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Hypoxia inducible factor-1α in renal cell carcinoma
Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences.
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hypoxia Inducible Factor-1α in Renal Cell Carcinoma

Departments of Surgical and Perioperative Sciences, Urology and Andrology; Radiation Sciences, Oncology; Medical Biosciences, Pathology; and Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden

Background: Renal cell carcinoma (RCC) accounts for approximately 2-3% of all human cancers. A distinguished feature of RCC is vascularisation and among the three dominating RCC types conventional RCC (cRCC) generally is more vascularised than papillary RCC (pRCC) and chromophobe RCC (chRCC). Angiogenesis is a critical step in tumour progression controlled by a balance involving molecules that have positive and negative regulatory activity. A balance distorted by metabolic stress such as hypoxia, acidosis, and inflammation. Hypoxia-Inducible Factor 1α (HIF-1α) is a key transcription factor in angiogenesis and tumour progression, targeting more than a 100 genes involved in vascular growth and regulation, iron metabolism and erythropoesis, collagen matrix formation, regulation of extracellular pH, glucose uptake and metabolism, proliferation, apoptosis, differentiation, and cell viability.

Methods: Tumour tissue and corresponding kidney cortex from nephrectomised RCC patients was used in order to characterize HIF-1α expression and one of its target genes, Glucose Transporter 1 (GLUT-1). All tumour samples were thoroughly described regarding tumour type, TNM stage, nuclear grade, tumour size, vein invasion, and patient survival. Utilizing RT-PCR, Westen Blot and Tissue micro array (TMA) we studied HIF-1α mRNA and protein expression as well as GLUT-1 protein expression, correlating them to each other and clinicopathological parameters.

Results: Using Western Blot, HIF-1α protein expression differed significantly between the different RCC types and kidney cortex. In cRCC, high expression of HIF-1α was an independent prognostic factor for favourable prognosis.

TMA is a useful method to analyze HIF-1α protein expression in RCC. HIF-1α levels were significantly lower in locally aggressive cRCC and patients with high levels of HIF-1 tended to have a better prognosis.

GLUT-1 levels were higher in cRCC than in other RCC types and for cRCC a correlation to HIF-1α was seen.

HIF-1α mRNA levels were significantly lower in cRCC compared to other RCC types and kidney cortex. An inverse correlation between HIF-1α protein expression and mRNA levels was observed.

Summary: These results demonstrate a discrepancy between RCC types, highlighting the need to separately evaluate biological events in different RCC types. Overexpression of HIF-1α protein is not necessarily all bad and translational regulation appears more critical than anticipated. Further studies are encouraged to clarify angiogenic pathways in RCC.

Place, publisher, year, edition, pages
Umeå: Kirurgisk och perioperativ vetenskap , 2007. , 60 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1141
Keyword [en]
renal cell carcinoma, hypoxia, RT-PCR, angiogenesis, western blot, tissue microarray, protein, mRNA, HIF-1 alpha, GLUT-1, survival
National Category
Urology and Nephrology
Identifiers
URN: urn:nbn:se:umu:diva-1462ISBN: 978-91-7264-452-6 (print)OAI: oai:DiVA.org:umu-1462DiVA: diva2:141141
Public defence
2007-12-21, Betula, 6M, NUS, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2007-12-05 Created: 2007-12-05 Last updated: 2009-09-22Bibliographically approved
List of papers
1. The expression of hypoxia-inducible factor 1alpha is a favorable independent prognostic factor in renal cell carcinoma
Open this publication in new window or tab >>The expression of hypoxia-inducible factor 1alpha is a favorable independent prognostic factor in renal cell carcinoma
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2005 (English)In: Clinical Cancer Research, ISSN 1078-0432, Vol. 11, no 3, 1129-1135 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-14449 (URN)15709180 (PubMedID)
Available from: 2007-09-14 Created: 2007-09-14 Last updated: 2009-09-22Bibliographically approved
2. Hypoxia-inducible factor 1alpha expression in renal cell carcinoma analyzed by tissue microarray
Open this publication in new window or tab >>Hypoxia-inducible factor 1alpha expression in renal cell carcinoma analyzed by tissue microarray
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2006 (English)In: European Urology, ISSN 0302-2838, Vol. 50, no 6, 1272-1277 p.Article in journal (Refereed) Published
Keyword
Hypoxia-inducible factor, HIF-1alpha, RCC, prognosis, tissue microarray
Identifiers
urn:nbn:se:umu:diva-15717 (URN)doi:10.1016/j.eururo.2006.05.043 (DOI)16814458 (PubMedID)
Available from: 2007-09-14 Created: 2007-09-14 Last updated: 2009-05-28Bibliographically approved
3. Glucose transporter-1 expression in renal cell carcinoma and its correlation with hypoxia inducible factor-1 alpha.
Open this publication in new window or tab >>Glucose transporter-1 expression in renal cell carcinoma and its correlation with hypoxia inducible factor-1 alpha.
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2008 (English)In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 101, no 4, 480-484 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE:

To evaluate transcription factor hypoxia inducible factor-1 alpha (HIF-1 alpha) activity, by analysing a target gene for HIF-1 alpha, glucose transporter-1 (GLUT-1), using a tissue microarray (TMA) in different types of renal cell carcinoma (RCC, a tumour with a variable clinical course, partly due to angiogenic activity), as angiogenesis is important for tumour progression and metastatic spread, and is activated by hypoxia.

PATIENTS AND METHODS:

GLUT-1 and HIF-1 alpha expressions were semiquantitatively analysed using immunohistological staining of a prepared TMA, using samples from 187 patients, including 148 with conventional, 26 with papillary and 13 with chromophobe RCC.

RESULTS:

GLUT-1 staining was found mainly in the cytoplasm. The tumours were subdivided into GLUT -1(LOW) and GLUT-1(HIGH), based on staining intensity. There was a significant difference in GLUT-1 expression between RCC types (P < 0.05). In conventional RCC, GLUT-1 had no correlation with clinicopathological variables. By contrast there was a correlation with tumour stage in papillary RCC. There was an insignificant trend to better survival of patients with GLUT-1(LOW) expression in both conventional and papillary RCC. GLUT-1 correlated significantly (P = 0.008) with HIF-1 alpha.

CONCLUSIONS:

Most patients with conventional RCC had GLUT-1(HIGH) staining and there was a significant correlation with HIF-1 alpha. In papillary RCC, GLUT-1 expression was associated with stage; GLUT-1 expression was significantly higher in conventional RCC than in papillary and chromophobe RCC. GLUT-1(LOW) in both papillary and conventional RCC appeared to correspond with a better prognosis.

Keyword
glucose transporter-1, hypoxia inducible factor 1 alpha, RCC, prognosis, tissue microarray
Identifiers
urn:nbn:se:umu:diva-8815 (URN)doi:10.1111/j.1464-410X.2007.07238.x (DOI)17922867 (PubMedID)
Available from: 2008-02-14 Created: 2008-02-14 Last updated: 2011-08-25Bibliographically approved
4. Hypoxia-inducible factor-1α mRNA and protein levels in renal cell carcinoma and in relation to kidney cortex tissue
Open this publication in new window or tab >>Hypoxia-inducible factor-1α mRNA and protein levels in renal cell carcinoma and in relation to kidney cortex tissue
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Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-2841 (URN)
Available from: 2007-12-05 Created: 2007-12-05 Last updated: 2010-01-13Bibliographically approved

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