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J. Biol. Chem., Vol. 283, Issue 29, 20277-20287, July 18, 2008

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Polypyrimidine Tract-binding Protein (PTB) Differentially Affects Malignancy in a Cell Line-dependent Manner^*

Chen Wang, John T. Norton, Supurna Ghosh, Julie Kim^¶, Kazuo Fushimi^||, Jane Y. Wu^||, M. Sharon Stack¹, and Sui Huang²

From the Department of Cell and Molecular Biology, Department of Medicine, Breast Center, ^¶Department of Medicine, Obstetrics and Gynecology, Prentice Hospital, and the ^||Department of Neurology, Feinberg School of Medicine of Northwestern University, Chicago, Illinois 60611

RNA processing is altered during malignant transformation, and expression of the polypyrimidine tract-binding protein (PTB) is often increased in cancer cells. Although some data support that PTB promotes cancer, the functional contribution of PTB to the malignant phenotype remains to be clarified. Here we report that although PTB levels are generally increased in cancer cell lines from multiple origins and in endometrial adenocarcinoma tumors, there appears to be no correlation between PTB levels and disease severity or metastatic capacity. The three isoforms of PTB increase heterogeneously among different tumor cells. PTB knockdown in transformed cells by small interfering RNA decreases cellular growth in monolayer culture and to a greater extent in semi-solid media without inducing apoptosis. Down-regulation of PTB expression in a normal cell line reduces proliferation even more significantly. Reduction of PTB inhibits the invasive behavior of two cancer cell lines in Matrigel invasion assays but enhances the invasive behavior of another. At the molecular level, PTB in various cell lines differentially affects the alternative splicing pattern of the same substrates, such as caspase 2. Furthermore, overexpression of PTB does not enhance proliferation, anchorage-independent growth, or invasion in immortalized or normal cells. These data demonstrate that PTB is not oncogenic and can either promote or antagonize a malignant trait dependent upon the specific intra-cellular environment.

Received for publication, May 13, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grants GM070967 (to J. Y. W.), CA 097761, and GM078555-01 (to S. H.). This work was also supported by a Young Investigators Award and the Northwestern Memorial Foundation and Friends of Prentice (to J. K.). 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.

¹ Present address: Dept. of Pathology and Anatomical Sciences, University of Missouri, Columbia, MO 65211.

² To whom correspondence should be addressed: Dept. of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Ward Bldg. 11-240, 303 E. Chicago Ave., Chicago, IL 60611. Tel.: 312-503-4269; Fax: 312-503-7912; E-mail: s-huang2{at}northwestern.edu.

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