Regulation of stem cell-like phenotype and response to chemotherapy in bladder cancer by beta-arrestins.

461Background: Identification of molecular drivers that promote a muscle invasive phenotype and chemoresistance in bladder cancer, as well as an understanding of their mechanism of action should help in designing potential prognostic markers and effective targeted treatments for patients with advanced bladder cancer. β-arrestins (ARRBs) are classic attenuators of G-Protein coupled receptor signaling. However, they have multiple roles in cellular physiology, including carcinogenesis. Methods: β-arrestin-1 (ARRB1) and β-arrestin-2 (ARRB2) mRNA levels were measured by quantitative RT-PCR in two clinical specimen cohorts (n = 63; n = 43). The role of ARRBs in regulating a stem cell-like phenotype and response to chemotherapy treatments was investigated using CRISPR-Cas9 mediated gene-knockout of ARRB1. The consequence of forced expression of ARRBs on tumor growth and response to gemcitabine in vivo were investigated using bladder tumor xenografts in nude mice. Results: ARRB1 levels were significantly elevated...