Carcinogenesis Advance Access originally published online on June 4, 2007
Carcinogenesis 2007 28(10):2096-2104; doi:10.1093/carcin/bgm124
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MAP17 enhances the malignant behavior of tumor cells through ROS increase
Experimental Therapeutics Program
1 Molecular Pathology Program, Centro Nacional de Investigaciones Oncológicas, Melchor Fernandez Almagro, 3, 28029 Madrid, Spain
2 Departmento Anatomía Patológica, Hospital Vall d'Hebrón 08035, Barcelona, Spain
* To whom correspondence should be addressed. Tel: +34 91 732 8021; Fax: +34 91 224 6976; Email: acarnero{at}cnio.es
Tumorigenesis occurs when the mechanisms involved in the control of tissue homeostasis are disrupted and cells stop responding to physiological signals. Therefore, genes capable of desensitizing tumoral cells from physiological signals may provide a selective advantage within the tumoral mass and influence the outcome of the disease. We undertook a large-scale genetic screen to identify genes able to alter the cellular response to physiological signals and provide selective advantage once tumorigenesis has begun. We identified MAP17, a small 17 kDa non-glycosylated membrane protein previously identified by differential display being over-expressed in carcinomas. Tumor cells that over-express MAP17 show an increased tumoral phenotype with enhanced proliferative capabilities both in presence or absence of contact inhibition, decreased apoptotic sensitivity and increased migration. MAP17-expressing clones also grow better in nude mice. The increased malignant cell behavior induced by MAP17 are associated with an increase in reactive oxygen species (ROS) production, and the treatment of MAP17-expressing cells with antioxidants results in a reduction in the tumorigenic properties of these cells. Treatment of melanoma cells with inhibitors of Na+-coupled co-transporters lead to an inhibition of ROS increase and a decrease in the malignant cell behavior in MAP17-expressing clones. Finally, we show that MAP17-dependent ROS increase and tumorigenesis are dependent on its PDZ-binding domain, since disruption of its sequence by point mutations abolishes its ability to enhance ROS production and tumorigenesis. Our work shows the tumorigenic capability of MAP17 through a connection between Na+-coupled co-transporters and ROS.
Abbreviations: FBS, fetal bovine serum; DMEM, Dulbecco's modified Eagle's medium; PBS, phosphate-buffered saline; ROS, reactive oxygen species; MAP17, membrane associated protein 17 kDa
Received March 27, 2007; revised May 8, 2007; accepted May 14, 2007.
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