Oxygen-Dependent and -Independent Regulation of HIF-1alpha

Chun, Yang Sook; Kim, Myung Suk; Park, Jong-Wan

doi:10.3346/jkms.2002.17.5.581

Cited by 138 publications

(131 citation statements)

References 64 publications

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“…We have observed two patterns of HIF-1α expression representative of two distinct mechanisms of induction (12). Focal strong HIF-1α expression in the tumor cells around necrosis and invading margins indicated its induction by hypoxia while the diffused nuclear and/or cytoplasm staining suggested an oxygenindependent pathway.…”

Section: Discussionmentioning

confidence: 94%

Expression of hypoxia-inducible factor-1 alpha and associated proteins in pancreatic ductal adenocarcinoma and their impact on prognosis

Sun

Qiu²,

Liu³

et al. 2007

Int J Oncol

103

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Abstract. The aim of this study was to assess the significance of expression of hypoxia-inducible factor-1α (HIF-1α) and associated proteins in pancreatic ductal adenocarcinoma (PDA) and their impact on prognosis. Expression of HIF-1α, vascular endothelial growth factor (VEGF), glucose transporter-1 (Glut-1), survivin, CD34 and Ki-67 and apoptotic cells was demonstrated by immunohistochemistry or TUNEL in 58 PDAs and 20 normal pancreatic tissue samples. Our results show positivity of HIF-1α, VEGF, Glut-1 and survivin in 70.7%, 77.6%, 67.2% and 84.5% of the patients with PDA, respectively, which is significantly higher than in the normal counterparts. Expression of HIF-1α correlated positively with VEGF and Glut-1 expression but not with survivin. Strong HIF-1α expression associated with decreased apoptotic index and increased intratumoral microvessel density. Higher HIF-1α, VEGF and Glut-1 expression significantly associated with advanced tumor stage and lymph node metastasis. Patients with high HIF-1α, VEGF and Glut-1 expressing tumors had a poorer overall survival. Furthermore, Cox regression analysis showed that HIF-1α is a prognostic marker of borderline significance while VEGF was important in predicting poor outcome. These results suggest that over-expression of HIF-1α may play an important role in cancer progression through upregulation of VEGF and Glut-1 in PDA patients. HIF-1α and VEGF are potential candidates for predicting survival.

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Section: Discussionmentioning

confidence: 94%

Expression of hypoxia-inducible factor-1 alpha and associated proteins in pancreatic ductal adenocarcinoma and their impact on prognosis

Sun

Qiu²,

Liu³

et al. 2007

Int J Oncol

103

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“…One of these is the PI3 kinase pathway (Zhong et al, 2000;Chun et al, 2002). Thioredoxin has been shown to regulate this pathway by inhibiting PTEN, which in turn is a negative regulator of the PI3K pathway (Meuillet et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic and antiangiogenic activity of AW464 (NSC 706704), a novel thioredoxin inhibitor: an in vitro study

et al. 2005

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AW464 (NSC 706704) is a novel benzothiazole substituted quinol compound active against colon, renal and certain breast cancer cell lines. NCI COMPARE analysis indicates possible interaction with thioredoxin/thioredoxin reductase, which is upregulated under hypoxia. Through activity on HIF1a, VEGF levels are regulated and angiogenesis controlled. A thioredoxin inhibitor could therefore exhibit enhanced hypoxic toxicity and indirect antiangiogenic effects. In vitro experiments were performed on colorectal and breast cancer cell lines under both normoxic and hypoxic conditions and results compared against those obtained with normal cell lines, fibroblasts and keratinocytes. Antiangiogenic effects were studied using both large and microvessel cells. Indirect antiangiogenic effects (production of angiogenic growth factors) were studied via ELISA. We show that AW464 exerts antiproliferative effects on tumour cell lines as well as endothelial cells with an IC 50 of B0.5 mM. Fibroblasts are however resistant. Proliferating, rather than quiescent, endothelial cells are sensitive to the drug indicating potential antiangiogenic rather than antivascular action. Endothelial differentiation is also inhibited in vitro. Hypoxia (1% O 2 for 48 h) sensitises colorectal cells to lower drug concentrations, and in HT29s greater inhibition of VEGF is observed under such conditions. In contrast, bFGF levels are unaffected, suggesting possible involvement of HIF1a. Thus, AW464 is a promising chemotherapeutic drug that may have enhanced potency under hypoxic conditions and also additional antiangiogenic activity.

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“…HIF-1 protein is known to activate the transcription of genes encoding transferrin, VEGF, endothelin-1, and inducible nitric oxide synthetase, which are implicated in vasodilation, neovascularization, and tumor metastasis, and plays an essential role in oxygen homeostasis (2,18,19). In the present study, we investigated the differential expression of HIF-1 protein among common histologic types of NSCLC.…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of Hypoxia Inducible Factor-1 alpha and Tumor Cell Proliferation Between Squamous Cell Carcinomas and Adenocarcinomas Among Operable Non-Small Cell Lung Carcinomas

Lee

Kang

et al. 2003

J Korean Med Sci

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This study aimed to evaluate whether the elevated level of hypoxia-inducible factor-1 (HIF-1 ) correlated with histologic types, angiogenesis, tumor cell proliferation, and clinical parameters in common non-small cell lung carcinomas (NSCLCs). We performed immunohistochemical stains using paraffin-embedded tissue blocks from 84 cases of operable NSCLC [No. of squamous cell carcinoma (SCC), 45; No. of adenocarcinoma (AC), 39]. HIF-1 expression was related with histologic types (66.7% in SCCs vs 20.5% in ACs, p<0.001), but not with lymph node status, tumor stage, vascular endothelial growth factor expression, microvessel density (MVD), and proliferating cell nuclear antigen (PCNA) index (p>0.05, respectively). As for the histologic types, MVD and PCNA index were significantly higher in SCCs than in ACs (p=0.009 and p=0.016, respectively). Among HIF-1 positive carcinomas, MVD was significantly higher in HIF-1 positive SCCs than in HIF-1 positive ACs (p= 0.023). The overall survival curves were not associated with HIF-1 expression or any other histologic parameters (p>0.05). These findings suggest that HIF-1 expression in NSCLCs may play a differential role according to histologic types, but its prognostic significance is indeterminate.

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Oxygen-Dependent and -Independent Regulation of HIF-1alpha

Cited by 138 publications

References 64 publications

Expression of hypoxia-inducible factor-1 alpha and associated proteins in pancreatic ductal adenocarcinoma and their impact on prognosis

Expression of hypoxia-inducible factor-1 alpha and associated proteins in pancreatic ductal adenocarcinoma and their impact on prognosis

Cytotoxic and antiangiogenic activity of AW464 (NSC 706704), a novel thioredoxin inhibitor: an in vitro study

Differential Expression of Hypoxia Inducible Factor-1 alpha and Tumor Cell Proliferation Between Squamous Cell Carcinomas and Adenocarcinomas Among Operable Non-Small Cell Lung Carcinomas

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