OVER EXPRESSION OF HYPOXIA-INDUCIBLE FACTOR-1α IN RENAL AND BLADDER CANCER CELLS INCREASES TUMORIGENIC POTENCY

Kondo, Yukihiro; Hamada, Junko; Kobayashi, Chie; Nakamura, Ryosuke; Suzuki, Yasutomo; Kimata, Ryoji; Nishimura, Takuya; Kitagawa, Toshikazu; Kunimoto, Manabu; Imura, Nobumasa; Hara, Shuntaro

doi:10.1097/01.ju.0000154343.35444.09

Cited by 24 publications

(24 citation statements)

References 13 publications

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“…These results underscore the importance of HIF activation for cell proliferation and tumor progression in these cell lines. This is consistent with previous observations that the activation of HIF activity through its overexpression (28) or chronic hypoxia (52) leads to increased tumor growth. Conversely, decreasing HIF transcriptional activity through antisense, dominant-negative, or short interfering RNA constructs (12,14,27,30,39) slows tumor progression.…”

Section: Discussionsupporting

confidence: 82%

“…Some evidence suggests that the flavin adenine dinucleotide site in SdhA is the principal source of superoxide generation, due to the exposure of VOL. 28,2008 SdhB DISRUPTION ALTERS ROS, HIF, AND TUMOR GROWTH 727…”

Section: Discussionmentioning

confidence: 99%

“…Both SdhB and SdhA shRNA cell lines respond normally to hypoxia (data not shown), indicating that the disruption of complex II does not affect the VOL. 28,2008 SdhB DISRUPTION ALTERS ROS, HIF, AND TUMOR GROWTH 723…”

Section: Vol 28 2008 Sdhb Disruption Alters Ros Hif and Tumor Gromentioning

confidence: 99%

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Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis

Guzy¹,

Sharma²,

Bell

et al. 2008

Molecular and Cellular Biology

380

330

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Mitochondrial complex II is a tumor suppressor comprised of four subunits (SdhA, SdhB, SdhC, and SdhD). Mutations in any of these should disrupt complex II enzymatic activity, yet defects in SdhA produce bioenergetic deficiency while defects in SdhB, SdhC, or SdhD induce tumor formation. The mechanisms underlying these differences are not known. We show that the inhibition of distal subunits of complex II, either pharmacologically or via RNA interference of SdhB, increases normoxic reactive oxygen species (ROS) production, increases hypoxia-inducible factor alpha (HIF-α) stabilization in an ROS-dependent manner, and increases growth rates in vitro and in vivo without affecting hypoxia-mediated activation of HIF-α. Proximal pharmacologic inhibition or RNA interference of complex II at SdhA, however, does not increase normoxic ROS production or HIF-α stabilization and results in decreased growth rates in vitro and in vivo. Furthermore, the enhanced growth rates resulting from SdhB suppression are inhibited by the suppression of HIF-1α and/or HIF-2α, indicating that the mechanism of SdhB-induced tumor formation relies upon ROS production and subsequent HIF-α activation. Therefore, differences in ROS production, HIF proliferation, and cell proliferation contribute to the differences in tumor phenotype in cells lacking SdhB as opposed to those lacking SdhA.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis

Guzy¹,

Sharma²,

Bell

et al. 2008

Molecular and Cellular Biology

380

330

View full text Add to dashboard Cite

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“…They showed that the resulting HIF-1␣ ϩ/ϩ tumors grew significantly faster than HIF-1␣ Ϫ/Ϫ tumors. In line with these studies, an in vivo experiment by Kondo et al [84] suggested that overexpression of HIF-1␣ increased the tumor growth of renal cancer cells in nude mice. In contrast, Savai et al [85] concluded that, in subcutaneous tumors derived from HIF-1␣-overexpressing A549 cells, tumor growth was negatively affected as a result of decreased proliferation and increased apoptosis.…”

Section: Hypoxia and Tumor Growthsupporting

confidence: 54%

Review: Implications of In Vitro Research on the Effect of Radiotherapy and Chemotherapy Under Hypoxic Conditions

et al. 2007

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LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Argue why hypoxic regions in solid tumors often contain viable cells that are intrinsically more resistant to treatment with radiotherapy or chemotherapy.2. Describe how exposure of cells or cell lines to hypoxic conditions has major implications on multiple intracellular pathways.3. Evaluate the importance of investigating chemoradiotherapy combinations in vitro under both normoxic and hypoxic conditions.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTAs it is now well established that human solid tumors frequently contain a substantial fraction of cells that are hypoxic, more and more in vitro research is focusing on the impact of hypoxia on the outcome of radiotherapy and chemotherapy. Indeed, the efficacy of irradiation and many cytotoxic drugs relies on an adequate oxygen supply. Consequently, hypoxic regions in solid tumors often contain viable cells that are intrinsically more resistant to treatment with radiotherapy or chemotherapy. Moreover, efforts have been made to exploit hypoxia as a potential difference between malignant and normal tissues. Nowadays, a body of evidence indicates that oxygen deficiency clearly influences some major intracellular pathways such as those involved in cell proliferation, cell cycle progression, apoptosis, cell adhesion, and others. Obviously, when investigating the effects of radiotherapy or chemotherapy or both combined under hypoxic conditions, it is essential to consider the influences of hypoxia itself on the cell. In this review, we first focus on the effects of hypoxia per se on some critical biological pathways. Next, we sketch an overview of preclinical and clinical research on radiotherapy, chemotherapy, and chemoradiation under hypoxic conditions. The Oncologist 2007;12: 690 -712

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“…The formation of tumor microvessels is stimulated by angiogenic factors, especially vascular endothelial growth factor (VEGF) [3][4][5] . Hypoxia is related to tumor cell growth, differentiation, invasion and metastasis activity.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma

Zhang²,

Ru³

et al. 2007

WJG

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of HIF-1α and VEGF. The mean survival time and the 5-year survival rate in cases with positive expression HIF-1α and VEGF and MVD value ≥ 41.5/0.72 mm 2 were significantly lower than those with negative expression of HIF-1α and VEGF and MVD value < 41.5/0.72 mm 2 . CONCLUSION:Overexpression of HIF-1α is found in gastric carcinoma. HIF-1α may induce the angiogenesis in gastric carcinoma by upregulating the transcription of VEGF gene, and take part in tumor invasion and metastasis. They can be used as prognostic markers of gastric cancer in clinical practice. INTRODUCTIONAngiogenesis plays an important role in tumor growth and metastasis [1,2] . The formation of tumor microvessels is stimulated by angiogenic factors, especially vascular endothelial growth factor (VEGF) [3][4][5] . Hypoxia is related to tumor cell growth, differentiation, invasion and metastasis activity. In recent years, studies showed that hypoxia inducible factor-1 (HIF-1) played an important role in oxygen balance and tumor angiogenesis [6] . HIF-1 consists of α and β subunits, and HIF-1α is a key subunit of HIF activity regulated by hypoxia [1] . HIF-1 mRNA and protein overexpression was found in a variety of tumors, including breast cancer, prostate cancer, kidney cancer, rectal adenocarcinoma, etc [2,4,[7][8][9] . However, research on HIF-1α in gastric cancer was rarely reported. In the present study, BASIC RESEARCHUpregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma Abstract AIM:To investigate the implication of the hypoxia inducible factor HIF-1α mRNA in gastric carcinoma and its relation to the expression of vascular endothelial growth factor (VEGF) protein, tumor angiogenesis invasion/metastasis and the patient's survival. METHODS:In situ hybridization was used to examine expression of HIF-1α mRNA, and immunohistochemical staining was used to examine expression of VEGF protein and CD34 in 118 specimens from patients with gastric carcinoma. RESULTS:The positive rates of HIF-1α mRNA and VEGF protein were 49.15% and 55.92%, respectively. Positive expressions of HIF-1α and VEGF in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis were dramatically stronger than stage T1-T2 cases and those without vessel invasion, lymph node metastasis and distant metastasis. The mean microvascular density (MVD) in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis was significantly higher than stage T1-T2 tumors and those without vessel invasion, lymph node metastasis and distant metastasis. The mean MVD in tumors with positive HIF-1α and VEGF expression was significantly higher than that in tumors with negative HIF-1α and VEGF expression. The expression of HIF-1α was positively correlated with VEGF protein. There were positive correlations between MVD and expression

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OVER EXPRESSION OF HYPOXIA-INDUCIBLE FACTOR-1α IN RENAL AND BLADDER CANCER CELLS INCREASES TUMORIGENIC POTENCY

Abstract: These results suggest that HIF-1alpha may have important roles in bladder and renal cancer angiogenesis and proliferation.

Cited by 24 publications

References 13 publications

Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis

Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis

Review: Implications of In Vitro Research on the Effect of Radiotherapy and Chemotherapy Under Hypoxic Conditions

Upregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma

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