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

Assaad Semaan, Aamer M Qazi, Shelly Seward, Sreedhar Chamala, Christopher S Bryant, Sanjeev Kumar, Robert Morris, Christopher P Steffes, David L Bouwman, Adnan R Munkarah, Donald W Weaver, Scott A Gruber, Ramesh B Batchu
Pharmaceutical Research 2011, 28 (12): 3079-90

PURPOSE: 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).

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: MiR-101 re-expression appears to have antitumor effects, providing a better understanding of the role of miR-101 in EOC.

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