Hypoxia inducible factor-1? in renal cell carcinoma
Hypoxia Inducible Factor-1? in Renal Cell CarcinomaDepartments of Surgical and Perioperative Sciences, Urology and Andrology; Radiation Sciences, Oncology; Medical Biosciences, Pathology; and Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, SwedenBackground: 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 1? (HIF-1?) 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-1? 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-1? mRNA and protein expression as well as GLUT-1 protein expression, correlating them to each other and clinicopathological parameters.Results: Using Western Blot, HIF-1? protein expression differed significantly between the different RCC types and kidney cortex. In cRCC, high expression of HIF-1? was an independent prognostic factor for favourable prognosis.TMA is a useful method to analyze HIF-1? protein expression in RCC. HIF-1? 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-1? was seen.HIF-1? mRNA levels were significantly lower in cRCC compared to other RCC types and kidney cortex. An inverse correlation between HIF-1? 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-1? protein is not necessarily all bad and translational regulation appears more critical than anticipated. Further studies are encouraged to clarify angiogenic pathways in RCC.
Source Type:Doctoral Dissertation
Keywords:MEDICINE; Surgery; Surgical research; Urology and andrology; renal cell carcinoma; hypoxia; RT-PCR; angiogenesis; western blot; tissue microarray; protein; mRNA; HIF-1 alpha; GLUT-1; survival
Date of Publication:01/01/2007