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Originally published online as doi:10.2353/ajpath.2009.080592 on March 5, 2009

Published online before print March 5, 2009
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(American Journal of Pathology. 2009;174:1504-1514.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080592

RNA Interference-Mediated Inhibition of Erythropoietin Receptor Expression Suppresses Tumor Growth and Invasiveness in A2780 Human Ovarian Carcinoma Cells

Gyorgy Paragh*, Suresh M. Kumar{dagger}, Zsuzsa Rakosy*, Soek-Choel Choi*, Xiaowei Xu{dagger} and Geza Acs*{ddagger}

From the Experimental Therapeutics Program,* and the Department of Pathology and Laboratory Medicine,{dagger} University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and the Department of Anatomic Pathology,{ddagger} Moffitt Cancer Center, Tampa, Florida

Although recombinant human erythropoietin (rHuEpo) has revolutionized the treatment of anemia, recent clinical trials suggested that rHuEpo use may be associated with decreased survival in cancer patients. Although the expression of erythropoietin (Epo) receptor (EpoR) has been demonstrated in various human cancers, the effect of exogenous Epo on the growth and therapy resistance of EpoR-bearing tumor cells is unclear at present. In the current study, we examined the hypothesis that EpoR may contribute to tumor growth independent of Epo in A2780 human ovarian carcinoma cells. A2780 human ovarian carcinoma cells showed high levels of EpoR expression, but lacked expression of Epo mRNA and biologically active Epo protein under both normoxic and hypoxic conditions. Exogenous Epo did not stimulate EpoR-mediated signaling, proliferation, invasiveness, or resistance to cytotoxic drugs in A2780 cells. In contrast, specific inhibition of EpoR expression using a short hairpin RNA (shRNA) expression plasmid resulted in markedly reduced proliferation and invasiveness in vitro. In addition, inhibition of EpoR expression led to abrogated in vivo ovarian cancer cell growth in a tumor xenograft system and resulted in decreased EpoR signaling. Our findings suggest that EpoR may be constitutively active in some cancer cells in the absence of Epo and provide the first evidence for a potential role of an Epo-independent, EpoR-mediated pathway in the growth of some human cancers.






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