• Asian Pacific Journal of Cancer Prevention
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• 제15권16호
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• pp.6911-6917
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• 2014

Background: Hepatocellular carcinoma is a complex and heterogeneous tumor with poor prognosis due to frequent intrahepatic spread and extrahepatic metastasis. The molecular mechanisms underlying HCC pathogenesis still remain obscure. Objectives: We aimed to investigate the abundance and the DNA binding activity of nuclear factor kappa B/p65 subunit in peripheral blood mononuclear cells from patients with HCC and to assess its prognostic significance and association with hypoxia inducible factor one alpha (HIF-$1{\alpha}$) in blood. Subjects and methods: This study was carried out on 40 patients classified equally into liver cirrhosis (group I) and HCC (group II), in addition to 20 healthy volunteers (group III). All groups were subjected to measurement of NF-${\kappa}B$/P65 subunit expression levels by real time-PCR, and DNA binding activity was evaluated by transcription factor binding immunoassay. Serum HIF-$1{\alpha}$ levels were estimated by enzyme-linked immunosorbent assay (ELISA). Significant increase of both the expression level and DNA binding activity of NF-${\kappa}B$/P65 subunit together with serum HIF-1 alpha levels was noted in HCC patients compared to liver cirrhosis and control subjects, with significant positive correlation with parameters for bad prognosis of HCC. In conclusion, NF-${\kappa}B$ signaling is activated in HCC and associated with disease prognosis and with high circulating levels of HIF-1 alpha.

• Asian Pacific Journal of Cancer Prevention
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• 제15권11호
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• pp.4637-4642
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• 2014

Background: Hypoxia-inducible factor $1{\alpha}$ (HIF-$1{\alpha}$) plays an important role in regulating cell survival and angiogenesis, which are critical for tumor growth and metastasis. Genetic variations of HIF1A have been shown to influence the susceptibility to many kinds of human tumors. Increased expression of HIF-$1{\alpha}$ has also been demonstrated to be involved in tumor progression. However, the prognostic value of single nucleotide polymorphisms (SNPs) inthe HIF1A gene remains to be determined in most cancer types, including colorectal cancer (CRC). In this study, we sought to investigate the predictive role of HIF1A SNPs in prognosis of CRC patients and efficacy of chemotherapy. Materials and Methods: We genotyped two functional SNPs in HIF1A gene using the Sequenom iPLEX genotyping system and then assessed their associations with clinicopathological parameters and clinical outcomes of 697 CRC patients receiving radical surgery using Cox logistic regression model and Kaplan Meier curves. Results: Generally, no significant association was found between these 2 SNPs and clinical outcomes of CRC. In stratified analysis of subgroup without adjuvant chemotherapy, patients carrying CT/TT genotypes of rs2057482 exhibited a borderline significant association with better overall survival when compared with those carrying CC genotype [Hazard ratio (HR), 0.47; 95% confidence interval (95% CI): 0.29-0.76; P < 0.01]. Moreover, significant protective effects on CRC outcomes conferred by adjuvant chemotherapy were exclusively observed in patients carrying CC genotype of rs2057482 and in those carrying AC/CC genotype of rs2301113. Conclusions: Genetic variations in HIF1A gene may modulate the efficacy of adjuvant chemotherapy after surgery in CRC patients.

• Fisheries and Aquatic Sciences
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• 제17권3호
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• pp.305-311
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• 2014

Dieckol is a polyphenol compound isolated from brown algae that has anti-oxidant, anti-inflammatory, and anti-tumor activity. We examined the anti-angiogenic effects of dieckol in endothelial cells under hypoxic conditions. Treatment with $CoCl_2$, a hypoxic mimetic agent, increased proliferation, adhesion, migration, and tube formation in HUVECs, as well as vessel sprouting in rat aortic rings, which correlated well with increased expression of hypoxia-inducible factor 1-alpha ($HIF1{\alpha}$) and ${\beta}1$-integrin. Dieckol suppressed $CoCl_2$-induced adhesion, migration, and tube formation in HUVECs and vessel sprouting in rat aortic rings. Dieckol treatment decreased $CoCl_2$-induced overexpression of $HIF1{\alpha}$ and its downstream signaling molecules, including ${\beta}1$-integrin/Fak, Akt/eNOS, and p38 MAPK. These results suggest that dieckol is a novel angiogenesis inhibitor and a potential treatment for angiogenesis-dependent diseases in humans, such as malignant tumors.

• Molecules and Cells
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• 제22권3호
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• pp.291-299
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• 2006

Vitexin, a natural flavonoid compound identified as apigenin-8-C-${\beta}$-D-glucopyranoside, has been reported to exhibit antioxidative and anti-inflammatory properties. In this study, we investigated its effect on hypoxiainducible factor-$1{\alpha}$ (HIF-$1{\alpha}$) in rat pheochromacytoma (PC12), human osteosarcoma (HOS) and human hepatoma (HepG2) cells. Vitexin inhibited HIF-$1{\alpha}$ in PC12 cells, but not in HOS or HepG2 cells. In addition, it diminished the mRNA levels of hypoxia-inducible genes such as vascular endothelial growth factor (VEGF), smad3, aldolase A, enolase 1, and collagen type III in the PC12 cells. We found that vitexin inhibited the migration of PC12 cells as well as their invasion rates, and it also inhibited tube formation by human umbilical vein endothelium cells (HUVECs). Interestingly, vitexin inhibited the hypoxia-induced activation of c-jun N-terminal kinase (JNK), but not of extracellular-signal regulated protein kinase (ERK), implying that it acts in part via the JNK pathway. Overall, these results suggest the potential use of vitexin as a treatment for diseases such as cancer.

• 한방안이비인후피부과학회지
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• 제19권3호통권31호
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• pp.1-12
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• 2006

Objective : Angiogenesis is an essential process for metastasis of solid tumors and Psoriasis. Lots of Researches for anti-angiogenic effect to angiogenic factors have been carried out in the world. So this experiment was carried out for whether Lacca Sinica Exsiccata(LSE) extracts have an anti-angiogenic effect for angiogenic factors. Methods: To investigate the roles of the LSE extracts, we performed MIS assay, western blots using HaCaT cells and HepG2 cells. And then, HaCaT cells were treated with 10, 50, 100, 250, $500{\mu}g/ml$ LSE extracts. After 4hrs, HaCaT cells were theated with IGF-II protein for 1hr. HepG2 cells were treated with 1, 10, 25, 50, 100, 200 ${\mu}g/ml$ LSE extracts. After 4hrs, HepG2 cells were theated with $CoCl_2$ for 24hrs Results: 1. In $50{\mu}g/ml$ and $100{\mu}g/ml$ density we confirmed the inhibition effect of LSE extracts to $HIF-1{\alpha}$ activation which was induced by IGF-II in HaCaT cells. 2. In $50{\mu}g/ml$ density we confirmed the inhibition effect of LSE extracts to $HIF-1{\alpha}$ activation which was induced by $CoCl_2$ in HepG2 cells. 3. In $25{\mu}g/ml$ density we confirmed the inhibition effect of LSE extracts to VEGF activation which was induced by $CoCl_2$ in HepG2 cells. Conclusion: The above-mentioned results proved that LSE extracts reduced $HIF-1{\alpha}$ protein level in the HaCaT cells and HepG2 cells. These results suggest that inhibition of HaCaT cell and HepG2 cell proliferation by LSE extracts contributes to the anti-angiogenic activities on the keratinocytes and hepatocellular carcinoma.

• Asian Pacific Journal of Cancer Prevention
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• 제15권5호
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• pp.2353-2358
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• 2014

Purpose: We aimed to detect the expression of HIF-1${\alpha}$, VEGF, HPSE-1 and CD31 in SKOV3 xenografts in nude mice treated with different doses of ionizing radiation, trying to explore the possible mechanism of hypoxia and radioresistance. Methods: Nude mice bearing SKOV3 xenografts were randomly divided into 4 groups: Group A (control group, no ionizing radiation), Group B (treated with low dose of ionizing radiation: 50cGy), Group C (treated with high dose of ionizing radiation: 300cGy), Group D ( combined ionizing radiation, treated with ionizing radiation from low dose to high dose : 50cGy first and 300cGy after 6h interval). The mRNA levels of HIF-1 and VEGF in each group were detected by real time polymerase chain reaction, while HPSE-1 expression was measured by ELISA. The microvessel density (MVD) and hypoxic cells were determined through immunohistochemical (IHC) staining of CD31 and HIF-1a. Results: Significant differences of HIF-1${\alpha}$ mRNA level could be found among the 4 groups (F=74.164, P<0.001): Group C>Group A>Group D> Group B. The mRNA level of VEGF in Group C was significantly higher than in the other three groups (t=-5.267, P=0.000), while no significant difference was observed among Group A, B and D (t=1.528, 1.588; P=0.205, 0.222). In addition, the MVD was shown to be the highest in Group C (t=6.253, P=0.000), whereas the HPSE-1 level in Group A was lower than in Group B (t=14.066, P=0.000) and higher than in Group C (t=-21.919, P=0.000), and similar with Group D (t=-2.066, P=0.058). Through IHC staining of HIF-1a, the expression of hypoxic cells in Group A was (++), Group B was (+), Group C was (+++) and Group D was (+). Conclusion: Ionizing radiation with lowerdoses might improve tumor hypoxia through inhibiting the expression of HIF-1 and HPSE-1, whereas higherdoses worsen tumor hypoxic conditions by up-regulating HIF-1${\alpha}$, HPSE-1, VEGF and CD31 levels. A protocol of low-dose ionizing radiation followed by a high-dose irradiation might at least partly improve tumor hypoxia and enhance radiosensitivity.

• Molecules and Cells
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• 제44권10호
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• pp.710-722
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• 2021

Hypoxia, or low oxygen tension, is a hallmark of the tumor microenvironment. The hypoxia-inducible factor-1α (HIF-1α) subunit plays a critical role in the adaptive cellular response of hypoxic tumor cells to low oxygen tension by activating gene-expression programs that control cancer cell metabolism, angiogenesis, and therapy resistance. Phosphorylation is involved in the stabilization and regulation of HIF-1α transcriptional activity. HIF-1α is activated by several factors, including the mitogen-activated protein kinase (MAPK) superfamily. MAPK phosphatase 3 (MKP-3) is a cytoplasmic dual-specificity phosphatase specific for extracellular signal-regulated kinase 1/2 (Erk1/2). Recent evidence indicates that hypoxia increases the endogenous levels of both MKP-3 mRNA and protein. However, its role in the response of cells to hypoxia is poorly understood. Herein, we demonstrated that small-interfering RNA (siRNA)-mediated knockdown of MKP-3 enhanced HIF-1α (not HIF-2α) levels. Conversely, MKP-3 overexpression suppressed HIF-1α (not HIF-2α) levels, as well as the expression levels of hypoxia-responsive genes (LDHA, CA9, GLUT-1, and VEGF), in hypoxic colon cancer cells. These findings indicated that MKP-3, induced by HIF-1α in hypoxia, negatively regulates HIF-1α protein levels and hypoxia-responsive genes. However, we also found that long-term hypoxia (>12 h) induced proteasomal degradation of MKP-3 in a lactic acid-dependent manner. Taken together, MKP-3 expression is modulated by the hypoxic conditions prevailing in colon cancer, and plays a role in cellular adaptation to tumor hypoxia and tumor progression. Thus, MKP-3 may serve as a potential therapeutic target for colon cancer treatment.

• Radiation Oncology Journal
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• 제24권4호
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• pp.255-262
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• 2006

목 적: 진행된 직장암의 수술 후 보조적 방사선 치료를 시행한 환자에서 국소 재발한 군의 병리학적 예후 인자를 규명함으로써 향후 치료 방침의 결정에 도움이 되고자 하였다. 대상 및 방법: 1993년 2월부터 2001년 12월까지 원자력의학원에서 수술을 시행한 후 병기 3기 이상으로 방사선치료 및 항암 요법을 시행 받은 직장암 환자 110명을 대상으로 검체를 모두 조사하여 면역조직화학검사가 가능한 총 54명을 대상으로 하였다. 이중 국소전이가 발견된 군이 14명, 발견되지 않은 군이 40명이었다. 이들의 조직 검체를 대상으로 종양의 침윤 깊이, 종양의 조직학적 등급, 임파절 침윤 여부, 혈관 침윤 여부, 신경 침윤 여부 등의 병리적인 특징 및 p53, Ki-67, c-erb, ezrin, c-met, phospho-S6K, S100A4, HIF-1 alpha의 다양한 암 유전자의 발현양상을 단변량 분석 및 다변량 분석, hierarchical clustering 분석 기법을 사용하여 치료 후 예후와 관련된 인자를 찾았다. 결 과: 병리학적 예후 인자 중 단변량 분석상 종양 침윤 깊이, 종양의 등급, 혈관 침범이 의미 있었고 다변량 분석상 침윤의 깊이가 5.5 mm 이하, 혈관 침윤이 없는 경우가 국소 재발이 낮은 군이었다. 면역조직화학검사 결과의 단변량 분석상 c-met 양성, HIF-1 alpha 양성이 국소 재발률이 높은 예후 인자였고 다변량 분석상 c-met이 의미 있는 예후 인자였다. Hierarchical clustering을 통해서 조사한 결과 HIF-1 alpha, c-met 및 종양 침윤 깊이가 국소재발과 관련된 인자로써 국소 재발을 한 군의 71.4%가 3가지 인자 중 2개 이상을 가지고 있는 반면 국소 재발을 하지 않은 군에서는 27.5%가 2개 이상을 가지고 있었다. 결 론: 국소적으로 진행되어 방사선 치료를 시행해야 하는 직장암 환자군 중에서 HIF-1 alpha 양성, c-met 양성, 종양 침윤 깊이 5.5 mm 이상의 병리학적 예후 인자를 두 개 이상 가지는 환자는 국소 재발의 가능성이 높다. 이러한 인자가 방사선치료 저항군의 지표로써 유용한지에 대한 전향적 연구가 향후 필요할 것이다.

• 동의생리병리학회지
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• 제20권3호
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• pp.557-562
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• 2006

Hypoxia induced angiogenesis and inflammation are essential processes for metastasis and progress of solid tumors. We examined the anti-angiogenic and inflammation related activity of Kochiae Fructus (KF) extract. To investigate the roles of the KF extract, we performed MTS assay, western blots using HaCaT cells and $HepG_2$ cells. The results are as follows. The protein level of $HIF-1{\alpha}$ was reduced when induced by $CoCl_2$ in $HepG_2$ cells treated with KF extract and induced by IGF-11 in HaCaT cells treated with KF extract. KF extract reduced the mRNA level of VEGF in HaCaT cells and KF extract reduced the protein level of iNOS in HaCaT cells. These results suggest that KF extract contributes to the anti-angiogenic and anti-inflammatory activities and also we could assume that KF extract act as antioxidant or anti-inflammatory agents via reduction of $HIF-1{\alpha}$.

• 동의생리병리학회지
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• 제21권3호
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• pp.741-747
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• 2007

This study evaluated neuroprotective effects of Yanggyuksanhwa-tang (YST), which have been known to be efficacy in the treatment of the stroke and diabetes. on focal cerebral ischemia of diabetic rats. On primary experiment, diabetic condition in rats was induced by streptozotocin injection, then, focal cerebral ischemia was induced by the middle cerebral artery occlusion (MCAO) under the diabetic condition. Then neuroprotective effect of YST was observed with changes of infarct size and volume, expressions of c-Fos, Bax, and hypoxia inducible factor (HIF)-1${\alpha}$ in the brain tissues by using 2% 2,3,5-triphenyltetrazolium chloride (TTC) staining and immunohistochemistry. YST treatment showed a significant decrease of infarct size and volume induced by MCAO in diabetic rats. YST treatment showed a significant decrease of c-Fos and Bax positive neurons in cortex penumbra. YST treatment showed a decrease of HIF-l${\alpha}$ positive neurons in cortex penumbra, but it was not significant statistically. These results suggest that YST has effects on neuroprotection against cerebral infarct under diabetic condition. And it is supposed that neuroprotective effect of YST reveals by anti-apoptosis mechanism.