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

• Published in: The Journal of pathology Vol. 228; no. 2; pp. 148 - 157
• Main Authors: Shi, Ming, Du, Libin, Liu, Dan, Qian, Lu, Hu, Meiru, Yu, Ming, Yang, Zhengyan, Zhao, Mingzhen, Chen, Changguo, Guo, Liang, Wang, Lina, Song, Lun, Ma, Yuanfang, Guo, Ning
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.10.2012; Wiley
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - virology; Anti-Inflammatory Agents - pharmacology; Apoptosis; Biological and medical sciences; Blotting, Northern; Cell Migration Assays; cervical cancer; chemoresistance; DNA-Binding Proteins; Down-Regulation - drug effects; Drug Resistance, Neoplasm - genetics; Female; Female genital diseases; Flow Cytometry; Gene Expression Regulation, Neoplastic - drug effects; glucocorticoids; Gynecology. Andrology. Obstetrics; HeLa Cells; HPV; Humans; Hydrocortisone - pharmacology; Investigative techniques, diagnostic techniques (general aspects); Medical sciences; MicroRNAs - genetics; miR-145; Oncogene Proteins, Viral - genetics; p53; Papillomavirus Infections - drug therapy; Papillomavirus Infections - genetics; Papillomavirus Infections - virology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Real-Time Polymerase Chain Reaction; stress; Transfection; Tumor Suppressor Protein p53 - genetics; Tumors; Uterine Cervical Neoplasms - drug therapy; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - virology; V-Onc gene; Tumorous infiltration; Papovaviridae; Metastasis; Glucocorticoid; HPV; p53; Papillomavirus; Human papillomavirus; Regulation(control); TP53 Gene; miR-145; glucocorticoids; Tumor cell; Tumor suppressor gene; Treatment resistance; Malignant tumor; Invasion; Stress; Female genital diseases; Virus; Anatomic pathology; chemoresistance; Treatment; Uterine cervix diseases; Cervical cancer; Cancer
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.3997

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.