Glucocorticoids are stress-responsive neuroendocrine mediators and play an important role in malignant progression, especially in solid tumors. We demonstrate a novel mechanism by which glucocorticoids modulate p53-dependent miR-145 expression in HPV positive cervical cancer cells through induction of E6 proteins. We found that expression of miR-145 was reduced in cervical cancer tissues. Cortisol induced HPV E6 expression and suppressed p53 and miR-145 in cervical cancer cells. MiR-145 expression in cervical cancer cells was wild-type p53-dependent, and cortisol-induced downregulation of miR-145 expression prevented chemotherapy-induced apoptosis whereas overexpression of miR-145 enhanced sensitivity to mitomycin and reversed the chemoresistance induced by glucocorticoids. We also show that miR-145 augments the effects of p53 by suppressing the inhibition of p53 in cervical cancer cells, suggesting that miR-145 plays a role in p53 tumor suppression. Finally, we demonstrate that miR-145 inhibits both the motility and invasion of cervical cancer cells. Our findings identify a novel pathway through which the neuroendocrine macroenvironment affects cervical tumor growth, invasion and therapy-resistance and show that miR-145 may serve as a target for cervical cancer therapy.

Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

PMID: 22287315 [PubMed - as supplied by publisher] Source: National Library of Medicine.