Hypoxia-mediated up-regulation of MGr1-Ag/37LRP in gastric cancers occurs via hypoxia-inducible-factor 1-dependent mechanism and contributes to drug resistance

✍ Scribed by Lili Liu; Li Sun; Hongbo Zhang; Zhichao Li; Xiaoxuan Ning; Yongquan Shi; Changcun Guo; Shuang Han; Kaichun Wu; Daiming Fan

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: French
• Weight: 589 KB
• Volume: 124
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.24135

✦ Synopsis

Abstract

Our previous study demonstrated hypoxia‐inducible factor‐1(HIF‐1) could prompt multidrug resistance (MDR) phenotype and MGr1‐Ag/37LRP, a novel drug‐resistance protein was reported by our labortary, associated with multidrug resistance in gastric cancer. Given this association, we hypothesized that MGr1‐Ag/37LRP contributed to HIF‐1‐dependent hypoxia‐induced MDR phenotype. Initial experiments revealed that blocking MGr1‐Ag/37LRP expression by siRNA in gastric cancer cells effectively reversed multidrug resistance phenotype induced by hypoxia. Subsequent analysis of MGr1‐Ag/37LRP mRNA and protein in gastric cancer cells revealed a time‐dependent manner increase with hypoxia. While the up‐regulation of MGr1‐Ag/37LRP was abolished by HIF‐1 inhibition with siRNA. Studies using luciferase promoter constructs revealed a significant increase in activity in cells subject to hypoxia and such hypoxia inducibility was lost in cells co‐transfected siRNA targeting HIF‐1. Analysis of the MGr1‐Ag/37LRP promoter revealed several potential binding sites for HIF‐1. Electrophoretic mobility shift assay and chromatin immunoprecipitation demonstrated a functional HIF‐1 binding site within MGr1‐Ag/37LRP gene regulatory sequence located at −16 to −11 relative to the transcriptional initiation point. These observations demonstrate that MGr1‐Ag/37LRP is actively engaged by hypoxia and represent a novel HIF‐1 target. Such results suggest hypoxia‐elicited MGr1‐Ag/37LRP expression as a pathway for resistance of gastric cancer to chemotherapeutics. © 2008 Wiley‐Liss, Inc.