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Background: The inhibitor of differentiation (ID) genes have been implicated as promoters of tumor progression and metastasis in many human cancers. The current study investigated the expression and functional roles of ID genes in seeding and prognosis of medulloblastoma.Methods: ID gene expression was screened in human medulloblastoma tissues. Knockdown of ID3 gene was performed in medulloblastoma cells in vitro. The expression of metastasis-related genes after ID3 knockdown was assessed. The effect of ID3 knockdown on tumor seeding was observed in an animal model in vivo. The survival of medulloblastoma patients was plotted according to the ID3 expression levels.Results: Significantly higher ID3 expression was observed in medulloblastoma with cerebrospinal fluid seeding than tumors without seeding. Knockdown of ID3 decreased proliferation, increased apoptosis, and suppressed the migration of D283 medulloblastoma cells in vitro. In a seeding model of medulloblastoma, ID3 knockdown in vivo with shRNA inhibited the growth of primary tumors, prevented the development of leptomeningeal seeding, and prolonged animal survival. High ID3 expression was associated with shorter survival of medulloblastoma patients, especially in Group 4 medulloblastomas.Conclusions: High ID3 expression is associated with medulloblastoma seeding and is a poor prognostic factor, especially in patients with Group 4 tumors. ID3 may represent the metastatic/ aggressive phenotype of a subgroup of medulloblastoma. [ABSTRACT FROM AUTHOR]

Background: The primary cause of treatment failure in medulloblastomas (MB) is the development of leptomeningeal dissemination (seeding). For translational research on MB seeding, one of the major challenges is the development of reliable experimental models that simulate the seeding and growth characteristics of MBs. To overcome this obstacle, we improved an experimental mouse model by intracisternal inoculation of human MB cells and monitoring with in vivo live images., Methods: Human MB cells (UW426, D283 and MED8A) were transfected with a firefly luciferase gene and a Thy1.1 (CD90.1) marker linked with IRES under the control of the CMV promoter in a retroviral DNA backbone (effLuc). The MB-effLuc cells were injected into the cisterna magna using an intrathecal catheter, and bioluminescence images were captured. We performed histopathological analysis to confirm the extent of tumor seeding., Results: The luciferase activity of MB-effLuc cells displayed a gradually increasing pattern, which correlated with a quantitative luminometric assay. Live imaging showed that the MB-effLuc cells were diffusely distributed in the cervical spinal cord and the lumbosacral area. All mice injected with UW426-effLuc, D283-effLuc and MED8A-effLuc died within 51 days. The median survival was 22, 41 and 12 days after injection of 1.2 × 10(6) UW426-effLuc, D283-effLuc and MED8A-effLuc cells, respectively. The histopathological studies revealed that the MB-effLuc cells spread extensively and diffusely along the leptomeninges of the brain and spinal cord, forming tumor cell-coated layers. The tumor cells in the subarachnoid space expressed a human nuclei marker and Ki-67. Compared with the intracerebellar injection method in which the subfrontal area and distal spinal cord were spared by tumor cell seeding in some mice, the intracisternal injection model more closely resembled the widespread leptomeningeal seeding observed in MB patients., Conclusion: The results and described method are valuable resources for further translational research to overcome MB seeding.

Background: Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant brain tumor that almost exclusively develops in young children. AT/RT belongs to the embryonal brain tumor group, comprising primitive tumors recapitulating the early development of the central nervous system during embryogenesis. The loss of SMARCB1 protein expression is a hallmark of AT/RT pathogenesis. LIN28A/B is a key gene in embryonic development and for the maintenance of pluripotency in stem cells. LIN28B might be an important co-player in AT/RT pathogenesis, considering the primitive nature and young age onset of AT/RT., Methods: We explored the expression patterns of LIN28B in AT/RT and compared it with the expression in cortical dysplasia and medulloblastoma. The functional role of LIN28B was assessed using LIN28B-siRNAs in primary cultured AT/RT cells., Results: LIN28B is highly expressed in AT/RT compared with medulloblastoma and other embryonal tumors, whereas primary let-7g miRNA is down-regulated. AT/RT also showed higher expression of CCND1 and MYC, and lower expression of CDKN1C. The suppression of CCND1 expression and enhanced expression of CDKN1C were also observed. The knockdown of LIN28B decreased cell viability and proliferation, induced cell cycle arrest, and reduced migration in primary cultured AT/RT cells. Furthermore, we showed that the knockdown of LIN28B decreased the expression of other pluripotency-related genes (OCT4 and NANOG) and the mesenchymal-epithelial transition signature. We also transfected wild-type SMARCB1 into primary cultured AT/RT cells. The restoration of SMARCB1 in AT/RT cells decreased the expression of LIN28B and CCND1., Conclusions: These results show that LIN28B might be regulated through SMARCB1; the loss of SMARCB1 protein in AT/RT results in the unopposed expression of LIN28B and related oncogenes such as CCND1, leading to tumorigenesis. Therefore, the strategic role of LIN28B in AT/RT might be utilized as an important therapeutic target.