Ectopic expression of PTTGI/securin promotes tumorigenesis in human embryonic kidney cells

Background: Pituitary tumor transforming gene I (PTTGI) is a novel oncogene that is expressed in most tumors. It encodes a protein that is primarily involved in the regulation of sister chromatid separation during cell division. The oncogenic potential of PTTGI has been well characterized in the mouse, particularly mouse fibroblast (NIH3T3) cells, in which it induces cell proliferation, promotes tumor formation and angiogenesis. Human tumorigenesis is a complex and a multistep process often requiring concordant expression of a number of genes. Also due to differences between rodent and human cell biology it is difficult to extrapolate results from mouse models to humans. To determine if PTTGI functions similarly as an oncogene in humans, we have characterized its effects on human embryonic kidney (HEK293) cells. Results: We report that introduction of human PTTGI into HEK293 cells through transfection with PTTGI cDNA resulted in increased cell proliferation, anchorage-independent growth in soft agar, and formation of tumors after subcutaneous injection of nu/nu mice. Pathologic analysis revealed that these tumors were poorly differentiated. Both analysis of HEK293 cells transiently transfected with PTTGI cDNA and analysis of tumors developed on injection of HEK293 cells that had been stably transfected with PTTGI cDNA indicated significantly higher levels of secretion and expression of bFGF, VEGF and IL-8 compared to HEK293 cells transfected with pcDNA3.1 vector or uninvolved tissues collected from the mice. Mutation of the proline-rich motifs at the C-terminal of PTTGI abolished its oncogenic properties. Mice injected with this mutated PTTGI either did not form tumors or formed very small tumors. Taken together our results suggest that PTTGI is a human oncogene that possesses the ability to promote tumorigenesis in human cells at least in part through the regulation of expression or secretion of bFGF, VEGF and IL-8. Conclusions: Our results demonstrate that PTTGI is a potent human oncogene and has the ability to induce cellular transformation of human cells. Overexpression of PTTGI in HEK293 cells leads to an increase in the secretion and expression of bFGF, VEGF and IL-8. Mutation of C-terminal proline-rich motifs abrogates the oncogenic function of PTTGI. To our knowledge, this is the first study demonstrating the importance of PTTGI in human tumorigenesis.