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PAX6 Suppresses the Invasiveness of Glioblastoma Cells and the Expression of the Matrix Metalloproteinase-2 Gene

Departments of ¹ Neurobiology and Developmental Sciences and ² Biostatistics, and ³ Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas and ⁴ Departments of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Yi-Hong Zhou, University of California, Irvine, 101 The City Drive, Building 56, Suit 400, Zot 5397, Orange, CA 92868. Phone: 949-824-5767; Fax: 714-456-8284; E-mail: yihongz{at}uci.edu.

Glioblastoma multiforme (GBM) is the most invasive brain tumor. We have previously reported that the transcription factor PAX6 suppresses the tumorigenecity of GBM cells. By an in vitro Matrigel invasion assay on two GBM cell lines stably transfected with wild-type and/or two mutant forms of PAX6, this study displays the first evidence that PAX6 inhibits the invasiveness of GBM cells and that the DNA-binding domain of PAX6 is required for this function. Using real-time quantitative reverse transcription-PCR (RT-PCR), gelatin zymography, and immunohistochemistry assays, the expression of the gene encoding matrix metalloproteinase-2 (MMP2) in GBM cell lines grown in vitro or in intracranial xenografts in nude mice was shown to be repressed by either stable or adenoviral-mediated overexpression of PAX6. Luciferase promoter assays revealed PAX6-mediated suppression of MMP2 promoter activity. Electrophoretic mobility shift assays showed direct binding of PAX6 to the MMP2 promoter. A significant reverse correlation (P < 0.05) occurred between PAX6 and MMP2 expression quantified by real-time quantitative RT-PCR in 41 GBMs, 43 anaplastic astrocytomas, and 7 adjacent normal tissues. Interestingly, the degree and significance of the reverse correlation increased after excluding astrocytomas, whereas it became insignificant after excluding GBMs. In GBM cells stably transfected with a dominant negative mutant PAX6 showing increased MMP2 expression and invasiveness, knock-down of MMP2 revealed that MMP2 is one of the PAX6 target genes mediating its suppression of invasion. Overall data delineated a mechanism for the suppressive function of PAX6 in GBM: suppression of cell invasion by repressing the expression of proinvasive genes such as MMP2. (Cancer Res 2006; 66(20): 9809-17)

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