Author:
Egeberg Dorte L,Lethan Mette,Manguso Robert,Schneider Linda,Awan Aashir,Jørgensen Tue S,Byskov Anne G,Pedersen Lotte B,Christensen Søren T
Abstract
Abstract
Background
Ovarian cancer is the fourth leading cause of cancer-related deaths among women in Denmark, largely due to the advanced stage at diagnosis in most patients. Approximately 90% of ovarian cancers originate from the single-layered ovarian surface epithelium (OSE). Defects in the primary cilium, a solitary sensory organelle in most cells types including OSE, were recently implicated in tumorigenesis, mainly due to deregulation of ciliary signaling pathways such as Hedgehog (Hh) signaling. However, a possible link between primary cilia and epithelial ovarian cancer has not previously been investigated.
Methods
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.
Results
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.
Conclusions
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.
Publisher
Springer Science and Business Media LLC
Reference95 articles.
1. Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin. 2010, 60: 277-300. 10.3322/caac.20073.
2. Aletti GD, Gallenberg MM, Cliby WA, Jatoi A, Hartmann LC: Current management strategies for ovarian cancer. Mayo Clin Proc. 2007, 82: 751-770.
3. Jelovac D, Armstrong DK: Recent progress in the diagnosis and treatment of ovarian cancer. CA Cancer J Clin. 2011, 61: 183-10.3322/caac.20113.
4. Aoki Y, Kawada N, Tanaka K: Early form of ovarian cancer originating in inclusion cysts. A case report. J Reprod Med. 2000, 45: 159-161.
5. Deligdisch L, Einstein AJ, Guera D, Gil J: Ovarian dysplasia in epithelial inclusion cysts. A morphometric approach using neural networks. Cancer. 1995, 76: 1027-1034. 10.1002/1097-0142(19950915)76:6<1027::AID-CNCR2820760617>3.0.CO;2-6.
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