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.
Du
Rui
R
Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, PR China.
Huang
Chen
C
Bi
Qian
Q
Zhai
Ying
Y
Xia
Lin
L
Liu
Jie
J
Sun
Shiren
S
Fan
Daiming
D
D000199:Actins / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D015687:Cell Hypoxia; D054338:Cell Transdifferentiation; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology* / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D051820:TCF Transcription Factors / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014746:Vimentin / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
D000199:Actins; D015820:Cadherins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051820:TCF Transcription Factors; D015534:Trans-Activators; C547681:VWCE protein, human; D014746:Vimentin; D051176:beta Catenin; D010100:Oxygen