STEAP1 Is Associated with the Invasive and Oxidative Stress Phenotype of Ewing Tumors

Abstract

Ewing tumors comprise the second most common type of bone-associated cancer in children and are characterized by oncogenic EWS/FLI1 fusion proteins and early metastasis. Compelling evidence suggests that elevated levels of intracellular oxidative stress contribute to enhanced aggressiveness of numerous cancers, possibly including Ewing tumors. Using comprehensive microarray analyses and RNA interference, we identified the six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-a membrane-bound mesenchymal stem cell marker of unknown function-as a highly expressed protein in Ewing tumors compared with benign tissues and show its regulation by EWS/FLI1. In addition, we show that STEAP1 knockdown reduces Ewing tumor proliferation, anchorage-independent colony formation as well as invasion in vitro and decreases growth and metastasis of Ewing tumor xenografts in vivo. Moreover, transcriptome and proteome analyses as well as functional studies revealed that STEAP1 expression correlates with oxidative stress responses and elevated levels of reactive oxygen species that in turn are able to regulate redox-sensitive and proinvasive genes. In synopsis, our data suggest that STEAP1 is associated with the invasive behavior and oxidative stress phenotype of Ewing tumors and point to a hitherto unanticipated oncogenic function of STEAP1. Mol Cancer Res; 10(1); 52-65. Ó2011 AACR.

The posterior HOXD locus: Its contribution to phenotype and malignancy of Ewing sarcoma

“…As shown in Figure 5C, A673 and SK-N-MC HOXD10, HOXD11 and HOXD13 shRNA infectants revealed a significant contribution of at least HOXD11 and HOXD13 to in vitro invasiveness. Recent results of our laboratory already indicated a strong contribution of MMP1 to invasion and metastasis of ES and its possible induction via several, presumably independent pathways [5,38,39]. Figure S5B) signifying that the reduced invasive potential of HOXD11 or HOXD13 and probably HOXD10 silenced ES cells may be mediated at least in part via MMP1.…”

Transgenic antigen-specific, HLA-A*02:01-allo-restricted cytotoxic T cells recognize tumor-associated target antigen STEAP1 with high specificity

“…18 STEAP proteins are homologs of NADPH-oxidases (NOX), involved in cellular ROS metabolism and frequently overexpressed in cancers. We demonstrated that STEAP1 is induced by EWS-FLI1 and that its expression promotes proliferation, invasiveness, anchorage-independent colony formation, tumorigenicity and metastasis of ES cells, 19 as well as impacting on patient survival. 35 Apart from minor expression in prostate and urothelium, STEAP1 is only weakly expressed in normal tissues.…”

“…19 Apart from minor expression in prostate and urothelium, STEAP1 is only weakly expressed in normal tissues (Figs. S1 and S2A).…”

“…4E). 19 The P2A5 TCR-transgenic CD8 C T SCM cells together with 5 £ 10 6 CD8 C -depleted, autologous PBMCs or with unspecific PBMCs as a control (Fig. 5A), respectively.…”

“…In addition to ES, where STEAP1 influences the invasive behavior and oxidative stress phenotype, 19 STEAP1 is also overexpressed in many cancers including prostate and bladder carcinoma, 20 but almost absent in normal tissues, except for urothelium and prostate.…”