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J. Biol. Chem., Vol. 283, Issue 19, 13205-13215, May 9, 2008

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Profiling MicroRNA Expression in Hepatocellular Carcinoma Reveals MicroRNA-224 Up-regulation and Apoptosis Inhibitor-5 as a MicroRNA-224-specific Target^*

Yu Wang¹, Alvin T. C. Lee¹, Joel Z. I. Ma, Jingbo Wang, Jianwei Ren, Yuchen Yang^¶2, Erwin Tantoso^¶, Kuo-Bin Li^¶3, London L. P. J Ooi^||**, Patrick Tan, and Caroline G. L. Lee⁴

From the Department of Biochemistry, National University of Singapore, Singapore 119077, Singapore, the Division of Medical Sciences and ^||Department of Surgical Oncology, National Cancer Centre, Singapore 169610, Singapore, the ^¶Bioinformatics Institute, Singapore 138671, Singapore, the ^**Department of Surgery, Singapore General Hospital, Singapore 169608, and the Duke-NUS Graduate Medical School, Singapore 169547, Singapore

Like other cancers, aberrant gene regulation features significantly in hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) were recently found to regulate gene expression at the post-transcriptional/translational levels. The expression profiles of 157 miRNAs were examined in 19 HCC patients, and 19 up-regulated and 3 down-regulated miRNAs were found to be associated with HCC. Putative gene targets of these 22 miRNAs were predicted in silico and were significantly enriched in 34 biological pathways, most of which are frequently dysregulated during carcinogenesis. Further characterization of microRNA-224 (miR-224), the most significantly up-regulated miRNA in HCC patients, revealed that miR-224 increases apoptotic cell death as well as proliferation and targets apoptosis inhibitor-5 (API-5) to inhibit API-5 transcript expression. Significantly, miR-224 expression was found to be inversely correlated with API-5 expression in HCC patients (p < 0.05). Hence, our findings define a true in vivo target of miR-224 and reaffirm the important role of miRNAs in the dysregulation of cellular processes that may ultimately lead to tumorigenesis.

Received for publication, September 11, 2007 , and in revised form, February 5, 2008.

^* This work was supported by a National Medical Research Council of Singapore block grant through the National Cancer Centre (to C. G. L.), an individual grant from the National Medical Research Council, and a grant from the BioMedical Research Council (to C. G. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3 and Table S1.

¹ These authors contributed equally to this work.

² Present address: Institute of Molecular and Cell Biology, Singapore.

³ Present address: Bioinformatics Center, National Yang-Ming University, Taipei, 112, Taiwan.

⁴ To whom correspondence should be addressed: Division of Medical Sciences, National Cancer Center, Level 6, Lab 5, 11 Hospital Dr., Singapore 169610, Singapore. Tel.: 65-6436-8353; Fax: 65-6372-0161; E-mail: bchleec{at}nus.edu.sg.

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