Primary cilia and aberrant cell signaling in epithelial ovarian cancer

The presence of primary cilia was analyzed in sections of fixed human ovarian tissue as well as in cultures of normal human ovarian surface epithelium (OSE) cells and two human OSE-derived cancer cell lines. We also used immunofluorescence microscopy, western blotting, RT-PCR and siRNA to investigate ciliary signaling pathways in these cells.We show that ovarian cancer cells display significantly reduced numbers of primary cilia. The reduction in ciliation frequency in these cells was not due to a failure to enter growth arrest, and correlated with persistent centrosomal localization of aurora A kinase (AURA). Further, we demonstrate that ovarian cancer cells have deregulated Hh signaling and platelet-derived growth factor receptor alpha (PDGFRα) expression and that promotion of ciliary formation/stability by AURA siRNA depletion decreases Hh signaling in ovarian cancer cells. Lastly, we show that the tumor suppressor protein and negative regulator of AURA, checkpoint with forkhead-associated and ring finger domains (CHFR), localizes to the centrosome/primary cilium axis.Our results suggest that primary cilia play a role in maintaining OSE homeostasis and that the low frequency of primary cilia in cancer OSE cells may result in part from over-expression of AURA, leading to aberrant Hh signaling and ovarian tumorigenesis.Epithelial ovarian cancer (EOC) belongs to a heterogeneous group of neoplasms that exhibit a wide range of molecular defects, affecting cell survival, proliferation, differentiation and migration. EOC is the most lethal of the gynecologic malignancies, accounting for more than 90% of all ovarian malignancies, and is mainly a disease of postmenopausal women [1]. The high mortality rate of EOC is primarily due to difficulties in diagnosing early stages of the disease. Most patients (approximately 75%) present with advanced stage (III/IV) tumors, for which the five-year survival rate is below 46% [1]. This is not surprising given the size and location o