MicroRNA-101 inhibits growth of epithelial ovarian cancer by relieving chromatin-mediated transcriptional repression of p21(waf¹/cip¹)

• Published in: Pharmaceutical research 2011-12, Vol.28 (12), p.3079-3090
• Main Authors: Semaan, Assaad, Qazi, Aamer M, Seward, Shelly, Chamala, Sreedhar, Bryant, Christopher S, Kumar, Sanjeev, Morris, Robert, Steffes, Christopher P, Bouwman, David L, Munkarah, Adnan R, Weaver, Donald W, Gruber, Scott A, Batchu, Ramesh B
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cell Proliferation; Chromatin - genetics; Chromatin - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enhancer of Zeste Homolog 2 Protein; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, SCID; MicroRNAs - genetics; MicroRNAs - metabolism; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; Neoplasms, Glandular and Epithelial - genetics; Neoplasms, Glandular and Epithelial - metabolism; Neoplasms, Glandular and Epithelial - pathology; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Ovary - metabolism; Ovary - pathology; Polycomb Repressive Complex 2; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 1573-904X
• DOI: 10.1007/s11095-011-0547-x

MicroRNA-101 (miR-101) expression is negatively associated with tumor growth and proliferation in several solid epithelial cancers. Enhancer of zeste homolog 2 (EzH2) appears to be a functional target of miR-101. We explore the role of miR-101 and its interaction with EzH2 in epithelial ovarian carcinoma (EOC). In situ hybridization (ISH) for miR-101 was performed on EOC patient tissues and normal controls. EOC cell lines were transfected with miR-101 and subjected to growth analysis and clonogenic assays. Cell motility was assessed by Boyden chamber and wound-healing assays. P21(waf1/cip1) and EzH2 interaction was assessed by Chromatin Immunoprecipitation (ChIP) assay in MDAH-2774 cells. SCID mice were assessed for tumor burden after injection with miR-101 or control vector-treated MDAH-2774 cells. ISH analysis revealed a decrease in miR-101 expression in EOC compared with normal tissue. MiR-101 re-expression in EOC cell lines resulted in increased apoptosis, decreased cellular proliferation, invasiveness, and reduced growth of tumor xenografts. CHIP assays revealed that re-expression of miR-101 inhibited the interaction of EzH2 with p21(waf1/cip1) promoter. MiR-101 re-expression appears to have antitumor effects, providing a better understanding of the role of miR-101 in EOC.