This study is to investigate the role of peroxisome proliferator-activated receptor gamma (PPAR gamma) in the progression of urothelial carcinoma (UC) after renal transplants (RT). A total of 114 UC patients were gathered, including 60 cases of primary UC and 54 cases UC after RT. RT-PCR was used to detect the mRNA expression of the 54 patients with UC after RT, and immunohistochemistry and western blot were used to examine the protein expression. The proliferative ability of two UC cell lines, and 5637, were measured by WST-1 assay. Transwell system was used to analyze the migration and invasion of UC cells. PPAR gamma agonist Rosiglitazone and the antagonist GW9662 were used to alter the PPAR gamma expression. siRNA targeting LEF1 and expression vector containing full-length cDNA of LEF1 regulated the expression of LEF1. Pathway analysis indicated that PPAR gamma expression was significantly down regulated. Compared with normal urothelium and primary UC, the expression of PPAR gamma in UC was significantly decreased in RT group. PPAR gamma expression was correlated with tumor size, clinical stage, pathological and recurrence. PPAR gamma inactivates LEF1/beta-catenin signaling in UC cells. PPAR gamma decreased the protein expression of MMP2, and calpain-2. PPAR gamma suppresses the proliferation, and invasion of UC cells depending on the expression of LEF1. PPAR gamma inhibited tumor proliferation and metastasis by inhibiting LEF1/beta-catenin signaling, and the expression of PPAR gamma in UC after RT decreased significantly. Our findings also suggested that PPAR gamma may be a potential biomarker for the diagnosis of UC after RT. [GRAPHICS] .