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Bcl-2 Promotes Invasion and Lung Metastasis by Inducing Matrix Metalloproteinase-2

¹ Department of Biochemistry, College of Medicine, Ewha Women's University; ² Molecular Therapy Research Center and ³ Department of Thoracic Surgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Ilwon-dong, Kangnam-ku, Seoul, Korea; and ⁴ Department of Cell Biology, The University of Alabama at Birmingham, Birmingham, Alabama

Requests for reprints: Kyoungsook Park, Molecular Therapy Research Center, Sungkyunkwan University, Samsung Medical Center, Annex 8F, 50 Ilwon-dong, Kangnam-ku, 135-710 Seoul, Korea. Phone: 82-2-3410-3638; Fax: 82-2-3410-3649; E-mail: hannah05{at}dreamwiz.com.

Bcl-2 is involved in the progression of human malignancies, but the precise role and mechanism of Bcl-2 for tumor invasion and metastasis remains unclear. In this study, we have investigated the role and mechanism of Bcl-2 on tumor cell invasion and metastasis by using Bcl-2 overexpressing non–small cell lung cancer cells. Matrix metalloproteinases (MMPs) are important proteins involved in the processes of tumor invasion and metastasis. In vitro Matrigel invasion assays showed that Bcl-2 overexpression increased tumor cell invasion by 15-fold. Moreover, Bcl-2 overexpression enhanced in vivo lung metastasis by 4-fold. Consistent with its effect on invasion and metastasis, Bcl-2 overexpression induced not only MMP-2 mRNA and its protein expression, but this also activated the pro-MMP-2 protein to its active form. To explore the induction mechanism of MMP-2 by Bcl-2, we investigated the effects of Bcl-2 overexpression on MMP-2 transcriptional regulation. Nuclear run-on assays showed a 6-fold increase in the transcription rate of MMP-2 mRNA in the Bcl-2 transfectants (H157/Bcl-2) compared with that of the H157/vector control cells (H157/C). Overexpression of Bcl-2 induced the nuclear transcription factor activator protein 1 family, including the c-Jun, JunD, c-Fos, FosB, and Fra-1 proteins. Reporter assays combined with deletion mutagenesis analysis and gel shift assays showed the involvement of activator protein 1 in the activation of MMP-2 promoter activity by Bcl-2. Taken together, we have shown that Bcl-2 promotes tumor invasion and lung metastasis by inducing MMP-2 gene expression through the combined action of transcriptional and posttranslational mechanisms.

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