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J. Biol. Chem., Vol. 282, Issue 25, 18634-18644, June 22, 2007

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Silencing of Insulin-like Growth Factor-binding Protein-2 in Human Glioblastoma Cells Reduces Both Invasiveness and Expression of Progression-associated Gene CD24^*

Tsuyoshi Fukushima, Tomoaki Tezuka^¶, Takeshi Shimomura^¶, Shinichi Nakano, and Hiroaki Kataoka¹

From the Section of Oncopathology and Regenerative Biology, Department of Pathology, and the Department of Neurosurgery, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan and the ^¶Pharmaceuticals Research Division, Mitsubishi Pharma Corporation, Yokohama 227-0033, Japan

Glioblastoma multiforme (GBM) is a malignant brain tumor characterized by rapid growth and extensive invasiveness. Overexpression of insulin-like growth factor-binding protein-2 (IGFBP-2) has been reported in GBM. However, it remains to be determined how IGFBP-2 is involved in the progression of GBM. We utilized short hairpin-RNA (shRNA) expression retroviral vectors to inactivate the IGFBP-2 gene permanently in two human GBM cell lines, U251 and YKG-1. The stable knockdown of IGFBP-2 resulted in decreased invasiveness, decreased saturation density of the cells in vitro, and decreased tumorigenicity in nude mice. Transcriptional profiling of both lines revealed several genes that were significantly down-regulated by inactivation of IGFBP-2. One such gene was CD24, which has been implicated in progression of various cancers. Indeed, CD24 was expressed in most GBM cases and the inactivation of CD24 in GBM cells suppressed cellular invasiveness, as was the case for IGFBP-2. Forced overexpression of CD24 led to increased invasiveness of both IGFBP-2-inactivated GBM cell lines and also A172, a human GBM cell line with low endogenous CD24. Further supporting the inter-relationship between IGFBP-2 and CD24, knockdown of IGFBP-2 suppressed the CD24 promoter activity. Moreover, both CD24 promoter activity and in vitro invasiveness were restored in knockdown cells by transfection with an IGFBP-2 expression plasmid. These results indicate that CD24 is modulated by IGFBP-2 and contributes to IGFBP-2-enhanced invasiveness of GBM cells.

Received for publication, October 11, 2006 , and in revised form, May 1, 2007.

^* This work was supported in part by Grant-in-Aid for Scientific Research (B) 17390116 and 21st Century COE program (Life Science) from the Ministry of Education, Science, Sports and Culture, Japan, and a grant-in-aid for Cancer Research from the Ministry of Health, Labor and Welfare (15-13). 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.

¹ To whom correspondence should be addressed: 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan. Tel.: 81-985-85-2809; Fax: 81-985-85-6003; E-mail: mejina{at}fc.miyazaki-u.ac.jp.

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