MicroRNA-21 Modulates the Levels of Reactive Oxygen Species by Targeting SOD3 and TNFα

• Authors: Xiangming Zhang, Emory University; Wooi-Loon Ng, Emory University; Ping Wang, Emory University; LinLin Tian, Emory University; Erica Werner, Emory University; Huichen Wang, Emory University; Paul Doetsch, Emory University; Ya Wang, Emory University
• Journal Title: Cancer Research
• Volume: Volume 72, Number 18
• Publisher: American Association for Cancer Research | 2012-09-15, Pages 4707-4713
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1158/0008-5472.CAN-12-0639
• Subjects: Health Sciences, Oncology; Chemistry, Biochemistry
• Keywords: miR-21; SOD; TNFα; Reactive Oxygen Species (ROS); ionizing radiation

Abstract

MicroRNA-21 (miR-21) is an oncomir overexpressed in most human tumors where it promotes malignant growth and progression by acting on multiple targets. Here we broaden the impact of miR-21 in cancer by demonstrating that it regulates formation of reactive oxygen species (ROS) that promote tumorigenesis. Key targets of miR-21 in mediating this function were SOD3 and TNF-a. We found that miR-21 inhibited the metabolism of superoxide to hydrogen peroxide, produced either by endogenous basal activities or exposure to ionizing radiation, by directing attenuating SOD3 or by an indirect mechanism that limited TNF-a production, thereby reducing SOD2 levels. Importantly, both effects contributed to an elevation of IR-induced cell transformation. Our findings therefore establish that miR-21 promotes tumorigenesis to a large extent through its regulation of cellular ROS levels.