title: Glucocorticoid regulation of a novel HPV-E6-p53-miR-145 pathway modulates invasion and therapy resistance of cervical cancer cells.
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.
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Shi
authors.forename: Libin
authors.initials: L
authors.lastname: Du
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: Lu
authors.initials: L
authors.lastname: Qian
authors.forename: Meiru
authors.initials: M
authors.lastname: Hu
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.forename: Zhengyan
authors.initials: Z
authors.lastname: Yang
authors.forename: Mingzhen
authors.initials: M
authors.lastname: Zhao
authors.forename: Changguo
authors.initials: C
authors.lastname: Chen
authors.forename: Liang
authors.initials: L
authors.lastname: Guo
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.forename: Lun
authors.initials: L
authors.lastname: Song
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Ma
authors.forename: Ning
authors.initials: N
authors.lastname: Guo
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000821:virology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis; D015152:Blotting, Northern; D054443:Cell Migration Assays; D004268:DNA-Binding Proteins; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D035683:MicroRNAs / Q000235:genetics*; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D030361:Papillomavirus Infections / Q000188:drug therapy / Q000235:genetics* / Q000821:virology; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000821:virology
chemical_list: D000893:Anti-Inflammatory Agents; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D009856:Oncogene Proteins, Viral; D016159:Tumor Suppressor Protein p53; D006854:Hydrocortisone