• Asian Pacific Journal of Cancer Prevention
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• v.15 no.16
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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.

• Proceedings of the Korean Society of Toxicology Conference
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• 2001.10a
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• pp.199-199
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• 2001

Both hypoxia and insulin induce same target genes including vascular endothelial growth factor (VEGF), glycolitic enzymes and glucose transporters. However these two signals eventually trigger quite different metabolic pathways. Hypoxia induces glycolysis for anaerobic ATP production, while insulin increase glycolysis for lipogenesis and energy storage. Hypoxia-induced gene expression is mediated by Hypoxia-inducible Factorl (HIF-1) that consists of HIF-1 $\alpha$ and $\beta$ subunit.(omitted)

• Proceedings of the Korean Society of Toxicology Conference
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• 2001.05a
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• pp.41-83
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• 2001

Under low oxygen tension, cells increase the transcription of specific genes that are involved in angiogenesis, erythropoiesis and glycolysis. Hypoxia-induced gene expression primarily depends on the stabilization of the subunit of Hypoxia-Inducible Factor-1 (HIF-1), which acts as a heterodimeric transactivator.(omitted)

• BMB Reports
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• v.36 no.1
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• pp.120-127
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• 2003

The formation of new blood vessels, angiogenesis, is an essential process during development and disease. Angiogenesis is well known as a crucial step in tumor growth and progression. Angiogenesis is induced by hypoxic conditions and regulated by the hypoxia-inducible factor 1 (HIF-1). The expression of HIF-1 correlates with hypoxia-induced angiogenesis as a result of the induction of the major HIF-1 target gene, vascular endothelial cell growth factor (VEGF). In this review, a brief overview of the mechanism of angiogenesis is discussed, focusing on the regulatory processes of the HIF-1 transcription factor. HIF-1 consists of a constitutively expressed HIF-1 beta(HIF-1β) subunit and an oxygen-regulated HIF-1 alpha(HIF-1α) subunit. The stability and activity of HIF-1α are regulated by the interaction with various proteins, such as pVHL, p53, and p300/CBP as well as by post-translational modifications, hydroxylation, acetylation, and phosphorylation. It was recently reported that HIF-1α binds a co-activator of the AP-1 transciption factor, Jab-1, which inhibits the p53-dependent degradation of HIF-1 and enhances the transcriptional activity of HIF-1 and the subsequent VEGF expression under hypoxic conditions. ARD1 acetylates HIF-1α and stimulates pVHL-mediated ubiquitination of HIF-1α. With a growing knowledge of the molecular mechanisms in this field, novel strategies to prevent tumor angiogenesis can be developed, and form these, new anticancer therapies may arise.

• The Korean Journal of Physiology and Pharmacology
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• v.28 no.1
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• pp.83-91
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• 2024

Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor activated under hypoxic conditions, and it plays a crucial role in cellular stress regulation. While HIF-1α activity is essential in normal tissues, its presence in the tumor microenvironment represents a significant risk factor as it can induce angiogenesis and confer resistance to anti-cancer drugs, thereby contributing to poor prognoses. Typically, HIF-1α undergoes rapid degradation in normoxic conditions via oxygen-dependent degradation mechanisms. However, certain cancer cells can express HIF-1α even under normoxia. In this study, we observed an inclination toward increased normoxic HIF-1α expression in cancer cell lines exhibiting increased HDAC6 expression, which prompted the hypothesis that HDAC6 may modulate HIF-1α stability in normoxic conditions. To prove this hypothesis, several cancer cells with relatively higher HIF-1α levels under normoxic conditions were treated with ACY-241, a selective HDAC6 inhibitor, and small interfering RNAs for HDAC6 knockdown. Our data revealed a significant reduction in HIF-1α expression upon HDAC6 inhibition. Moreover, the downregulation of HIF-1α under normoxic conditions decreased zinc finger E-box-binding homeobox 1 expression and increased E-cadherin levels in lung cancer H1975 cells, consequently suppressing cell invasion and migration. ACY-241 treatment also demonstrated an inhibitory effect on cell invasion and migration by reducing HIF-1α level. This study confirms that HDAC6 knockdown and ACY-241 treatment effectively decrease HIF-1α expression under normoxia, thereby suppressing the epithelial-mesenchymal transition. These findings highlight the potential of selective HDAC6 inhibition as an innovative therapeutic strategy for lung cancer.

• Molecules and Cells
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• v.44 no.10
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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.

• Journal of Chest Surgery
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• v.37 no.8
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• pp.691-701
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• 2004

Background: Tissue hypoxia is a characteristic of many human malignant neoplasms, and hypoxia inducible factor-1 (HIF-1) plays a pivotal role in essential adaptive response to hypoxia, and activates a signal pathway for the expression of the hypoxia-regulated genes, resulting in increased oxygen delivery or facilitating metabolic adaptation to hypoxia. Increased level of HIF-1 a has been reported in many human malignancies, but in esophageal squamous cell carcinoma, the influence of HIF-1 a on tumor biology, including neovascularization, is not still defined. Material and Method: The influence of HIF-1 a expression on angiogenic factors, correlation between the tumor proliferation and HIF-1 a expression, interaction of HIF-1 a expression and p53, and correlation between HIF-1 a expression and clinicopathological prognostic parameters were investigated, using immunohistochemical stains for HIF-1 a, VEGF, CD34, p53, and Ki-67 on 77 cases of resected esophageal squamous cell carcinoma. Result: HIF-1 a expression in cancer cells was found in 33 of 77 esophageal squamous cell carcinoma cases. The 33 cases (42.9%) showed positive stain for HIF-1 a. High HIF-1 a expression was significantly associated with several pathological parameters, such as histologic grade (p=0.032), pathological TMN stage (p=0.002), the depth of tumor invasion (p=0.022), regional lymph node metastasis (p=0.002), distant metastasis (p=0.049), and lymphatic invasion (p=0.004). High HIF-1 a expression had significant VEGF immunoreactivity (p=0.008) and Ki-67 labeling index (p<0.001), but was not correlated with microvascular density within tumors (p=0.088). The high HIF-1 a expression was correlated with aberrant p53 accumulation with a marginal significance (p=0.056). The overall 5-year survival rate was 34.9%. The survival rate of patients with a high HIF-1 a expression was worse than that of patients with low-expression tumors (log-rank test, p=0.0001). High HIF-1 a expression was independent unfavorable factors although statistical significance is marginal in multivariate analysis. Conclusion: It is suggested that (1) high HIF-1 a expression in esophageal squamous cell carcinoma is associated with tumor hypoxia, or with genetic alteration in early carcinogenesis and progressive stages, (2) high HIF-1 a expression may be associated with intratumoral neovascularization through HIF-VEGF pathway, and (3) high HIF-1 a expression is associated with poor prognosis in patients with esophageal squamous cell carcinoma and may playa role as biomarker for regional lymph node metastasis.

• Proceedings of the Korean Biophysical Society Conference
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• 2003.06a
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• pp.28-28
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• 2003

To discover new drugs more quickly and more efficiently, pharmaceutical companies and biotechnology firms are increasingly turning to the genomics and the structural proteomics technologies. Structural-proteomics can provide a foundation for this through the determination and analysis for protein structure on a genomics scale. Among many structures determined by CGI, we will present with the representative examples drawn from our work on novel structures or complex structures of the disease-related proteins. The alpha subunit of Hypoxia-inducible factor (HIF) is targeted for degradation under normoxic conditions by an ubiquitin-ligase complex that recognizes a hydroxylated proline residue in HIF, Hydroxylation is catalysed by HIF prolyl 4-hydroxylases (HIFPH) which are Fe(II) and 2-oxoglutarate (2-OG) dependent oxygenases. Here, we discuss the first crystal structure of the catalytic domain of HIFPH in complexes, with the Fe(II)/2-OG at 1.8 ${\AA}$. These structures suggest that the L1 region (residues 236-253), which is also conserved in mammals, form a ‘lid’ that closes over the active site. The structural and mutagenesis analyses allow us to provide a focus for understanding cellular responses to hypoxia and a target for the therapeutic manipulation.

• Proceedings of the Korea Crystallographic Association Conference
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• 2003.05a
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• pp.15-15
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• 2003

To discover new drugs more quickly and more efficiently, pharmaceutical companies and biotechnology firms are increasingly turning to the genomics and the structural proteomics technologies. Structural-proteomics can provide a foundation for this through the determination and analysis for protein structure on a genomics scale. Among many structures determined by CGI, we will present with the representative examples drawn from our work on novel structures or complex structures of the disease-related proteins. The alpha subunit of Hypoxia-inducible factor (HIF) is targeted for degradation under normoxic conditions by an ubiquitin-ligase complex that recognizes a hydroxylated proline residue in HIF. Hydroxylation is catalysed by HIF prolyl 4-hydroxylases (HIFPH) which are fe(II) and 2-oxoglutarate (2-OG) dependent oxygenases. Here, we discuss the first crystal structure of the catalytic domain of HIFPH in complexes, with the Fe(II)/2-OG at 1.8Å. These structures suggest that the Ll region (residues 236-253), which is also conserved in mammals, form a 'lid' that closes over the active site. The structural and mutagenesis analyses allow us to provide a focus for understanding cellular responses to hypoxia and a target for the therapeutic manipulation.