PATH-54. Gli3 INDUCES NEURONAL DIFFERENTIATION IN WNT- AND SHH- ACTIVATED MEDULLOBLASTOMA

Abstract

We have previously investigated the expression of Gli3, a downstream target of the Sonic Hedgehog pathway, which main function is to suppress Gli1/2 in medulloblastomas. We found that Gli3 is associated with neuronal and glial differentiation in desmoplastic / nodular (D/N) type medulloblastomas (Miyahara et al., Neuropathology, 2013). In the present study, we investigated the relationship between Gli3 expression and molecular subgroup of medulloblastoma. Thirty-five medulloblastomas treated at Department of Neurosurgery, Niigata University between 1982 and 2013 were retrospectively studied. Molecular classification into 4 subgroups (WNT-activated, SHH-activated, Group 3 and Group 4) was performed using Nanostring. HE and NeuN, GFAP, β-catenin, GAB-1, and YAP-1 immunohistochemistry was performed. Furthermore, Gli3 and Gli1 expression in each molecular subgroup was assessed in the public data base “R2”. Nanostring was feasible in 34 cases. Four cases were classified as WNT- activated, 5 cases as SHH-activated, 4 cases as Group 3 and 21 cases as Group 4. Gli3 was positive in 17 cases, including all 4 (100%) WNT-activated cases and 3 (60%) SHH-activated cases. R2 database analysis confirmed that Gli3 was elevated in WNT- and SHH-activated medulloblastoma. Gli1 was elevated in SHH-activated cases but suppressed in WNT-activated cases. IHC analysis revealed that Gli3 was elevated inside the nodules of D/N type medulloblastoma. Neuronal differentiation was seen in these nodules. These results suggest that Gli3 is elevated inside the nodules of SHH-activated medulloblastoma, whereas in WNT-activated cases, Gli3 suppresses HH signaling in the entire tumor.