URG11 mediates hypoxia-induced epithelial-to-mesenchymal transition by modulation of E-cadherin and beta-catenin.

Upregulated gene 11 (URG11), recently identified as a new HBx-upregulated gene that may activate beta-catenin and Wnt signaling, was found to be upregulated in a human tubule cell line under low oxygen. Here, we investigated the potential role of URG11 in hypoxia-induced renal tubular epithelial-to-mesenchymal (EMT). Overexpression of URG11 in a human proximal tubule cell line (HK2) promoted a mesenchymal phenotype accompanied by reduced expression of the epithelial marker E-cadherin and increased expression of the mesenchymal markers vimentin and alpha-SMA, while URG11 knockdown by siRNA effectively reversed hypoxia-induced EMT. URG11 promoted the expression of beta-catenin and increased its nuclear accumulation under normoxic conditions through transactivation of the beta-catenin promoter. This in turn upregulated beta-catenin/T-cell factor (TCF) and its downstream effector genes, vimentin, and alpha-SMA. In vivo, strong expression of URG11 was observed in the tubular epithelia of 5/6-nephrectomized rats, and a Western blot analysis demonstrated a close correlation between HIF-1alpha and URG11 protein levels. Altogether, our results indicate that URG11 mediates hypoxia-induced EMT through the suppression of E-cadherin and the activation of the beta-catenin/TCF pathway.