Investigating HIF-MYC Interactions within a Clear Cell Renal Cell Carcinoma Murine Model

项目总结/文摘

Project Summary/Abstract Renal cell carcinoma (RCC) ranks among the 7th and 10th most common cancer among men and women respectively, with an estimated 61,500 new cases and 14,000 deaths in 2015. Specifically, clear-cell renal cell carcinoma (ccRCC) accounts for approximately 70% of renal malignancies among adults. Extensive research has been conducted on understanding the genetic alterations underlying the pathological features of ccRCC. Early and more recent studies have shown that the most common mutation to occur within ccRCC patients is the inactivation of the tumor suppressor gene, VHL. Such discoveries have led to the generation of targeted therapies that are directed toward VEGF (or its receptor) and mTOR. However, responses of primary ccRCC tumors to theses agents are variable. As such, the need to discover alternative and efficient molecular targets for targeted drug therapy is essential. Our group has generated a novel genetically engineered murine model (GEMM) of ccRCC that shares histology to ccRCC patients. I will utilize this model as a platform to investigate the molecular interactions between HIFα subunits and the proto-oncogene, MYC. I hypothesize that HIF1α and HIF2α (H1H2) and HIF2α (H2) expressing ccRCC cells differentially regulate MYC's transcriptional activity and chromatin localization throughout the genome. Additionally, I hypothesize that the overexpression of MYC confers additional stability to HIFα subunits despite the loss of Vhl. Utilizing cell lines generated from our GEMM ccRCC model and Next Generation Sequencing analysis (RNA-seq and ChIP-seq), I will set out to interrogate the following aims: 1) Investigate whether MYC's transcriptional activity is differentially altered between ccRCC cells expressing H1H2 versus H2 only and 2) Determine how MYC positively regulates HIF1α and HIF2α levels within ccRCC.!