Glucocorticoid regulation of a novel HPV–E6–p53– miR‐145 pathway modulates invasion and therapy resistance of cervical cancer cells

Citations Over TimeTop 10% of 2012 papers

Abstract

Abstract Glucocorticoids are stress‐responsive neuroendocrine mediators and play an important role in malignant progression, especially in solid tumours. 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 down‐regulation of miR‐145 expression prevented chemotherapy‐induced apoptosis, whereas over‐expression 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 inhibitors of p53 in cervical cancer cells, suggesting that miR‐145 plays a role in p53 tumour 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 tumour 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.

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