Co‐expression of Hif1α and CAIX is associated with poor prognosis in oral squamous cell carcinoma patients

Eckert, Alexander W.; Lautner, M.H.W.; Schütze, Andreas; Bolte, Kimberly; Bache, Matthias; Kappler, Matthias; Schubert, Johannes; Täubert, Helge; Bilkenroth, Udo

doi:10.1111/j.1600-0714.2009.00829.x

Cited by 52 publications

(43 citation statements)

References 26 publications

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“…HIF1α regulates genes involved in tumor initiation, progression, and metastasis (55), and HIF1α overexpression correlates with a poor prognosis in human head and neck cancer (56). We show that RARγ and RXR agonists inhibit the HIF1α signaling pathway in the context of tongue carcinogenesis (Fig.…”

Section: Discussionmentioning

confidence: 61%

Combination of bexarotene and the retinoid CD1530 reduces murine oral-cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide

Tang¹,

Osei-Sarfo²,

Urvalek³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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We investigated the effects of bexarotene (a retinoid X receptor agonist), CD1530 (a retinoic acid receptor γ selective agonist), and the combination of these two drugs for the prevention of oral carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in a mouse model of human oral-cavity and esophageal squamous-cell carcinoma previously generated in our laboratory. We observed decreased numbers of neoplastic tongue lesions and reduced lesion severity in the 4-NQO plus CD1530 (4N+C) and 4-NQO plus bexarotene plus CD1530 (4N+B+C) groups compared with the 4-NQO group. RNA-Seq analyses showed increases in transcripts in cell proliferation/cell cycle progression pathways in the 4-NQO vs. the untreated group. In addition, β-catenin and matrix metallopeptidase 9 (MMP9) protein levels and reactive oxygen species (ROS), as assessed by 4-hydroxynonenal (4-HNE) staining, were elevated in tongue tissues 17 wk after the termination of the 4-NQO treatment. The 4N+B, 4N+C, and 4N+B+C groups showed dramatically lower levels of β-catenin, MMP9, and 4-HNE staining compared with the 4-NQO group. The major reduction in 4-HNE staining in the retinoid treatment groups suggests a novel mechanism of action, reduction of ROS, by which bexarotene and CD1530 inhibit carcinogenesis.cancer prevention | retinoic acid receptor gamma agonist | retinoid X receptor | tongue squamous cell carcinoma | oral cancer

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Section: Discussionmentioning

confidence: 61%

Combination of bexarotene and the retinoid CD1530 reduces murine oral-cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide

Tang¹,

Osei-Sarfo²,

Urvalek³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…24 Because of these difficulties, additional independent prognostic markers need to be identified to improve the diagnosis and therapeutic regimens. 6,7 It has been suggested that hypoxia is an independent adverse prognostic factor in patients with head and neck cancer. 25 The main transcription factor activated by hypoxia is HIF-1a, which regulates cell metabolism as part of the cell's response to hypoxia.…”

Section: Discussionmentioning

confidence: 99%

“…The largest functional group of genes consistently regulated by HIF-1a are the genes associated with glucose metabolism. 6 HIF-1a increases the rate of glucose uptake through the transcriptional activation of the facultative glucose transporters GLUT-1 and GLUT-3. Elevated expression of either HIF1-a or GLUT-1 has been detected in many different cancers, including head and neck tumor.…”

Section: Discussionmentioning

confidence: 99%

“…4,5 Therefore, additional independent prognostic markers need to be identified to improve the diagnosis and therapeutic regimens. 6,7 The presence of neck metastases is the most important prognostic factor for OSCC; if present, it results in a 50% reduction in survival rates. 5 The growth and metastasis of solid tumors require the induction of angiogenesis (ie, the formation and remodeling of new blood vessels from a pre-existing vascular network to ensure the delivery of oxygen, nutrients, and growth factors to the rapidly dividing transformed cells).…”

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confidence: 99%

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Distribution of Hypoxia-Inducible Factor-1α and Glucose Transporter-1 in Human Tongue Cancers

Vasconcelos

Oliveira

et al. 2015

Journal of Oral and Maxillofacial Surgery

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Purpose: Oral squamous cell carcinomas have the potential for rapid and unlimited growth. Therefore, hypoxic tissue areas are common in these malignant tumors and contribute to cancer progression, therapy resistance, and poor outcomes. The aim of the present study was to analyze the gene product distribution of hypoxia-inducible factor-1a (HIF-1a) and glucose transporter-1 (GLUT-1) in cases of tongue squamous cell carcinoma (TSCC) and to identify a preliminary correlation between these proteins and clinical staging and Brynes's histologic grading system (HGS). Materials and Methods:The sample included 57 cases of TSCC. Histologic sections of 3 mm were submitted to the immunoperoxidase method and semiquantitative analysis. The association between HIF-1a and GLUT-1 expression in TSCC and the clinical stage and the HGS of Bryne (1998) was evaluated using the c 2 test, with the significance level set at 0.05 (a = 0.05).Results: HIF-1a was mainly expressed in the nucleus/cytoplasm of neoplastic cells, most specimens exhibited diffuse staining in neoplastic cells (84.2%), and focal staining was only observed in perinecrotic areas (15.8%). GLUT-1 was expressed in the cytoplasm and membrane of malignant cells, and diffuse staining was observed in all cases. The intensity of HIF-1a expression correlated significantly with clinical stage (P = .011) and HGS (P = .002). A significant association was observed between the distribution of HIF-1a expression and metastasis (P = .040). Immunoexpression of GLUT-1 correlated significantly with clinical stage (P = .002) and HGS (P = .000). GLUT-1 expression in the peripheral island was predominant in most low-grade tumors (78.6%); in the high-grade cases, the expression prevailed in the location center/periphery (55.8%). Comparison of the location of the tumor island in the different histologic grades showed a statistically significant difference (P = .025).

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“…A Cox proportional hazards model was applied to identify prognostic variables that predict overall survival and disease-free survival. The power calculation was done with PASS (V. 08.0.3, NCSS), assuming the 5-year survival rate to be 50% (27), hazard ratio to vary from 2.17 to 4.53 (21,(28)(29)(30), the proportion in control group 1 to be 47.5% (HIF-1α negative) or 39.2% (HIF-2α negative), and twoside α as 0.05. The log-rank test with an overall sample size of 97 subjects achieved 81.72% to 99.94% power for HIF-1α and 76.69% to 99.74% power for HIF-2α.…”

Section: Statisticsmentioning

confidence: 99%

Hypoxia Inducible Factor 1α and Hypoxia Inducible Factor 2α Play Distinct and Functionally Overlapping Roles in Oral Squamous Cell Carcinoma

Zhu

Tang

et al. 2010

Clinical Cancer Research

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Purpose: This study aimed to investigate the functional difference between hypoxia inducible factor (HIF)-1α and HIF-2α in oral squamous cell carcinomas (OSCC).Experimental Design: We evaluated the correlations between HIF-1α and HIF-2α expression and the clinical-pathologic characteristics of 97 patients with OSCC by immunohistochemical staining. OSCC cell lines transfected with lentivirus encoding short hairpin RNA against HIF-1α/2α were used to investigate the HIF-1α/2α-dependent target genes. Xenograft tumors in nude mice were established using cells affected by lentivirus, and tumor growth, angiogenesis, proliferation, and apoptosis were measured.Results: HIF-1α expression was significantly associated with T stage (P = 0.004), lymph node involvement (P = 0.006), histologic differentiation (P = 0.013), and microvessel density (P = 0.014), whereas that of HIF-2α was associated with T stage (P = 0.011) and microvessel density (P = 0.005). Patients with positive HIF-1α nuclear staining had a significantly worse overall survival (P < 0.001) and disease-free survival (P < 0.001) than those with negative HIF-1α staining. When OSCC cells were cultured at 5% O 2 , only HIF-2α contributed to the expression of vascular endothelial growth factor. At 1% O 2 , vascular endothelial growth factor was regulated by both HIF-1α and HIF-2α, but glucose transporter 1, carbonic anhydrase 9, and urokinase-type plasminogen activator receptor were regulated by HIF-1α rather than by HIF-2α. Knocking down HIF-1α or HIF-2α individually inhibited the xenograft tumor angiogenesis and growth, and knocking them down simultaneously revealed a better inhibitory effect than knocking down either unit alone.

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Co‐expression of Hif1α and CAIX is associated with poor prognosis in oral squamous cell carcinoma patients

Abstract: A co-detection of low Hif1alpha/CAIX expression is significantly correlated with a better prognosis for OSCC patients, which may have implications for therapy options for these patients.

Cited by 52 publications

References 26 publications

Combination of bexarotene and the retinoid CD1530 reduces murine oral-cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide

Combination of bexarotene and the retinoid CD1530 reduces murine oral-cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide

Distribution of Hypoxia-Inducible Factor-1α and Glucose Transporter-1 in Human Tongue Cancers

Hypoxia Inducible Factor 1α and Hypoxia Inducible Factor 2α Play Distinct and Functionally Overlapping Roles in Oral Squamous Cell Carcinoma

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