dc.description.abstract | Abstract
Clear-cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma in the world. Over 70% of ccRCC patients have mutations in the von Hippel–Lindau (VHL) tumor suppress gene. Mutations in VHL activate hypoxia-inducible factor 1-alpha (HIF1A) and result in alteration of microenvironment and metabolic pathways. We have generated conditional VHL knockout mouse model to study the etiology of ccRCC progression. In this mouse model, we observed that inactivation of VHL in the kidney tubules resulted in tissue inflammation and fibrosis. Further, it was reported that patients of chronic kidney disease (CKD), a chronic inflammatory disorder, were more likely to develop this cancer compared to the general population. These observations suggest a role of inflammation in kidney cancer development. The goal of this study is to dissect the correlation between inflammation and kidney cancer development. By analyzing expression profiles of mouse VHL mutant kidneys relative to wild-type kidneys, we found a cluster of genes involved in immune response were over-represented. These over-represented immune response genes include regulators of macrophage functions, in addition to those involved in cellular transformation such as Myc. We then compared this gene expression profile to those of the chronic kidney disease (CKD) kidney (GSE66494), and stage 1 and stage 3 ccRCC, obtained from the public domain database (GSE36895;only those containing VHL mutations were selected). Many genes significantly down-regulated in inflammatory kidney (VHL knockout mouse and CKD patients) and in early stage and/or late stage ccRCC are associated with metabolic processes, confirming that metabolic abnormality is the feature of VHL mutation and inflammatory kidney. We hypothesized that genes activated in inflammation kidneys and early-stage cancer may play important roles in the initiation of inflammation-induced cancer. For example, we found genes involved in the developmental process were over-represented in both inflammatory tissues and in early-stage cancer. This may suggest that dedifferentiation process central to cancer formation may occur in precancerous inflammation. Further, genes that were activated only in inflammation kidneys and late-stage cancers and genes consistently up-regulated in all diseased kidneys included many immune response genes, suggesting that inflammation may be not only precursor of cancer formation but also may play important roles in cancer progression. Moreover, chemokines that are involved in immune cell recruit may also be involved in the induction of metastasis. Genes that were significantly up-regulated both in stage1 and stage3 cancers but not in VHL knockout mouse or CKD kidneys include DNA damage response associated genes. This result suggests that DNA damages occur at the onset of cancer. The result of immunohistochemistry (IHC) suggested that accumulation of DNA damages occurred in pre-cancerous inflammation tissues. Based on these results, we proposed the genetic model for ccRCC initiation and progression. | en_US |