Date of Award
Restricted Access Dissertation
Doctor of Philosophy
Field of Study
Graduate School of Biomedical Sciences
Renal cell carcinoma Renal cell carcinoma (RCC) is one of the top ten leading causes of cancer deaths in USA. The National Cancer Institute’s statistics reveal doubling of the risk of RCC in past 50 years and recent data indicates that RCC contributes to loss of 195,000 person-years of productivity per calendar year making it an important public health problem . Hence, analysis of the specific signaling pathways and networks in aggressive types of RCC and characterization of the mechanisms of action of novel anti-cancer agents that selectively target the processes of oncogenic transformation and tumor progression in kidney has gained momentum in the translational research in renal oncology.
RCC was first described by Konig in the year 1826. The proximal renal tubular origin of many renal tumors was confirmed by Robin and Waldeyer in 1855 and 1867, respectively . The major histological sub-types of renal epithelial tumors are comprised of clear cell RCC (75%), papillary type 1 RCC (5%), papillary type 2 RCC (10%), chromophobe RCC (5%) and oncocytoma (5%) . RCC occurs in both sporadic and hereditary forms. The deletions and loss of function mutations in the tumor suppressor von Hippel-Lindau (VHL) gene which is located on chromosome 3p25.3 leading to “VHL syndrome” (Online Mendelian Inheritance in Man, OMIM, catalogue number: 193300) is a major genetic risk factor for the incidence of clear cell RCC, a major sub-type of RCC [4-6]. The VHL syndrome was first described more than a 2 century ago by Treacher Collins and Eugene von Hippel following the observation of familial inheritance pattern of retinal angiomas [7,8]. Later, Arvind Lindau, a neuropathologist, described the incidence of cerebellar hemangioblastomas . The VHL syndrome is also characterized by an increased predisposition to tumors of adrenal glands, inner ear, spine, and pancreatic cysts and hemangioblastomas [10-15]. Hereditary loss of VHL leads to incidence of multifocal, bilateral and highly vascular tumors in kidneys characterized by an aggressive and metastatic course of progression in younger years of life in contrast to sporadic RCC which generally affects mainly elderly population . The VHL mutations have also been detected in many cases of sporadic RCC which in turn reveals the susceptibility of VHL locus to acquired mutations during life time . The life-style and environmental risks for the incidence of sporadic RCC include cigarette smoking, obesity and asbestos exposure [17-20].
The significance of VHL in tumor formation and progression is due to its designated role in oxygen-sensing machinery of the cell which in turn regulates a plethora of cellular proliferative, metabolic and transcriptional processes. The cellular levels of oxygen in drosophila as well as mammals are sensed by a family of hypoxia inducible factors (HIF), proteins characterized by the presence of basic-helix-loop-helix structure and a PAS (dimerization) domain characteristic of many transcription factors. The human HIFs include HIF1-α, HIF1-β, HIF2-α, HIF2-β, HIF3- α and HIF3-β which participate in oxygen dependent re-programming of cellular transcription [21, 22]. The HIF-α subunits have N-terminal transactivation domain (NTAD) and C-terminal transactivation domain (CTAD) which are specifically regulated in oxygen dependent manner . In hypoxic conditions, the transcriptional co-activators like cAMP-response-elementbinding protein (CREB)-binding protein (CBP) and p300 bind to CTAD of HIF-α. This leads to 3 activation of hypoxia inducible genes like EGFR, VEGF, PDGFβ and TGFα which in turn contribute to enhanced angiogenic and mitogenic potential to survive in hypoxic environment [24-27]. The VHL gene product, pVHL, plays a vital role in regulating the function of HIF-α when oxygen levels are normal in cells. In normoxic conditions, the HIF-α proteins are hydroxylated at asparagine residue in NTAD by factor inhibiting HIF-α (FIH) and at proline residues by HIF prolyl-hydroxylases [28,29]. The prolyl hydroxylation of HIF-α at NTAD leads to binding of pVHL-elongin-cullin2 complex to HIF-α followed by polyubiquitination and proteosomal degradation [29-33]. Thus, pVHL contributes to inhibition of HIF-α signaling.
The function of pVHL extends beyond regulation of hypoxic signaling in the cells. The pVHL is required for regulation of integrins and tight junctions in epithelial cells and VHL mutant (VHL-mut) cells have increased levels of HIF2-α, α5-integrin, cyclin D1 and lower p27 levels along with loss of epithelial morphology . The introduction of pVHL into VHL-mut RCC leads to cell cycle arrest, epithelial differentiation and suppression of tumor forming ability [35, 36]. Thus, pVHL plays a vital role in regulating multiple signaling processes of importance in oncogenic transformation, survival of tumors in hypoxic conditions along with a role in maintaining epithelial phenotype.
Dalasanur Nagaprashantina, L.
"Mercapturic Acid Pathway: A Novel Opportunity for Targeting VHL-Mutant Renal Cell Carcinoma" Fort Worth, Tx: University of North Texas Health Science Center;