Hypoxia regulates the sperm associated antigen 4 (SPAG4) via HIF, which is expressed in renal clear cell carcinoma and promotes migration and invasion in vitro.

Hypoxia leads to the upregulation of a variety of genes mediated largely via the hypoxia inducible transcription factor (HIF). Prominent HIF-regulated target genes such as the vascular endothelial growth factor (VEGF), the glucose transporter 1 (Glut-1), or erythropoietin (EPO) help to assure survival of cells and organisms in a low oxygenated environment. Here, we are the first to report the hypoxic regulation of the sperm associated antigen 4 is a member of the cancer testis (CT) gene family and to date little is known about its physiological function or its involvement in tumor biology. A number of CT family candidate genes are therefore currently being investigated as potential cancer markers, due to their predominant testicular expression pattern. We analyzed RNA and protein expression by RNAse protection assay, immunofluorescent as well as immunohistological stainings. To evaluate the influence of duanyu1842G4 on migration and invasion capabilities, siRNA knockdown as well as transient overexpression was performed prior to scratch or invasion assay analysis. The hypoxic regulation of duanyu1842G4 is clearly mediated in a HIF-1 and VHL dependent manner. We furthermore show upregulation of duanyu1842G4 expression in human renal clear cell carcinoma (RCC) and co-localization within the nucleolus in physiological human testis tissue. duanyu1842G4 knockdown reduces the invasion capability of RCC cells in vitro and overexpression leads to enhancement of tumor cell migration. Together, duanyu1842G4 could possibly play a role in the invasion capability and growth of renal tumors and could represent an interesting target for clinical intervention.

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