• Asian Pacific Journal of Cancer Prevention
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• 제17권4호
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• pp.2217-2221
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• 2016

Vascular endothelial growth factor 2 (VEGFR2) was initially identified as a receptor of VEGF on endothelial cells with a role in regulating angiogenesis during organism development and tumorigenesis. Previously, in cancer tissue, VEGFR2 has been reported to be expressed in endothelial cells. In our research, we found that VEGFR2 was expressed not only in endothelial cells but also cancer cells in head and neck squamous cell carcinomas (HNSCCs). Knockdown of VEGFR2 in Hep2 cells could arrest the cell cycle in G0/G1, leading to a decrease in proliferation. We also present evidence that MAPK/ERK signal pathways and expression of CDK1 downstream of VEGFR2 might regulate proliferation and cell cycle arrest. Furthermore, we discovered that down-regulate VEGRF2 in Hep2 cells could significantly affect the invasion ability. Taken together, our data suggest that VEGFR2 might regulate proliferation and invasion in HNSCC cancer cells in vivo.

• Asian Pacific Journal of Cancer Prevention
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• 제14권2호
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• pp.691-694
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• 2013

Purpose: By carrying out a meta-analysis of randomized controlled trials that compared sorafenib or combined chemotherapy with placebo or combined chemotherapy, the effectiveness of sorafenib in hepatocellular carcinoma was evaluated in the present study, which also provided clinical practice guidelines of evidence-based-medicine. Methods: We reviewed PubMed citations concerning sorafenib treating hepatocellular carcinoma in randomized controlled trials from Jan 2000 to July 2012. All the literature was extracted by Cochrane systematic reviews and underwent meta-analysis with RewMan 5.0 software. Results: Finally, four papers documenting randomized controlled studies were included. Compared with controls, sorafenib was shown to significantly increase overall survival (OS), time to progression (TTP), and disease control rates (DCR), but not the time to symptom progression (TTSP) in hepatocellular carcinoma patients. The incidence of grade-III/IV adverse reactions, including hand-foot-skin reactions, diarrhea, hypertension and skin rash or desquamation, in sorafenib treatment group was higher than that in controls. However, there was no significant difference in the incidence of hypodynamia between the two groups. Conclusions: Sorafenib exerts significant curative effects in hepatocellular carcinoma.

• Molecules and Cells
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• 제39권11호
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• pp.790-796
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• 2016

Dental pulp is a highly vascularized tissue requiring adequate blood supply for successful regeneration. In this study, we investigated the functional role of stem cells from human exfoliated deciduous teeth (SHEDs) as a perivascular source for in vivo formation of vessel-like structures. Primarily isolated SHEDs showed mesenchymal stem cell (MSC)-like characteristics including the expression of surface antigens and in vitro osteogenic and adipogenic differentiation potentials. Moreover, SHEDs were positive for NG2, ${\alpha}$-smooth muscle actin (SMA), platelet-derived growth factor receptor beta ($PDGFR{\beta}$), and CD146 as pericyte markers. To prove feasibility of SHEDs as perivascular source, SHEDs were transplanted into immunodeficient mouse using Matrigel with or without human umbilical vein endothelial cells (HUVECs). Transplantation of SHEDs alone or HUVECs alone resulted in no formation of vessel-like structures with enough red blood cells. However, when SHEDs and HUVECs were transplanted together, extensive vessel-like structures were formed. The presence of murine erythrocytes within lumens suggested the formation of anastomoses between newly formed vessel-like structures in Matrigel plug and the host circulatory system. To understand underlying mechanisms of in vivo angiogenesis, the expression of angiogenic cytokine and chemokine, their receptors, and MMPs was compared between SHEDs and HUVECs. SHEDs showed higher expression of1VEGF, SDF-$1{\alpha}$, and $PDGFR{\beta}$ than HUVECs. On the contrary, HUVECs showed higher expression of VEGF receptors, CXCR4, and PDGF-BB than SHEDs. This differential expression pattern suggested reciprocal interactions between SHEDs and HUVECs and their involvement during in vivo angiogenesis. In conclusion, SHEDs could be a feasible source of perivascular cells for in vivo angiogenesis.

• 생명과학회지
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• 제31권9호
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• pp.856-861
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• 2021

CD82/KAI1은 분자촉진제로서 암 전이억제자로 역할이 잘 알려져 있으나, 최근 줄기 전구 세포와 혈관 신생, 근육에서 다양한 역할들이 밝혀지고 있다. 이에 본 연구진은 최근에 보고된 CD82의 다양한 기능과 역할에 관하여 총설 하고자 한다. CD82는 4개의 막 통과 도메인을 가진 테트라스파닌의 한 종류로 암의 전이 과정에 관여하는 세포접착분자들과의 상호작용을 통하여 암세포의 이동 능력을 저해한다. 암 전이 억제자로의 기능 외에도 줄기세포 니쉬에서도 그 역할이 밝혀졌다. 골수에서 분화재생능력이 뛰어난 최상위 조혈모세포(LT-HSC)에서 CD82가 발현되며, DARC와의 상호결합으로 줄기세포의 휴면을 유도한다. 줄기세포의 휴면 조절 외에도, CD82는 Rac1 활성 조절을 통해 조혈모세포의 골수로의 귀환 및 생착에도 역할을 한다. 또한, CD82는 근육 줄기 세포의 분화능을 유지시키며, 혈관 내피세포에서 세포 접착 분자와 IL-6, VEGF와 같은 사이토카인의 발현을 저해하여 혈관 신생을 억제한다. CD82는 다양한 조직 및 줄기-전구 세포에서 계급을 구별할 수 있는 핵심 세포막 표면 단백질이며, 세포 자원의 증폭 및 검증에 있어 중요하다. 다양한 기관과 세포에서 CD82의 역할과 추가적인 연구들이 줄기세포치료의 임상적 적용에 있어 큰 도움이 되기를 기대한다.

• 대한화장품학회지
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• 제48권2호
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• pp.169-180
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• 2022

Streptococcus sp.는 일반적으로 히알루론산을 생산하는 균주로 알려져 있다. 본 연구에서는 Streptococcus 균주가 배양하면서 만들어내는 여러 대사산물 중 히알루론산 이외의 영양성분에 주목하였다. 히알루론산이 생성되지 않은 조건에서의 Streptococcus sp. 배양 여과물로 모발 실험용 샘플(HAIRCLE^TM)을 제조하고 모발에 미치는 효과를 확인하였다. 모발의 인장강도는 만능시험기(universal testing machine, UTM)로 측정하였으며, 모발표면의 미세구조는 atomic force microscope (AFM)으로 분석하였다. 이 연구를 통해 Streptococcus sp. 배양 여과물은 손상된 모표피개선, 마찰력증가 및 모발강도의 증가 등의 모발개선 효과가 있는 것으로 확인되었다. 또한 in vitro 모발관련 실험을 통해 Streptococcus sp. 배양 여과물이 모발성장인자인 혈관내피세포 성장인자(vascular endothelial growth factor, VEGF), 간세포성장인자(hepatocyte growth factor, HGF), Wnt10b의 발현 촉진 효과가 있음을 확인 하였으며, 안드로젠 수용체(androgen receptor, AR)와 TGF-β2 발현을 저해시켜 남성형 탈모완화 효과도 있음을 확인 하였다. 또한 산화스트레스에 대해 장벽 관련 인자(INV, CLDN-1)의 발현을 증가시키고, 염증성 인자인 COX-2 발현을 억제시킴으로써 손상된 두피 장벽을 개선하고 유도된 염증을 완화시키는 효능이 있음을 확인하였다.

• 한국환경독성학회:학술대회논문집
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• 한국환경독성학회 2003년도 춘계학술대회
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• pp.107-107
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• 2003

The heavy metal cadmium is a xenobiotic toxicant of environmental and occupational concern and it has been classified as a human carcinogen. Inhalation of cadmium has been implicated in the development of emphysema and pulmonary fibrosis, but, the detailed mechanism by which cadmium induces adverse biological effects is not yet known. Therefore, we undertook the investigation of genes that are induced after cadmium exposure to illustrate the mechanism of cadmium toxicity For this purpose, we employed the polymerase chain reaction-based suppression subtractive hybridization technique. We identified 29 different cadmium-inducible genes in human peripheral mononuclear cells, such as macrophage migration inhibitory factor, lysophosphatidic acid acyltransferase-${\alpha}$, enolase-1${\alpha}$, VEGF, Bax, neuron-derived orphan receptor-1, and Nur77, which are known to be associated with inflammation, cell survival, and apoptosis. Induction of these genes by cadmium treatment was further confirmed by semi-quantitative reverse-transcription polymerase chain reaction. Further, we found that these genes were also induced after cadmium exposure in normal human lung fibroblast cell line, WI-38, suggesting potential use of this induction profile to monitor cadmium toxicity in the lung. Next, Nur77, one of cadmium-inducible genes, was further studied since the products of Nur77 are known to be involved in the apoptotic process of lung cells. Following cadmium treatment, Nur77 gene expression was increased at protein-level in A549 cells. Consistently, the reporter containing Nur77 binding sequence was activated by 2.5-fold after exposure to cadmium in reporter gene analysis by transient transfection experiments. When the plasmid encoding dominant negative Nur77 that represses the transcriptional function of wild-type Nur77 was transfected into A549 cells, the expression of Bax was significantly reduced, suggesting that induction of Nur77 was an important process in cadmium-induced apoptosis in the cells. Cadmium induced the expression of Nur77 in vivo, confirming the relevance of the data obtained in viro. Together our results suggest that Nur77 gene expression in exposure to cadmium leads apoptosis of lung cells which may cause pathological changes in lung.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 2001년도 추계학술대회 및 정기총회
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• pp.100-100
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• 2001

Hypoxia is a pathophysiological condition that occurs during injury, ischemia, and stroke. Hypoxic stress induces the expression of genes associated with increased energy flux, including the glucose transporters Glutl and Glut3, several glycolytic enzymes, nitric oxide synthase, erythropoietin and vascular endothelial growth factor. Induction of these genes is mediated by a common basic helix-loop-helix PAS transcription complex, the hypoxia-inducible factor-l${\alpha}$ (HIF-1${\alpha}$)/ aryl hydrocarbon receptor nuclear translocator (ARNT). Insulin plays a central role in regulating metabolic pathways associated with energy storage and utilization. It triggers the conversion of glucose into glycogen and triglycerides and inhibits gluconeogenesis. Insulin also induced hypoxia-induced genes. However the underlying mechanism is unestablished. Here, we study the possibility that transcription factor HIF-1${\alpha}$ is involved in insulin-induced gene expression. We investigate the mechanism that regulates hypoxia-inducible gene expression In response to insulin We demonstrate that insulin increases the transcription of hypoxia- inducible gene. Insulin-induced transcription is not detected in Arnt defective cell lines. Under hypoxic condition, HIF- l${\alpha}$ stabilizes but does not under insulin treatment. Insulin-induced gene expression is inhibited by presence of PI-3 kinase inhibitor and Akt dominant negative mutant, whereas hypoxia-induced gene expression is not. ROS inhibitor differently affects insulin-induced gene expressions and hypoxia-induced gene expressions. Our results demonstrate that insulin also regulates hypoxia-inducible gene expression and this process is dependent on Arnt. However we suggest HIF-l${\alpha}$ is not involved insulin-induced gene expression and insulin- and hypoxia- induces same target genes via different signaling pathway.

• Biomolecules & Therapeutics
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• 제29권5호
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• pp.506-518
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• 2021

The imprinted tumour suppressor NOEY2 is downregulated in various cancer types, including ovarian cancers. Recent data suggest that NOEY2 plays an essential role in regulating the cell cycle, angiogenesis and autophagy in tumorigenesis. However, its detailed molecular function and mechanisms in ovarian tumours remain unclear. In this report, we initially demonstrated the inhibitory effect of NOEY2 on tumour growth by utilising a xenograft tumour model. NOEY2 attenuated the cell growth approximately fourfold and significantly reduced tumour vascularity. NOEY2 inhibited the phosphorylation of the signalling components downstream of phosphatidylinositol-3'-kinase (PI3K), including phosphoinositide-dependent protein kinase 1 (PDK-1), tuberous sclerosis complex 2 (TSC-2) and p70 ribosomal protein S6 kinase (p70S6K), during ovarian tumour progression via direct binding to vascular endothelial growth factor receptor-2 (VEGFR-2). Particularly, the N-terminal domain of NOEY2 (NOEY2-N) had a potent anti-angiogenic activity and dramatically downregulated VEGF and hypoxia-inducible factor-1α (HIF-1α), key regulators of angiogenesis. Since no X-ray or nuclear magnetic resonance structures is available for NOEY2, we constructed the three-dimensional structure of this protein via molecular modelling methods, such as homology modelling and molecular dynamic simulations. Thereby, Lys15 and Arg16 appeared as key residues in the N-terminal domain. We also found that NOEY2-N acts as a potent inhibitor of tumorigenesis and angiogenesis. These findings provide convincing evidence that NOEY2-N regulates endothelial cell function and angiogenesis by interrupting the VEGFR-2/PDK-1/GSK-3β signal transduction and thus strongly suggest that NOEY2-N might serve as a novel anti-tumour and anti-angiogenic agent against many diseases, including ovarian cancer.

• Nuclear Medicine and Molecular Imaging
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• 제42권4호
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• pp.307-313
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• 2008

목적: 혈관내피성장인자(VEGF)와 그 수용체는 종양의 성장과 전이에 매우 중요한 역할을 한다 3개의 수용체가 알려져 있는데 그 중에서도 VEGFR2 (Flk-1/KDR)가 종양 angiogenesis에 매우 밀접하게 관련한 것으로 알려져 있다. 본 연구에서는 마우스 Flk-1 항체로 알려진 DC101에 I-131을 표지하여 매우 공격적인 종양으로 알려진 흑색 종의 치료 정도를 확인해 보고자 하였다. 방법: 하이브리도마 세포에서 Flk-1 항체인 DC101을 분리하여 western blot, ELISA, maldi-tof 방법을 이용하여 순도를 확인하고 항체 에 chloramin T를 이용하여 I-131을 표지하였다. 누드마우스에 B16F10세포를 주사하여 흑색종 모델을 만들고 평균 $200-250\;mm^3$으로 키워 $^{131}I$-DC101을 주사하여 영상과 시간별 장기섭취율(%ID/g)을 비교하고, 종양내 Flk-1 발현을 확인하기 위하여 면역염색 등을 시행하였다. 흑색종 동물모델을 5개 군으로 나누어 각각 치료를 시행하였다. 1군은 PBS만을, 2군은 $^{131}I$-DC101 $50\;{\mu}g(200\;{\mu}Ci)$을, 3군은 DC101 $50\;{\mu}g$을, 4군은 $^{131}I$-DC101 $30\;{\mu}g(200\;{\mu}Ci)$을, 5군은 $^{131}I$-DC101 $15\;{\mu}g(200\;{\mu}Ci)$을 각각 매 3일 ${\sim}$ 4일마다 주사하고 전체 5회를 주사하였고 종양볼륨을 측정하였다. 결과: $^{131}I$-DC101을 흑색종 모델에 정맥주사하고 78시간까지 영상을 얻은 결과 시간에 따라 종양섭취가 증가 하는 영상을 보였다. 시간대별 장기섭취를 정확히 확인하기 위하여 1시간, 6시간, 24시간, 48시간, 72시간 장기섭취율을 비교한 결과 시간에 따라 혈액내 방사능치가 서서히 감소하였고 다른 장기의 섭취도 시간에 따라 감소하였고 종양의 섭취는 48시간까지 증가하였다가 그 이후는 감소하였다. 흑색종 동물모델에 $^{131}I$-DC101 치료를 시행한 결과 3번째 주사까지는 각군간의 유의한 차이를 보이지 않다가 4번째 주사를 시행한 때부터 1군과 2군, 또는 1군과 4군간의 유의한 차이를 보이기 시작했다. 또한 5번째 주사 이후에는 5군에서도 유의한 차이를 보여 I-131 에 의한 효과가 뚜렷해짐을 확인하였다. 결론 마우스 Flk-1 항체로 알려진 DC101을 흑색종 모델에 정맥내 주사하였을 때, 종양성장억제 효과를 보이지 않는 항체양에서도 I-131을 표지하여 치료를 시행했을 경우에는 효율적인 종양성장억제 효과를 보였다.

• 대한임상검사과학회지
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• 제51권3호
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• pp.360-369
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• 2019

Cadherin은 원형질막에 존재하며 세포-세포 결합에 관여하며, 황체 구조 유지에 필수적인 단백질이다. 본 연구에서는 prostaglandin F2 alpha ($PGF2{\alpha}$)가 황체의 협막세포(luteal theca cells, LTCs)의 E-cadherin, N-cadherin 및 세포-세포부착에 미치는 영향에 대해서 수행하였다. 황체세포는 소의 황체중기 조직으로부터 분리하였으며, 황체세포 중에서 mesenchymal 세포 형태학적 특성을 가지는 세포만을 분리하여 LTCs로 판단하였다. 이 후 steroidogenic 기능 및 혈관세포 유무를 판단하기 위해 $3{\beta}$-HSD 및 VEGF2R mRNA 발현을 확인하였으며, E-cadherin 및 N-cadherin mRNA를 사용하여 LTCs 내 cadherin의 존재여부를 판단하였다. 또한 0, $10^{-5}$, $10^{-4}$ 및 $10^{-3}M$ $PGF2{\alpha}$를 24시간 동안 처리하여 LTCs의 E- 및 N-cadherin 단백질을 관찰한 후 세포-세포 접착 실험을 실시하였다. 그 결과, LTCs에서 $3{\beta}$-HSD mRNA가 발현되었지만, VEGFR2 mRNA는 발현되지 않았으며, E-cadherin 및 N-cadherin mRNA 모두 발현되는 것을 확인하였다. 또한 E-및 N-cadherin 단백질은 $10^{-5}$, $10^{-4}$ 및 $10^{-3}M$ $PGF2{\alpha}$를 처리한 LTCs에서 응집되어 발현되는 것을 확인하였으며, $PGF2{\alpha}$에 의해 LTCs의 세포부착 효율이 유의적으로 감소된 것을 확인하였다. 결론적으로 $PGF2{\alpha}$는 LTCs의 E- 및 N-cadherin을 붕괴시켜 세포부착을 감소시켰고, 이러한 결과는 황체퇴행의 새로운 원인을 밝혀 내기 위한 cadherin과 세포부착의 역할을 이해하는데 중요한 자료로 활용될 것으로 판단된다.