Hypoxia inducible factor-1α in renal cell carcinoma
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
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.
Umeå University medical dissertations, ISSN 0346-6612 ; 1141
renal cell carcinoma, hypoxia, RT-PCR, angiogenesis, western blot, tissue microarray, protein, mRNA, HIF-1 alpha, GLUT-1, survival
Urology and Nephrology
IdentifiersURN: urn:nbn:se:umu:diva-1462ISBN: 978-91-7264-452-6OAI: oai:DiVA.org:umu-1462DiVA: diva2:141141
2007-12-21, Betula, 6M, NUS, Umeå, 09:00 (English)
Malmström, Per-Uno, Professor
Ljungberg, Börje, ProfessorRasmuson, Torgny, DocentGrankvist, Kjell, ProfessorBergh, Anders, Professor
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