| Twenty five percent of all deaths in the US are due to some form of cancer. One of the most expensive cancers is UCC, due to its extremely high recurrence rates of up to 70%. In the US there were an estimated 72,570 new cases and 15,210 deaths in 2013, ranking in the top ten in both categories. The five year overall survival rates for patients diagnosed with metastatic UCC is 5%, prompting an intensive biomarker search for early detection or prediction of recurrence.;The primary goal of these studies is determine what genes are involved in the early stages of bladder carcinogenesis and if they can serve as potential biomarkers for the prediction of recurrence in UCC patients. We have used a UCC transgenic mouse model, UPII-SV40Tag, in conjunction with microarray gene expression technology to generate a list of genes that are differentially expressed in the urothelium. Since our primary goal is to identify a biomarker for early detection, we focused on the genes that were most highly upregulated at the earliest time point in our analysis, 3 weeks of age. We tested these genes in patient UCC samples by immunohistochemistry (IHC) and urine by dot-blot analysis. We discovered high levels of RHAMM, PCNA, RacGAP1, Survivin, IL-18, and PON3 in high and low grade NMIBC samples. We then found that high levels of RacGAP1, RacGAP1 and PCNA combined, or RHAMM detected in the urine correlated with recurrence in patient urine samples from a Phase II trial.;RHAMM has been shown to be involved in tumor progression, promoting invasion and migration through the ERK1/2 signaling pathway. High levels of RHAMM have implicated its elevated activity in other types of cancer. In human UCC lines that we have generated, reduced levels of RHAMM results in a reduction in proliferation and cell migration. However, we don't detect any effects from treatment of cells with the RHAMM ligand, HA, nor do we detect any activation through the ERK1/2 signaling pathway. Our data suggests RHAMM plays a role in early stage UCC and has potential to serve as a urine biomarker for UCC recurrence. |
