ECE2020 Audio ePoster Presentations Endocrine-related Cancer (14 abstracts)
Diverse regulation of HIF-1 on VEGF in renal cell carcinoma
Bojana Beleslin Cokic 1 , Svetozar Damjanovic 2 , Sandra Bizic Radulovic 3 , Tijana Suboticki 4 , Vladan Cokic 4 , Ivana Milicevic 1 , Gordana Rodic 1 , Jadranka Antic 1 & Djuro Macut 1
1Clinics for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Genetic Laboratory, Belgrade, Serbia; 2Clinics for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Belgrade, Serbia; 3Clinic of Hematology, Clinical Center of Serbia, Outpatient Clinic and Diagnostic Department, Belgrade, Serbia; 4Institute for Medical Research, Laboratory of Experimental Hematology, Belgrade, Serbia
The clear cell renal cell carcinoma (ccRCC) can be sporadic or familiar, with the mutated von Hippel-Lindau (VHL) gene. The inactive VHL protein prevents degradation of hypoxia inducible factor (HIF) that promotes overexpression of angiogenic factors such as vascular endothelial growth factor (VEGF) and erythropoietin (EPO). Sequencing and multiplex ligation-dependent probe amplification (MLPA) of VHL gene in 43 samples of ccRCC in tumors vs surrounding healthy tissues revealed 27 somatic mutations. Further, testing the loss of heterozygosity (LOH) among 27 samples showed 23 biallelic and 4 monoallelic alterations in VHL gene. We detected an increase in VEGF mRNA and protein with a low HIF-1 gene expression in ccRCC compared to healthy tissue. To observe HIF-1 induction of VEGF mRNA, we examined tumors without or with VHL mutation (monoallelic and biallelic). In comparison to normal renal tissue, we observed a significant induction of VEGF mRNA expression in wild type tumor samples with a progressive increase in samples with monoallelic and biallelic inactivation of VHL. The human RCC 786-O cell line, a model with biallelic inactivation of VHL, demonstrated significant proliferation after 48 h at 21% and 3% oxygen. The human RCC Caki-1 cell line, a model with a wild type VHL, showed very slow proliferative effect at normal and low oxygen tension compared to 786-O cells, with significant changes after 48 h at normal oxygen tension and 10% FBS. HIF-1 protein expression was increased at low serum at 21% and 3% oxygen, both in 786-O and Caki1 cell lines. VEGF protein expression was generally low at 3% oxygen tension in 786-O cells, while it was induced at 3% and 21% oxygen after 24 h and 48 h, respectively at 10% FBS in Caki1 cells. Inactivation of VHL stimulated VEGF protein expression in RCC tumor tissues, but not in 786-O cell line. Hypoxia stimulated both VEGF and HIF-1 protein expression in Caki1 cell lines, regardless of VHL inactivation. Our data suggest diverse regulation of HIF-1 on VEGF, depending on VHL alternation, hypoxia and nutrition situation in tumor and RCC cell line.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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