Abstract
While testicular nuclear receptor 4 (TR4) may promote prostate cancer (PCa) metastasis, its role in the clear cell renal cell carcinoma (ccRCC) remains unclear. Here we found a higher expression of TR4 in ccRCC tumors from patients with distant metastases than those from metastasis-free patients, suggesting TR4 may play positive roles in the ccRCC metastasis. Results from multiple in vitro ccRCC cell lines also confirmed TR4's positive roles in promoting ccRCC cell invasion/migration via altering the microRNA (miR-32-5p)/TR4/HGF/Met/MMP2-MMP9 signaling. Mechanism dissection revealed that miR-32-5p could suppress TR4 protein expression levels via direct binding to the 3'UTR of TR4 mRNA, and TR4 might then alter the HGF/Met signaling at the transcriptional level via direct binding to the TR4-response-elements (TR4RE) on the HGF promoter. Then the in vitro data also demonstrated the efficacy of Sunitinib, a currently used drug to treat ccRCC, could be increased after targeting this newly identified miR-32-5p/TR4/HGF/Met signaling. The preclinical study using the in vivo mouse model with xenografted ccRCC cells confirmed the in vitro cell lines data. Together, these findings suggest that TR4 is a key player to promote ccRCC metastasis and targeting this miR-32-5p/TR4/HGF/Met signaling with small molecules including TR4-shRNA or miR-32-5p may help to develop a new therapy to better suppress the ccRCC metastasis.