MBRS-06. Gli3 INDUCES NEURONAL DIFFERENTIATION IN WNT- AND SHH- ACTIVATED MEDULLOBLASTOMA

BACKGROUND: 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 expression of Gli3 in molecular subgroups. METHOD: Thirty-one medulloblastomas treated at Niigata University between 1982 and 2013 were studied. Molecular classification into 4 subgroups (WNT-activated, SHH-activated, Group 3 and Group 4) using Nanostring and immunohistochemistry was performed. Furthermore, Gli3 and Gli1 expression in molecular subgroups was assessed using public data bases. RESULTS: Nanostring was considered reliable (confidence > 0.9) in 28 cases. Four cases were classified as WNT-, 5 cases as SHH-activated, 4 cases as Group 3 and 16 cases as Group 4. Gli3 was positive in 7 out of 9 (78%) WNT-/SHH- cases, but positive in only 8 out of 19 (42.1%) non-WNT-/SHH- subgroup cases (p = 0.1145, Fisher’s exact test). R2 database analysis confirmed that Gli3 was significantly 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 nodules showing neuronal differentiation in D/N type medulloblastoma. Results of single cell RNA analyses were consistent with those of IHC, Nanostring and R2. CONCLUSION: These results suggest that Gli3 is elevated inside the nodules of SHH-activated medulloblastoma, whereas in WNT-activated cases, Gli3 diffusely suppresses HH signaling.