Involvement of Wnt signaling pathway in murine medulloblastoma induced by human neurotropic JC virus

By using the early genome of the human neurotropic polyomavirus, JCV, we ha ve created transgenic animals that develop cerebellar primitive neuroectode rmal tumors which model human medulloblastoma. Expression of T-antigen was found in some, but not all, tumor cells, and examination of the clonal cell lines derived from the tumor population showed enhanced tumorigenicity of cells expressing T-antigen in comparison to T-antigen negative cells. Consi dering the earlier notion on the potential involvement of beta -catenin wit h human medulloblastoma, we investigated various components of the Wnt sign aling pathway including beta -catenin, its partner transcription factor, LE F-1, and their downstream target gene c-myc in these two cell populations. Immunohistochemical staining of the cells revealed enhanced nuclear appeara nce of beta -catenin in T-antigen positive cells. Results from Western blot showed higher levels of beta -catenin and LEF-1 in T-antigen positive cell s in comparison to those in T-antigen negative cells. The enhanced level of LEF-1 expression correlated with the increase in DNA binding activity of t his protein in nuclear extracts of T-antigen positive cells. Results from N orthern and Western blot analyses revealed that the level of c-myc expressi on is augmented both at the RNA and protein levels in T-antigen positive ce lls. These observations corroborated results from transfection studies indi cating the ability of JCV T-antigen to stimulate c-myc promoter activity. F urther, co-transfection experiments revealed that the amount of c-myc and T -antigen protein in tumor cells may dictate the activity of JCV early promo ter in these cells. These observations are interesting in light of recent d iscoveries on the association of JCV with human medulloblastoma and suggest that communication between JCV and the Wnt pathway may be an important eve nt in the genesis of these tumors.