PRDX2 protects against oxidative stress induced by H. pylori and promotes resistance to cisplatin in gastric cancer
Sen Wang,
Zheng Chen,
Shoumin Zhu,
Heng Lu,
Dunfa Peng,
Mohammed Soutto,
Huma Naz,
Richard Peek, Jr.,
Hao Xu,
Alexander Zaika,
Zekuan Xu,
Wael El-Rifai
Affiliations
Sen Wang
Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China; Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
Zheng Chen
Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
Shoumin Zhu
Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
Heng Lu
Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
Dunfa Peng
Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
Mohammed Soutto
Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
Huma Naz
Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
Richard Peek, Jr.
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, 37232, TN, USA
Hao Xu
Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China
Alexander Zaika
Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
Zekuan Xu
Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, 211166, China; Corresponding author. No.300, Guangzhou Rd, Nanjing, Jiangsu, 210029, PR China.
Wael El-Rifai
Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Department of Veterans Affairs, Miami Healthcare System, Miami, Florida, USA; Corresponding author.1600 NW 10th Ave, Miami, FL, 33136, USA.
Background: Helicobacter pylori (H. pylori) infection is the main risk factor for gastric cancer. The role of antioxidant enzyme peroxiredoxin 2 (PRDX2) in gastric tumorigenesis remains unknown. In vitro (AGS and SNU-1 cell lines) and in vivo mouse models were utilized to investigate the role of PRDX2 in response to H. pylori infection (7.13, J166 or PMSS1 strain). We detected high levels of PRDX2 expression in gastric cancer tissues. Gastric cancer patients with high expression levels of PRDX2 had significantly worse overall and progression-free survival than those with low levels. H. pylori infection induced activation of NF-κB with increased expression of PRDX2, in in vitro and in vivo models. The knockdown of PRDX2 led to an increase in the levels of reactive oxygen species (ROS), oxidative DNA damage, and double-strand DNA breaks, in response to H. pylori infection, as measured by H2DCFDA, 8-oxoguanine, and p-H2AXγ assays. Luciferase reporter and ChIP assays confirmed the presence of a putative binding site of NF-κB-p65 on PRDX2 promoter region. The inhibition of PRDX2 significantly sensitized AGS and SNU-1 cells to cisplatin treatment. Our data suggest that the future development of therapeutic approaches targeting PRDX2 may be useful in the treatment of gastric cancer. Keywords: NF-κB, Infection, Antioxidant response, Oxidative DNA damage, Apoptosis
