Clear cell renal cancers are the most common form of kidney cancers. Unfortunately, despite improvements in treatments, the mortality rate has not decreased markedly. Defined as a metabolic disease, a characteristic of clear cell renal cancers is dysregulated lipid metabolism; the cancer cells have increased lipid droplets and cholesterol esters. However, the underlying mechanisms leading to these changes are unclear. Like other cancers, kidney tumors are characterized by genomic aberrations including the loss of the VHL tumor suppressor. In addition, the loss of the 14q32 region leads to increased aggressiveness of the renal tumors and is associated with a poorer patient outcome. Interestingly, this 14q32 region harbors one of the largest miRNA clusters in the human genome; however, the role of these miRNAs in renal cancer biology is presently unknown. Although it is established that the miRNA expression of this cluster is downregulated in renal cancers, further work is needed to determine whether these miRNAs at this locus contribute to lipid dysregulation and renal tumorigenesis. Thus, we hypothesize that the miRNA cluster located at 14q32 elicits tumor suppressive activity and dysregulates lipid metabolic pathways via targeting of enzymes in lipogenesis/cholesterol biosynthesis, which is expected to increase the levels of lipids/cholesterol, characteristics of clear cell renal cancers.
In Aim 1, we will determine whether the 14q32 miRNA cluster modulates mTOR inhibitor chemotherapeutic response in renal cancer cells, is tumor suppressive and contributes to lipid dysregulation using intratumoral adenoviral-mediated delivery of the cluster in a murine tumor xenograft model.
In Aim 2, we will identify which miRNAs within the 14q32 cluster alters the tumor suppressive response and lipid droplet/cholesterol levels in addition to identifying their target genes within the lipogenesis and cholesterol biosynthesis pathways in renal cancer cells. Successful completion of the proposed aims may generate new therapeutic targets for treatment of renal cell carcinoma patients. We propose that miRNA-based therapies, which would alter expression of multiple targets including those involved in the lipid metabolic pathways, to be a more promising treatment strategy in the treatment of renal cancers.
Clear cell renal cancer is a metabolic disease that is characterized by increased lipids and cholesterol; however, the underlying mechanisms leading to these alterations are unclear. Loss of the 14q32 region (which contains one of the largest miRNA clusters in the human genome) occurs in ~45% of these patients and promotes increased tumor aggressiveness. We propose that these miRNAs located at 14q32 are (1) tumor suppressive with potential to modulate mTOR inhibitor chemotherapeutic response and (2) can alter lipid/cholesterol levels in renal cells by targeting specific enzymes involved in lipogenesis and cholesterol biosynthetic pathways; indeed, miRNA-based therapies which would alter expression of multiple targets such as those in lipid pathways may be a more promising treatment strategy in the treatment of renal clear cell cancers.
