We revealed that OMD−/− or PRELP−/− knockout mice caused a breakdown of the umbrella cell layer through weakening cell–cell integrity and the activation of partial EMT, which resulted in the formation of early bladder cancer-like structures, while OMD or PRELP application to bladder cancer cells inhibited cancer progression through reversing EMT, which was mediated by the inhibition of TGF-β and EGF. The gene discussed is OMD; the disease is urinary bladder cancer.