This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-09-0886v1 69/17/6790    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Lo, H.-W. Articles by Ali-Osman, F. PubMed PubMed Citation Articles by Lo, H.-W. Articles by Ali-Osman, F.

A Novel Splice Variant of GLI1 That Promotes Glioblastoma Cell Migration and Invasion

¹ Department of Surgery, Duke University; ² Duke Comprehensive Cancer Center; ³ Preston Robert Tisch Brain Tumor Center, Durham, North Carolina

Requests for reprints: Hui-Wen Lo, Department of Surgery, Duke University, Box 3156, 433A MSRB I, 103 Research Drive, Durham, NC 27710. Phone: 919-668-6792; Fax: 919-684-5483; E-mail: huiwen.lo{at}duke.edu.

Key Words: Hedgehog pathway • GLI1 • glioma • migration • invasion • CD24

The family of GLI zinc finger transcription factors regulates the expression of genes involved in many important cellular processes, notably embryonal development and cellular differentiation. The glioma-associated oncogene homologue 1 (GLI1) isoform, in particular, has attracted much attention because of its frequent activation in many human cancers and its interactions with other signaling pathways, such as those mediated by K-RAS, transforming growth factor-β, epidermal growth factor receptor, and protein kinase A. Here, we report the identification of a novel truncated GLI1 splice variant, tGLI1, with an in-frame deletion of 123 bases (41 codons) spanning the entire exon 3 and part of exon 4 of the GLI1 gene. Expression of tGLI1 is undetectable in normal cells but is high in glioblastoma multiforme (GBM) and other cancer cells. Although tGLI1 undergoes nuclear translocalization and transactivates GLI1-binding sites similar to GLI1, unlike GLI1, it is associated with increased motility and invasiveness of GBM cells. Using microarray analysis, we showed >100 genes to be differentially expressed in tGLI1-expressing compared with GLI1-expressing GBM cells, although both cell types expressed equal levels of known GLI1-regulated genes, such as PTCH1. We further showed one of the tGLI1 up-regulated genes, CD24, an invasion-associated gene, to be required for the migratory and invasive phenotype of GBM cells. These data provide conclusive evidence for a novel gain-of-function GLI1 splice variant that promotes migration and invasiveness of GBM cells and open up a new research paradigm on the role of the GLI1 pathway in malignancy. [Cancer Res 2009;69(17):6790–8]