• Journal of Chest Surgery
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• 제39권11호
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• pp.828-837
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• 2006

배경: 악성종양에서 신생혈관 생성 및 당분해의 증가는 저산소 상태의 미세환경을 나타내며, 이는 종양의 침습성, 전이 및 환자의 예후와 관련이 있는 것으로 알려져 있다. Hypoxia-inducible factor 1(HIF-1)는 당원 수송체, 당분해 효소, 혈관내피세포 성장인자 등의 유전자의 전사를 활성화한다고 알려져 있다. 그리고 HIF-1의 전사 활성도는 HIF-$1{\alpha}$ 아단위의 표현이 조절되는 정도에 의존한다. 비소세포 폐암에서 HIF-$1{\alpha}$의 발현이 혈관 생성능, 종양세포 증식능 및 이상형 p53의 축적 등 종양의 생물학적 특성에 미치는 영향과 환자의 수술 후 예후와의 관계를 규명하고자 한다. 대상 및 방법: 1997년부터 1999년까지 비소세포 폐암으로 진단받고 전폐절제술 혹은 폐엽절제술을 시행 받은 59명의 폐암 환자들에서 얻어진 파라핀 조직 블록을 대상으로 하였다. ABC(avidin-biotin complex) 방법에 기초한 면역조직화학검사를 이용하여 암조직과 정상조직에서 HIF-$1{\alpha}$, VEGF(vascular endothelial growth factor), p53 단백의 발현을 조사하고, Ki-67의 발현을 이용한 증식지수를 측정하였다. HIF-$1{\alpha}$ 발현과 환자의 생존기간을 포함한 임상적-병리학적 변수들과의 상관관계, VEGF, p53의 발현과 증식지수와의 상관관계를 분석하였다. 결과: HIF-$1{\alpha}$의 과발현은 40.7%(24예/59예)였다. HIF-$1{\alpha}$의 과발현은 병리학적 TNM병기(p=0.004), T병기(p=0.020), N병기(p=0.004), 림프관/혈관 침범(p=0.019) 등과 관련이 있었다. 또 혈관내피세포 성장인자의 발현(p<0.001) 및 이상형의 p53의 발현(p=0.040)과 관련성이 있었다. Kaplan-Meier 생존분석에서 HIF-$1{\alpha}$의 과발현이 있는 환자의 5년 생존울은 22%로 HIF-$1{\alpha}$의 저발현 환자의 5년 생존율 61%에 비해 불량한 생존율을 보였고, 단변량분석과 다변량분석에서 HIF-$1{\alpha}$의 발현은 불량한 예후를 나타내는 인자로 관찰되었다. 결론: 이상의 결과로 비소세포 폐암 환자에서 HIF-$1{\alpha}$의 과발현은 종양내 신생혈관의 생성과 림프절 전이와 관련이 있는 표지자로 여겨지며, 수술 후 불량한 예후를 나타내었다.

• The Korean Journal of Physiology and Pharmacology
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• 제14권5호
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• pp.331-336
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• 2010

In rapidly growing tumors, hypoxia commonly develops due to the imbalance between $O_2$ consumption and supply. Hypoxia Inducible Factor (HIF)-$1{\alpha}$ is a transcription factor responsible for tumor growth and angiogenesis in the hypoxic microenvironment; thus, its inhibition is regarded as a promising strategy for cancer therapy. Given that CamKII or PARP inhibitors are emerging anticancer agents, we investigated if they have the potential to be developed as new HIF-$1{\alpha}$-targeting drugs. When treating various cancer cells with the inhibitors, we found that a CamKII inhibitor, KN-62, effectively suppressed HIF-$1{\alpha}$ specifically in hepatoma cells. To examine the effect of KN-62 on HIF-$1{\alpha}$-driven gene expression, we analyzed the EPO-enhancer reporter activity and mRNA levels of HIF-$1{\alpha}$ downstream genes, such as EPO, LOX and CA9. Both the reporter activity and the mRNA expression were repressed by KN-62. We also found that KN-62 suppressed HIF-$1{\alpha}$ by impairing synthesis of HIF-$1{\alpha}$ protein. Based on these results, we propose that KN-62 is a candidate as a HIF-$1{\alpha}$-targeting anticancer agent.

• Radiation Oncology Journal
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• 제22권3호
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• pp.217-224
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• 2004

목적: 저산소증은 방사선 감수성을 현저히 감소시키며, 이에 대한 적응 반응에서 hypoxia-inducible factor 1 $\alpha$(HIF-1 u$\alpha$가 중요한 역할을 하고 있다. HIF-1 $\alpha$의 발현과 방사선 감수성과의 상관 관계를 알아보고자 하였다. 대상 및 방법: 쥐의 간암 세포주인 hepalclc7 세포와 HIF-1 $\beta$가 결손되어 HIF-1 $\alpha$의 기능이 억제된 hepaIC4 세포를 사용했다 저산소 유사 물질인 desferrioxamine (DFX)을 전처치하고 6시간 뒤에 방사선조사를 하여 western blot으로 HIF-1 $\alpha$ 발현을 조사하였다. Apoptosis는 DNA 분절화, propidium iodide 핵염색, 그리고 apoptotic cell death detection ELISA kit를 이용하였다. MTT assay법으로 방사선 감수성을 측정하고 SF2$_{2}$ SF$_{8}$, 그리고 mean inactivation dose (MID)를 산출하여 통계적 분석을 하였다. 결과: Hepalclc7 세포에서는 DFX 전처치를 한 경우 방사선에 의해 HIF-1 $\alpha$의 발현이 증가했으나, hepalC4 세포 주에서는 변화가 없었다 Hepa1C4 세포의 방사선 감수성은 DFX처리에 따른 영향이 없었으나 hepalclc7 세포의 방사선 감수성은 DFX를 전처치했을 때 유의하게 감소하였다. 결론: 저산소 유사 물질인 DFX에 의해 유도된 HIF-1 $\alpha$가 쥐의 간암 세포주에서 apoptosis와 방사선 감수성을 감소시켰다 이러한 결과는 종괴내의 저산소 세포에서 방사선에 의해 HIF-1 $\alpha$가 유도되고 이로 인해 저산소 세포에서 방사선 감수성을 저하시키는 것으로 생각되었다.

• Asian Pacific Journal of Cancer Prevention
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• 제14권6호
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• pp.3613-3618
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• 2013

Object: To detect expression of hypoxia inducible factor-$1{\alpha}$ (HIF-$1{\alpha}$) and lysyl oxidase (LOX) in non-small cell lung cancer (NSCLC) and explore their roles in prognosis. Methods: The mRNA levels of HIF-$1{\alpha}$ and LOX were investigated by real-time reverse-transcriptase polymerase chain reaction in 40 cases of tumour and paired normal tissues. In addition, protein expression of HIF-$1{\alpha}$ and LOX was examined by immunohistochemistry in 82 cases of tumour and 45 paired normal tissues. The relationship between HIF-$1{\alpha}$ or LOX and clinicopathologic characteristics, as well as the correlation between HIF-$1{\alpha}$ and LOX, were also examined. Kaplan-Meier survival curves and the log-rank test were used to analyze progression-free survival. Results: HIF-$1{\alpha}$ or LOX mRNA levels in tumor tissues was significantly higher than those in paired normal tissues (p<0.01). Positive HIF-$1{\alpha}$ or LOX protein expression in tumor tissues was noted in 46/82 (56.1%) and 49/82 (59.8%) of the cases, respectively, being significantly higher than those in paired normal tissues (p<0.05). There was significant correlation between the expression of HIF-$1{\alpha}$ or LOX and tumor size, lymph node metastasis and pathological stage (p<0.05). The expression of HIF-$1{\alpha}$ and LOX had a significant inverse impact on survival of patients with NSCLC. Conclusion: HIF-$1{\alpha}$ and LOX may play a pivotal role in the development of NSCLC, and may act in synergy to promote the progression of NSCLC.

• Molecules and Cells
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• 제27권2호
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• pp.243-250
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• 2009

Recent studies suggest a novel role of $HIF-1{\alpha}$ under nonhypoxic conditions, including antibacterial and antiviral innate immune responses. However, the identity of the pathogen-associated molecular pattern which triggers $HIF-1{\alpha}$ activation during the antiviral response remains to be identified. Here, we demonstrate that cellular administration of double-stranded nucleic acids, the molecular mimics of viral genomes, results in the induction of $HIF-1{\alpha}$ protein level as well as the increase in $HIF-1{\alpha}$ target gene expression. Whole-genome DNA microarray analysis revealed that double-stranded nucleic acid treatment triggers induction of a number of hypoxia-inducible genes, and induction of these genes are compromised upon siRNA-mediated $HIF-1{\alpha}$ knock-down. Interestingly, $HIF-1{\alpha}$ knock-down also resulted in down-regulation of a number of genes involved in antiviral innate immune responses. Our study demonstrates that $HIF-1{\alpha}$ activation upon nucleic acid-triggered antiviral innate immune responses plays an important role in regulation of genes involved in not only hypoxic response, but also immune response.

• Clinical and Experimental Reproductive Medicine
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• 제39권2호
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• pp.73-80
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• 2012

Objective: This study was undertaken to determine the effect of hypoxia inducible factor (HIF)-$1{\alpha}$ on the cell death, autophagy, and invasion of trophoblasts. Methods: To understand the effect of HIF-$1{\alpha}$, we inhibited HIF-$1{\alpha}$ using siRNA under normoxia and hypoxia conditions. Invasion assay and zymography were performed to determine changes in the invasion ability of HIF-$1{\alpha}$. Western blotting and immunofluorescence were performed to determine some of the signal events involved in apoptosis and autophagy. Results: There was no difference in cell death through the inhibition of HIF-$1{\alpha}$ expression by siRNA; however, the expression of LC3 and autophagosome formation increased. On the other hand, autophagy was increased, and the invasive ability of trophoblast cells decreased according to the inhibition of HIF-$1{\alpha}$ expression by siRNA. These experimental results mean that HIF-$1{\alpha}$ genes regulate the invasive ability of trophoblasts by increasing autophagy. Conclusion: This study contributes important data for understanding the mechanism of early pregnancy implantation and the invasive ability of trophoblasts by defining the relationship between the roles of HIF-$1{\alpha}$ and autophagy.

• BMB Reports
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• 제42권11호
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• pp.737-742
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• 2009

Hypoxia-inducible factor-$1{\alpha}/{\beta}$ (HIF-$1{\alpha}/{\beta}$) is a heterodimeric transcriptional activator that mediates gene expression in response to hypoxia. HIF-$1{\alpha}$ has been noted as an effective therapeutic target for ischemic diseases such as myocardiac infarction, stroke and cancer. By using a yeast two-hybrid system and a random peptide library, we found a 16-mer peptide named F29 that directly interacts with the bHLH-PAS domain of HIF-$1{\alpha}$. We found that F29 facilitates the interaction of the HIF-$1{\alpha/\beta}$ heterodimer with its target DNA sequence, hypoxia-responsive element (HRE). The transient transfection of an F29-expressing plasmid increases the expression of both an HRE-driven luciferase gene and the endogenous HIF-1 target gene, vascular endothelial growth factor (VEGF). Taken together, we conclude that F29 increases the DNA-binding ability of HIF-$1{\alpha}$, leading to increased expression of its target gene VEGF. Our results suggest that F29 can be a lead compound that directly targets HIF-$1{\alpha}$ and increases its activity.

• The Korean Journal of Physiology and Pharmacology
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• 제14권2호
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• pp.91-97
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• 2010

Epidermal keratinocytes overgrow in response to ultraviolet-B (UVB), which may be associated with skin photoaging and cancer development. Recently, we found that HIF-$1{\alpha}$ controls the keratinocyte cell cycle and thereby contributes to epidermal homeostasis. A further study demonstrated that HIF-$1{\alpha}$ is down-regulated by UVB and that this process is involved in UVB-induce skin hyperplasia. Therefore, we hypothesized that the forced expression of HIF-$1{\alpha}$ in keratinocytes would prevent UVB-induced keratinocyte overgrowth. Among several agents known to induce HIF-$1{\alpha}$, pyrithione-zinc (Py-Zn) overcame the UVB suppression of HIF-$1{\alpha}$ in cultured keratinocytes. Mechanistically, Py-Zn blocked the degradation of HIF-$1{\alpha}$ protein in keratinocytes, while it did not affect the synthesis of HIF-$1{\alpha}$. Moreover, the p21 cell cycle inhibitor was down-regulated after UVB exposure, but was robustly induced by Py-Zn. In mice repeatedly irradiated with UVB, the epidermis became hyperplastic and HIF-$1{\alpha}$ disappeared from nuclei of epidermal keratinocytes. However, a cream containing Py-Zn effectively prevented the skin thickening and up-regulated HIF-$1{\alpha}$ to the normal level. These results suggest that Py-Zn is a potential agent to prevent UVB-induced photoaging and skin cancer development. This work also provides insight into a molecular target for treatment of UVB-induced skin diseases.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 2008년도 Proceedings of the Convention
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• pp.55-74
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• 2008

Previously, we have shown that hypoxia, through HIF-1, induces ligand-independent $ER{\alpha}$ activation and the physical interaction of HIF-1 and $ER{\alpha}$. However, the effect of hypoxia on the transactivation of $ER{\beta}$ is not yet known. In the present study, we found that hypoxia activated the $ER{\beta}$-mediated transcriptional response in the HEK 293 cell line, as determined by the transient expression of$ER{\beta}$ and ER-responsive reporter plasmids. The hypoxia-induced estrogen response element-mediated transcriptional response was dependent on $ER{\beta}$ expression and was inhibited by the ER antagonist ICI 182,780. Transactivation of $ER{\beta}$ was induced by the expression of HIF-$1{\alpha}$ under normoxic conditions, as determined by the expression of oxygen-independent stable GFP-HIF-$1{\alpha}$. HIF-$1{\alpha}$-induced $ER{\beta}$ transactivation was abolished by the inhibition of HIF-$1{\alpha}$ activation. This was determined by using chemical inhibitors for the MAPK pathway. In addition, HIF-$1{\alpha}$ interacted with $ER{\beta}$ in a mammalian-two hybrid assay. We conclude that hypoxia activates $ER{\beta}$ in a ligand-independent manner, possibly through the interaction of HIF-$1{\alpha}$ and $ER{\beta}$.

• Asian Pacific Journal of Cancer Prevention
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• 제15권19호
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• pp.8251-8257
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• 2014

Apoptosis is one of main types of neural cell death and is reversible and is a major target of therapeutic interventions. However, detailed apoptotic cascades still need to be recognized. In present study, we determined the promotion of HIF-$1{\alpha}$ and survivin in brain samples of a mouse model of hypoxic-ischemia and in neuroblastoma SH-SY5Y cells post hypoxia treatment. Then gain-of-function and loss-of-function strategies were adopted to manipulate the HIF-$1{\alpha}$ in SH-SY5Y cells, and hypoxia-induced survivin upregulation and cell apoptosis were determined. Results demonstrated that the HIF-$1{\alpha}$ and survivin were significantly promoted in a mouse model of hypoxic-ischemia or in SH-SY5Y cells post hypoxia in vitro. Manually upregulated HIF-$1{\alpha}$ could promote the hypoxia-induced survivin upregulation and improve the hypoxia-induced SH-SY5Y cell apoptosis. On the other hand, the HIF-$1{\alpha}$ knockdown by RNAi reduced the hypoxia-induced survivin upregulation and cell apoptosis. Therefore, the present study confirmed the protective role of HIF-$1{\alpha}$ and survivin in the hypoxia-induced SH-SY5Y cell apoptosis, and the survivin upregulation by hypoxia is HIF-$1{\alpha}$-dependent. Promotion of HIF-$1{\alpha}$ and survivin might be a valuable stragegy for therapeutic intervention for hypoxic-ischemic encephalopathy.