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MicroRNA-224 Negatively Regulates p21 Expression During Late Neoplastic Progression in Inflammatory Bowel Disease

Olaru, Alexandru V. MD*; Yamanaka, Sumitaka PhD*; Vazquez, Christine BS; Mori, Yuriko MD, PhD*; Cheng, Yulan MD*; Abraham, John M. PhD*; Bayless, Theodore M. MD*; Harpaz, Noam MD; Selaru, Florin M. MD*; Meltzer, Stephen J. MD*

doi: 10.1097/MIB.0b013e31827e78eb
Original Basic Science Articles

Background: The development of colon cancer represents a major complication in patients with inflammatory bowel disease (IBD). The importance of microRNAs (miRs) in carcinogenesis is becoming clearer because miRs have been implicated in the regulation of cancer-related cellular processes to include apoptosis, differentiation, cell cycle progression, and immune function. In the current study, we sought to identify miR dysregulation specific to progression along the normal-inflammation-cancer axis in colonic specimens from patients with IBD.

Methods: MiR microarrays and quantitative reverse transcription PCR were used to detect and confirm dysregulated miRs. Receiver operating characteristic curve analysis was applied to evaluate the potential use of miR-224 as a neoplastic disease marker in IBD. For miR-224 target messenger RNA (mRNA) identification, mRNA microarrays were employed in combination with bioinformatic analyses, Western blotting, and luciferase activity measurements.

Results: We identified 30 miRs that were differentially expressed between chronically inflamed mucosae and cancers arising from IBD tissues. MiR-224 levels increased successively at each stage of IBD progression and accurately discriminated cancers from normal or chronically inflamed IBD tissues. Moreover, mRNA arrays combined with bioinformatic analyses suggested the participation of miR-224 in cell cycle regulation. Subsequently, cell cycle experiments indicated that miR-224 regulates the G1-S checkpoint. Finally, in silico prediction analyses, confirmed by Western blotting and luciferase assays, identified p21 as a specific direct mRNA target of miR-224.

Conclusions: These findings reveal miR dysregulation specific to IBD-associated colorectal carcinoma. MiR-224 is overexpressed in IBD cancers and targets p21, a key cell cycle regulator. Moreover, these results establish the participation of miR-224 in IBD carcinogenesis.

Supplemental Digital Content is Available in the Text.Article first published online 8 February 2013

*Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland

Department of Biochemistry and Molecular Biology, School of Public Health, Johns Hopkins University, Baltimore, Maryland

Division of Gastrointestinal Pathology, Department of Pathology, Mount Sinai School of Medicine, New York, New York.

Reprints: Florian M. Selaru, MD, Department of Gastroenterology, Johns Hopkins University School of Medicine, 1503 E Jefferson Street, Room 112, Baltimore, MD 21231 (

F.M. Selaru and S.J. Meltzer are co-senior authors and contributed equally to this work.

A. V. Olaru was supported by grants from the Broad Medical Research Program of the Broad Foundation (IBD-0271R); and S. J. Meltzer by the National Institutes of Health (RO1CA133012).

None of the authors has any conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Received May 29, 2012

Accepted June 12, 2012

© Crohn's & Colitis Foundation of America, Inc.
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