In cells that are exposed to hypoxia or lack functional VHL, HIF-a subunits accumulate and bind to HIF-b, forming heterodimers which transcriptionally activate a number of genes whose products are involved in cell adaptation to hypoxia and regulation of angiogenesis, which is one of the key processes in tumorigenesis. Several lines of evidence suggest that the function of VHL is likely to extend beyond its crucial role in oxygen signal transduction, and the loss of its function may result in deregulation of several signalling pathways that have key roles in biological processes such as cell proliferation, cell survival, cell invasion and metastasis. Aberrant expression of VHL tumor suppressor gene has been reported in a number of human malignancies, including kidney, colon, breast, gastric cancer and MEN2- associated medullary thyroid cancer. Arguments that prompted us to study the possible involvement of the VHL gene in PTC are: VHL gene is expressed, and VHL protein is detectable immunohistochemically in thyroid follicular epithelial cells and endothelial cells, the expression of VHL protein in nonneoplastic and neoplastic thyroid lesions correlates with tumor differentiation, clinicopathological correlations of VHL with PTC remain largely unknown. Therefore, we aimed this study at evaluation of the association between VHL status, and a AMN107 variety of demographic and cancer characteristics in a group of 264 Serbian patients admitted to our reference center for PTC from 1992 to 2008. Our work is the first large-scale study of this kind so far. Various tumor suppressor genes, oncogenes, and intricate networks of signaling cascades have been investigated previously in thyroid tumors. VHL protein is widely expressed in human tissues and its best documented tumor suppressor function is the negative regulation of hypoxia-inducible target genes involved in angiogenesis, erythropoiesis and energy metabolism. Accumulating evidence suggests that VHL may also have HIF-independent and tissue-specific tumor suppressor functions since it has been implicated in diverse cellular processes, including regulation of the extracellular matrix and cell invasion, cytoskeletal stability and cell-cycle control and differentiation. Several studies suggest that VHL plays a critical role in regulating apoptotic pathways in renal cell carcinoma. According to a recent report, VHL may be a positive regulator of TP53, providing insight into another potential mechanism by which VHL loss of function may contribute to carcinogenesis. The role of VHL in thyroid cancer development is obscure. Since it has been reported that normal follicular epithelium shows a strong expression of VHL protein and that a differential expression of VHL protein in nonneoplastic and neoplastic thyroid lesions is in proportion to the level of tumor differentiation, it is reasonable to assume that VHL may be involved in the development of the most common type of thyroid cancer, PTC. These reports prompted us to investigate the possible role of VHL as a classic tumor suppressor gene and a potential association of its expression level with the development and clinicopathological features of PTC.