v.27 no.1
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• pp.78-88
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• 2017

Angiogenesis, the formation of new blood vessels, plays an important role in tumor growth and metastasis; therefore, it has become an important target in cancer therapy. Novel anticancer pharmaceutical products that have relatively few side effects or are non-cytotoxic must be developed, and such products may be obtained from traditional herbal medicines. Coptis chinensis Franch. is an herb used in traditional medicine for the treatment of inflammatory diseases and diabetes. However, potential antiangiogenic effects of C. chinensis water extract (CCFWE) have not yet been studied. The purpose of this study was to determine the antiangiogenic effect of CCFWE in order to evaluate its potential for an anticancer drug. We found that the treatment with CCFWE inhibited the major steps of the angiogenesis process, such as the endothelial cell proliferation, migration, invasion, and capillary-like tube formation in response to vascular endothelial growth factor (VEGF), and also resulted in the growth inhibition of new blood vessels in an ex vivo rat aortic ring assay. We also observed that CCFWE treatment arrested the cell cycle at the G0/G1 phase, preventing the G0/G1 to S phase cell cycle progression in response to VEGF. In addition, the treatment reduced the VEGF-induced activation of matrix metalloproteinases 2 and 9. Taken together, these findings indicate that CCFWE should be considered a potential anticancer therapy against pathological conditions where angiogenesis is stimulated during tumor development.

• Journal of Chest Surgery
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• v.35 no.8
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• pp.611-615
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• 2002

Pneumoconiosis is fibrogenic disease, caused by inhalation of mineral dust. It is defined as the accumulation of dust in the lung and tissue reaction to its presence and the dust is considered to be an aerosal of solid and inanimate particles. It is among the most common and the most important occupational lung disease, especially in developing countries. It is required three prerequisites for making a clinical diagnosis of pneumoconiosis: 1) a full clinical and occupational history together with the result of physical examination; 2) previous X-ray for comparison; and 3) a clear understanding of the time scale involved in the progression of the diseases. Most pneumoconiosises are slow to evolve and changes in the appearances take many months -usually years- to occur. Pneumoconiosis is represented on a plain X-ray of the chest as multiple small round opacities, usually smaller than 1cm diameter. In 58 years old female patient, pneumoconiosis is manifested as $5{\times}4{\times}3$cm sized solitary pulmonary nodule without any occupational history and past history of exposure of dust. so we treated this case with right upper lobectomy. Therefore we report this case with a brief review of literatures.

• Journal of Life Science
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• v.17 no.9 s.89
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• pp.1298-1302
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• 2007

A hallmark of cancers is 'leaky' tight junctions (Tjs). TJs mediated paracellular permeability is elevated and TJs maintained cell polarity is frequently lost. Concomitantly, TJs-associated proteins including members of the claudin family of proteins are dysregulated. Recent findings indicate that these TJs changes can contribute to cancer progression. In this study, we examined the effects of ${\beta}-lapachone$, a quinone compound obtained from the bark of the lapacho tree (Tabebuia avellanedae), on the Tjs-associated regulators in human hepatocarcinoma cell lines, HepG2 and Hep3B. ${\beta}-lapachone$ treatment downregulated the levels of insulin-like growth factor 1 receptor (IGF-lR) proteins in both HepG2 and Hep3B cells. But the levels of claudin-3 and -4 proteins were increased in ${\beta}-lapachone$-treated HepG2 and Hep3B cells. And also the zonnula occludens-l (la-I) and p-catenin protein levels by ${\beta}-lapachone$ were increased in a time-dependent manner. However, claudin-3 and -4 mRNA levels were uninhibited by ${\beta}-lapachone$ in HepG2 and Hep3B. The present results suggest that the upregulation of claudin-3 and -4 protein levels by ${\beta}-lapachone$ occurs by a post-transcriptional mechanism and points to a novel mechanism by ${\beta}-lapachone$.

• Environmental Mutagens and Carcinogens
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• v.26 no.3
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• pp.77-85
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• 2006

2,3,7,8-Tetrachlorodibenzo-$\rho$-dioxin(TCDD) displays high toxicity in animals and has been implicated in human carcinogenesis. Although TCDD is recognized as potent carcinogens, relatively little is known about their role in the tumor promotion and carcinogenesis. It is known that TCDD can increase of cancer risk from various types of tissue by a mechanism possibly involving the aryl hydrocarbon receptor (AhR) activation. In this study, effects of TCDD on cellular proliferation of normal human skin and lung fibroblasts, Detroit551 and WI38 cells were investigated. In addition, to enhance our understanding of TCDD-mediated carcinogenesis, we have investigated process in which expression of Erk1/2, cyclinD1, oncogene such as Ha-ras and c-myc, and their cognate signaling pathway. TCDD that are potent activators of AhR-mediated activity was found to induce significant increase of cytochrome P4501A1 mRNA expression, suggesting a presence of functional AhR. These results support that CYP1A1 enzyme may be involved in the generation of TCDD-induced toxicity. Moreover mitogen-activated protein kinases (MARKs) phosphorylation and cyclin D1 overexpression are induced by TCDD, which corresponded with the progression of cellular proliferation. However, TCDD did not affected Ha-ras and c-myc mRNA expression. Taken together, it seems that TCDD are could be a part of cellular proliferation in non-tumorigenic normal human cells such as Detroit551 and WI38 cells through the upregulation of MAPKs signaling pathway regulating growth of cell population. Therefore, AhR-activating TCDD could potentially contribute to tumor promotion and Detroit551 and WI38 cells have been used as a detection system of tumorigenic effects of TCDD.

• Korean Journal of Head & Neck Oncology
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• v.29 no.1
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• pp.1-10
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• 2013

연구배경 및 목적 표피성장인자수용체(EGFR)는 HER2/neu(erbB2), HER3(erbB3), HER4(erbB4)를 포함하는 receptor tyrosine ki-nase의 erbB 그룹에 속하는 수용체이다. 표피성장인자수용체의 과발현은 다양한 종류의 암, 특히 두경부편평세포암에서 예후를 악화시킨다고 알려져 있다. 이에 저자들은 하인두편평세포암에서 표피성장인자수용체의 발현 및 분포를 확인하고, 하인두암에서 표피성장인자(EGF)가 암세포의 증식과 침습에 미치는 영향에 대해 알아보고자 하였다. 대상 및 방법 57명의 하인두편평세포암 환자의 조직에서 표피성장인자수용체의 발현을 면역화학적염색을 통해 확인하고, 이에 대해 임상병리학적 요인과 생존율에 대한 분석을 시행하고, 일부 환자의 정상 및 암조직에서 Western blot을 시행하였다. 하인두편평세포암 세포주인 FaDu에서 proliferative assay, colony dispersion, wound healing assay, invasion assay를 시행하여, 하인두암의 진행에서 표피성장인자의 역할에 대하여 분석하였다. 또한 RT-PCR과 Zymography를 통하여 Matrix metalloproteinase(MMP)-2, 9의 발현을 확인하였다. 결 과 63.2%의 하인두편평세포암 조직에서 표피성장인자수용체의 발현이 확인되었다. 표피성장인자수용체의 발현은 정상조직에서 비하여 하인두암 조직에서 유의하게 증가되어 있었으며, 병리학적 병기(p=0.022)가 올라갈수록 유의하게 증가하였으나, 증례수의 제한으로 생존율에서는 통계적 유의성을 얻지는 못했다(p=0.053). in vitro의 결과로 표피성장인자를 FaDu 세포주에 처리하였을 때, FaDu 세포주의 증식이 유의하게 증가되었으며(p<0.05), Transwell invasion chamber상 침습의 증가가 확인되었다(p<0.05). RT-PCR과 zymogram 실험상 표피성장인자처리시 FaDu 세포주의 MMP-2, 9이 발현이 증가되고 활성화되는 것이 확인하였다. 결 론 본 연구에서 표피성장인자수용체의 과발현이 하인두암의 예후 인자로서의 가능성을 확인하였고, 표피성장인자가 하인두편평세포암의 증식과 침습에 관여하는 것을 확인하였다.

• Radiation Oncology Journal
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• v.32 no.1
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• pp.14-22
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• 2014

Purpose: To evaluate the safety and efficacy of transcatheter arterial chemoembolization (TACE) followed by radiotherapy (RT) in treatment-na$\ddot{i}$ve patients with locally advanced hepatocellular carcinoma (HCC). Materials and Methods: Eligibility criteria were as follows: newly diagnosed with HCC, the Barcelona Clinic Liver Cancer stage C, Child-Pugh class A or B, and no prior treatment for HCC. Patients with extrahepatic spread were excluded. A total of 59 patients were retrospectively enrolled. All patients were treated with TACE followed by RT. The time interval between TACE and RT was 2 weeks as per protocol. A median RT dose was 47.25 $Gy_{10}$ as the biologically effective dose using the ${\alpha}/{\beta}$ = 10 (range, 39 to 65.25 $Gy_{10}$). Results: At 1 month, complete response was obtained in 3 patients (5%), partial response in 27 patients (46%), stable disease in 13 patients (22%), and progressive disease in 16 patients (27%). The actuarial one- and two-year OS rates were 60.1% and 47.2%, respectively. The median OS was 17 months (95% confidence interval, 5.6 to 28.4 months). The median time to progression was 4 months (range, 1 to 35 months). Grade 3 or greater liver enzyme elevation occurred in only two patients (3%) after RT. Grade 3 gastroduodenal toxicity developed in two patients (3%). Conclusion: The combination treatment of TACE followed by RT with two-week interval was safe and it showed favorable outcomes in treatment-na$\ddot{i}$ve patients with locally advanced HCC. A prospective randomized trial is needed to validate these results.

• Journal of Life Science
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• v.13 no.5
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• pp.642-650
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• 2003

To develop a new approach to the treatment of neuroblastoma cells we evaluated the effect of cAMP on the Ewing's sarcoma cell line CHP-100. We observed that the proliferation-inhibitory effect of cAMP analogs was due to cell cycle arrest and induction of apoptosis, which was confirmed by observing the morphological changes and DNA fragmentation. DNA flow cytometric analysis revealed that cAMP arrested the cell cycle progression at the G1 phase, which effects were associated with inhibition of phosphorylation of retinoblastoma protein (pRB) and enhanced binding of pRB and the transcription factor E2F-1. cAMP also suppressed the cyclin-dependent kinase (Cdk) 2 and cyclin E-associated kinase activity without changes of their expressions. Furthermore, cAMP induced the levels of Cdk inhibitor $p21^{WAF1/CIP1$ expression and p21 proteins induced by cAMP were associated with Cdk2. Overall, our results identify a combined mechanism involving the inhibition of pRB phosphorylation and induction of p21 as targets for cAMP, and this may explain some of its anti-cancer effects.

• Journal of Life Science
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• v.14 no.5
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• pp.874-881
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• 2004

Angiogenesis has been implicated in progression of inflammation, arthritis, psoriasis, atherosclerosis as well as tumor growth and metastasis. Intensive studies have been carried out to develop a strategy for cancer treatment by blocking angiogenesis. During angiogenesis, endothelial proliferation and migration essentially occurs upon activation. In this study, we compared the expression profiles of human umbilical endothelial cells activated by incubating in vitro in the rich medium containing several growth factors, and non-activated ones. cDNA targets derived from total RNAs of HUVEC activated for 13 h in M199 medium containing endothelial cell growth supplement, 20% fetal bovine serum, and heparin, after reaching 70～80% confluency, or non-activated, were hybridized onto oligonucleotide microarrays containing 1,8864 genetic elements. Unsupervised hierarchical clustering analysis resulted in two subgroups on dendrogram exhibiting activated and non-activated HUVECs. We then extracted 122 outlier genes which were shown to be up-regulated or under-expressed by at least 2-folds in activated HUVECs. Among these, 32 annotated genes were up-regulated and 38 were down-regulated in activated HUVECs. Interestingly, genes involved in cell proliferation, motility, and inflammation/ immune response were up-regulated in activated HUVEC, whereas genes for cell adhesion or vessel morphogenesis/function were down-regulated. Unexpectedly, the expression of genes well-characterized as angiogenesis markers was not changed except Eph-B4, which was down-regulated about 4 folds. 52 unknown genes were also up- or down-regulated. Therefore, these results could provide an opportunity to targeting new vascular molecules for the development of anti-angiogenic molecules.