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J. Biol. Chem., Vol. 283, Issue 11, 7251-7260, March 14, 2008

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Down-regulation of RNA Editing in Pediatric Astrocytomas

ADAR2 EDITING ACTIVITY INHIBITS CELL MIGRATION AND PROLIFERATION^*

Caterina Cenci¹, Rita Barzotti¹, Federica Galeano, Sandro Corbelli, Rossella Rota, Luca Massimi^¶, Concezio Di Rocco^¶, Mary A. O'Connell^||, and Angela Gallo²

From the RNA editing Laboratory, and Angiogenesis Laboratory, Ospedale Pediatrico Bambino Gesù Research Institute, Piazza S. Onofrio 4, 00165 Rome, Italy, the ^¶Pediatric Neurosurgery Policlinico Gemelli, Largo Agostino Gemelli, 8, 00168, Rome Italy, and the ^||MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU

Since alterations in post-transcriptional events can contribute to the appearance and/or progression of cancer, we investigated whether RNA editing, catalyzed by the ADAR (adenosine deaminases that act on RNA) enzymes, is altered in pediatric astrocytomas. We find a decrease in ADAR2 editing activity that seems to correlate with the grade of malignancy in children. Despite the loss of ADAR2 editing activity in tumor tissues, the high grade astrocytomas do not exhibit alterations in ADAR2 expression when compared with their specific control tissues. However, high expression levels of ADAR1 and ADAR3 were found in tumors when compared with normal tissues dissected in the same area of the brain. We reintroduced either ADAR2 or the inactive version of ADAR2 in three astrocytoma cell lines (U118, A172, U87). The "reverted" editing status is necessary and sufficient for a significant decrease in cell malignant behavior as measured by proliferation, cell cycle, and migration assays. We show that elevated levels of ADAR1, as found in astrocytomas, do indeed interfere with ADAR2 specific editing activity. Furthermore, we show that the endogenous ADAR1 can form heterodimers with ADAR2 in astrocytes.

Received for publication, October 5, 2007 , and in revised form, December 7, 2007.

^* This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) (to A. G.) and the Associazione "Ali di Scorta" (to A. G.). 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 three supplemental figures.

¹ Both authors contributed equally to the work.

² To whom correspondence should be addressed: Tel.: 39-06-68592658; Fax: 39-06-68592904; E-mail: gallo{at}opbg.net.

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