Expression of hypoxia‐inducible factor‐1α in esophageal squamous cell carcinoma

Matsuyama, Tomokazu; Nakanishi, Kuniaki; Hayashi, Takuya; Yoshizumi, Yutaka; Aiko, Satoshi; Sugiura, Yoshimi; Tanimoto, Takao; Uenoyama, Maki; Ozeki, Yuichi; Maehara, Tadaaki

doi:10.1111/j.1349-7006.2005.00025.x

Cited by 67 publications

(52 citation statements)

References 30 publications

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“…To evaluate the statistically significant difference in the ratio of cancerous EPAS1 mRNA level to histopathologically unchanged tissue EPAS1 mRNA level between the three DNA methylation ranges (0%-1% methylation, 1%-10% methylation, and 10%-100% methylation), the nonparametric Kruskal-Wallis test was used. HIF1A mRNA levels were increased in cancerous compared with noncancerous tissue (8,11,12,33,34). However, other studies reported a constant HIF1A mRNA level in tumor cells and suggested mainly posttranslational regulation of HIF1A expression (35)(36)(37), which is consistent with our observations.…”

Section: Discussionsupporting

confidence: 83%

Prognostic Potential of DNA Methylation and Transcript Levels of HIF1A and EPAS1 in Colorectal Cancer

Rawłuszko-Wieczorek¹,

Horbacka

Krokowicz

et al. 2014

Molecular Cancer Research

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Hypoxic conditions during the formation of colorectal cancer may support the development of more aggressive tumors. Hypoxia-inducible factor (HIF) is a heterodimeric complex, composed of oxygen-induced HIFa and constitutively expressed HIFb subunits, which mediates the primary transcriptional response to hypoxic stress. Among HIFa isoforms, HIF1a (HIF1A) and endothelial PAS domain-containing protein 1 (EPAS1) are able to robustly activate hypoxia-responsive gene signatures. Although posttranslational regulation of HIFa subunits is well described, less is known about their transcriptional regulation. Here, molecular analysis determined that EPAS1 mRNA was significantly reduced in primary colonic adenocarcinoma specimens compared with histopathologically nonneoplastic tissue from 120 patients. In contrast, no difference in HIF1A mRNA levels was observed between cancerous and noncancerous tissue. Bisulfite DNA sequencing and high-resolution melting analysis identified significant DNA hypermethylation in the EPAS1 regulatory region from cancerous tissue compared with nonneoplastic tissue. Importantly, multivariate Cox regression analysis revealed a high HR for patients with cancer with low EPAS1 transcript levels (HR, 4.91; 95% confidence interval, CI, 0.42-56.15; P ¼ 0.047) and hypermethylated EPAS1 DNA (HR, 33.94; 95% CI, 2.84-405.95; P ¼ 0.0054). Treatment with a DNA methyltransferase inhibitor, 5-Aza-2 0 -deoxycytidine (5-aza-dC/Decitabine), upregulated EPAS1 expression in hypoxic colorectal cancer cells that were associated with DNA demethylation of the EPAS1 regulatory region. In summary, EPAS1 is transcriptionally regulated by DNA methylation in colorectal cancer.Implications: DNA methylation and mRNA status of EPAS1 have novel prognostic potential for colorectal cancer.

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Section: Discussionsupporting

confidence: 83%

Prognostic Potential of DNA Methylation and Transcript Levels of HIF1A and EPAS1 in Colorectal Cancer

Rawłuszko-Wieczorek¹,

Horbacka

Krokowicz

et al. 2014

Molecular Cancer Research

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“…As a fast-growing cancer, ESCC has a hypoxic microenvironment and metabolic disturbance. Hypoxia suppresses the apoptosis of cancer cells, resulting in the resistance to chemotherapeutic agents and even treatment failure (Matsuyama et al, 2005;Tzao et al, 2008). As shown in our results (Figure 4), HIF-1a siRNA alone or in combination with cisplatin strongly induced apoptosis of ESCC TE-1 cell, which resulted in the growth suppression of transplanted ESCC in nude mice.…”

Section: Discussionsupporting

confidence: 50%

“…Thus, targeting HIF-1a may serve as a viable anticancer strategy to be used in clinics (Kurokawa et al, 2003;Kimura et al, 2004;Matsuyama et al, 2005). Herein, using the strategy of silencing HIF1a with targeted siRNA, we identified that HIF-1a siRNA could effectively inhibit the growth of transplanted ESCC in nude mice, down-regulate the HIF-1α mRNA and protein expression, and induce ESCC TE-1 cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…The slides were observed under microscope. Light brown in the cytoplasm suggested weakly positive, brown was regarded as strong positive, and primary color indicated negative (Matsuyama et al, 2005;Tzao et al, 2008). The optical density was analyzed with automatic image analysis system (Kontron IBAS 2.5, Germany) and positive unit (PU) was obtained.…”

Section: Detection Of Hif-1α Protein With Immunohistochemistrymentioning

confidence: 99%

“…More recently, evidences showed that increased expression of HIF-1α was closely correlated with the growth, invasion and resistance to chemotherapeutic agents of human cancer cells including ESCC. In contrast, the loss of HIF- 1a activity or suppression of HIF-1α overexpression can effectively inhibit tumor growth, suggesting that HIF-1a is a potent therapeutical target for ESCC (Matsuyama et al, 2005;Tzao et al, 2008). RNA interference (RNAi), which is a sequence-specific gene-silencing method induced by double-stranded RNA (dsRNA), can precisely regulate or silence the expression of target genes.…”

Section: Introductionmentioning

confidence: 99%

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HiF-1α siRNA and Cisplatin in Combination SuppressTumor Growth in a Nude Mice Model of Esophageal Squamous Cell Carcinoma

Liao

Wang²,

Gu³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Introduction: The esophagus squamous cell carcinoma (ESCC) is one of the most deadly malignances, and a current challenge is the development of effective therapeutic agents. Our present work addressed the effect of HIF-1α siRNA alone or in combination with cisplatin on the growth of ESCC in nude mice. Materials and Methods: Xenografts were established by inoculating ESCC TE-1 cells in nude mice, and transplanted tumors were treated with HIF-1α siRNA, cisplatin alone or together. Growth was assessed by measuring tumor volume. HIF-1α mRNA and protein expression were detected using RT-PCR and immunohistochemistry, respectively. Apoptosis of ESCC TE-1 cells was analyzed by flow cytometry. Results: In our nude mice model, HIF-1α siRNA effectively inhibited the growth of transplanted ESCC, downregulating HIF-1α mRNA and protein expression, and inducing ESCC TE-1 cell apoptosis. Notably when combinated with cisplatin, HIF-1α siRNA showed synergistic interaction in suppressing tumor growth. Furthermore, the proportion of apoptotic cells in HIF-1α siRNA plus cisplatin group was significantly higher than that in cisplatin or HIF-1α siRNA-treated groups (P<0.05). Conclusions: Down-regulated HIF-1α expression induced by siRNA could effectively suppress the growth of transplanted ESCC in vivo. HIF-1α siRNA could enhance the cytotoxicity of cisplatin, which suggests that a combination of these two agents may have potential for therapy of advanced ESCC.

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Increase in gene dosage is a mechanism of HIF‐1α constitutive expression in head and neck squamous cell carcinomas

Secades

Rodrigo

Hermsen

et al. 2009

Genes Chromosomes & Cancer

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The HIF-1alpha protein plays a key role in the cellular response to hypoxia via transcriptional regulation of genes involved in erythropoiesis, angiogenesis, and metabolism. Overexpression of HIF-1alpha is commonly found in solid tumors in significant association with increased patient mortality and resistance to therapy. The predominant mode of HIF-1alpha regulation by hypoxia occurs at the level of protein stability. In addition to hypoxia, HIF-1alpha protein stability and synthesis is regulated by nonhypoxic signals such as inactivation of tumor suppressors and activation of oncogenes. Here, we show that an increase in gene dosage may contribute to HIF-1alpha mRNA and protein overexpression in a nonhypoxic environment in head and neck squamous cell carcinomas (HNSCC). Increased HIF-1alpha gene dosage was found in one out of five HNSCC-derived cell lines and three out of 27 HNSCC primary tumors. Significantly, increased gene dosage in those samples was associated with high HIF-1alpha mRNA and protein levels. Normoxic overexpression of HIF-1alpha protein in HNSCC-derived cell lines was also paralleled by higher expression levels of HIF-1alpha target genes. Array CGH analysis confirmed the copy number increase of HIF-1alpha gene and revealed that the gene is contained within a region of amplification at 14q23-q24.2 both in the cell line and primary tumors. In addition, FISH analysis revealed the presence of 11-13 copies on a tetraploid background in SCC2 cells. These data suggest that increased HIF-1alpha gene dosage is a mechanism of HIF-1alpha protein overexpression in HNSCC that possibly prepares the cells for a higher activity in an intratumoral hypoxic environment.

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Expression of hypoxia‐inducible factor‐1α in esophageal squamous cell carcinoma

Cited by 67 publications

References 30 publications

Prognostic Potential of DNA Methylation and Transcript Levels of HIF1A and EPAS1 in Colorectal Cancer

Prognostic Potential of DNA Methylation and Transcript Levels of HIF1A and EPAS1 in Colorectal Cancer

HiF-1α siRNA and Cisplatin in Combination SuppressTumor Growth in a Nude Mice Model of Esophageal Squamous Cell Carcinoma

Increase in gene dosage is a mechanism of HIF‐1α constitutive expression in head and neck squamous cell carcinomas

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