Abstract
The PIM family of serine/threonine kinases has three highly conserved isoforms (PIM1, PIM2 and PIM3). PIM proteins are regulated through transcription and stability by JAK/STAT pathways and are overexpressed in hematological malignancies and solid tumors. The PIM kinases possess weak oncogenic abilities, but enhance other genes or chemical carcinogens to induce tumors. We generated conditional transgenic mice that overexpress PIM1 or PIM2 in male reproductive organs and analyzed their contribution to tumorigenesis. We found an increase in alterations of sexual organs and hyperplasia in the transgenic mice correlating with inflammation. We also found that PIM1/2 are overexpressed in a subset of human male germ cells and prostate tumors correlating with inflammatory features and stem cell markers. Our data suggest that PIM1/2 kinase overexpression is a common feature of male reproductive organs tumors, which provoke tissue alterations and a large inflammatory response that may act synergistically during the process of tumorigenesis. There is also a correlation with markers of cancer stem cells, which may contribute to the therapy resistance found in tumors overexpressing PIM kinases.
Highlights
The Proviral Insertion site in Moloney murine leukemia virus proteins (PIM) are a highly evolutionarily conserved family of serine/threonine kinases composed of three different isoforms (PIM1, PIM2 and PIM3)
We found an increase in alterations in the male sex organs, hyperplasia, and increased proliferation in the PIM1 and PIM2 transgenic mice
We found that PIM1 and PIM2 are overexpressed in a subset of human male germ cell and prostate tumors and that this overexpression correlated with clear inflammatory features and stem cell markers
Summary
The Proviral Insertion site in Moloney murine leukemia virus proteins (PIM) are a highly evolutionarily conserved family of serine/threonine kinases composed of three different isoforms (PIM1, PIM2 and PIM3) These proteins are regulated primarily through transcription and stability by pathways that are controlled by JAK/STAT transcription factors[1,2], cytokines, and growth factors involved in hematopoiesis, such as interleukins, GM-CSF and G-CSF3,4. Different members of the PIM family of kinases have been found to be overexpressed in hematological malignancies and solid tumors (reviewed at refs 1–4), which led to the idea that these proteins could be potentially interesting targets for anticancer drug therapy[17,18,19,20]. In these cancer types, PIM1 and PIM2 can be overexpressed in the same tumors, which suggest that there is only a partial redundancy among them and share some common physiological properties
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