Divergent Role of PAX2 in the Etiology and Progression of Ovarian Cancer

Abstract

PAX2 is a transcription factor that is essential for development. Aberrant expression of PAX2 in adult tissues is associated with carcinogenesis and experimental evidence shows that PAX2 generally exhibits oncogenic properties. Although PAX2 is not expressed in normal ovaries, it is highly expressed in low malignant potential and low-grade epithelial ovarian tumors, suggesting that PAX2 induction in ovarian surface epithelium (OSE) may contribute to transformation. Herein, we provide evidence that expression of PAX2 in normal murine OSE (mOSE) cells enhances their proliferation and survival and, when combined with loss of P53, induces tumorigenicity. In addition, OSE cells are known to gain an epithelial phenotype and express epithelial markers prior to their transformation. This study revealed that PAX2 induction in mOSE cells results in an enhanced epithelial phenotype associated with reduction of the epithelial-mesenchymal transition markers, SMA-α and COX-2. Furthermore, PAX2 inhibits the mesenchymal phenotype induced by TGF-β and reverses the TGF-β-mediated induction of both SMA-α and COX-2, in mOSE cells. Toward tumor progression, we found that when PAX2 was expressed in murine ovarian cancer cells, it enhanced or inhibited their aggressiveness, depending on the model system. In OSE cells transformed by K-RAS and MYC, PAX2 inhibited P53 accumulation and increased the level of pERK1/2 and COX-2. In addition, PAX2 inhibited apoptotic induction in these tumors, while increasing angiogenesis, both of which are enhancers of tumor aggressiveness. However, in a murine model of high-grade serous ovarian cancer, PAX2 expression reduced tumor mass and improved animal survival, likely via reduced proliferation and metastasis. Mechanistic studies showed that PAX2 increased Htra1 and decreased COX-2 in those tumors. Both HTRA1 and COX-2 are novel downstrream targets for PAX2 that are identified in the current study. These results suggest that PAX2 may not act as a classical oncogene or tumor suppressor in ovarian cancer; rather, it modulates tumorigenesis differently, depending on the tumor context. The observation that PAX2 targets distinct biological and molecular pathways might help to guide future studies to different therapeutic targets in low-grade vs. high-grade cancers.