ASC deficiency suppresses proliferation and prevents medulloblastoma incidence
| Autor: | Jenny P.-Y. Ting, Andrew J. Crowther, E R W Knight, Timothy R. Gershon, C A Flowers, Mohanish Deshmukh, Esita Patel, C. R. Miller |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Adult
Male Cancer Research endocrine system animal structures Adolescent animal diseases Mice Transgenic medicine.disease_cause Article Young Adult Transforming Growth Factor beta Precursor cell Genetics medicine Animals Humans Cerebellar Neoplasms Child Molecular Biology Caspase In Situ Hybridization Cell Proliferation Oligonucleotide Array Sequence Analysis Medulloblastoma Mice Knockout biology Reverse Transcriptase Polymerase Chain Reaction Gene Expression Profiling Infant hemic and immune systems Transforming growth factor beta medicine.disease Molecular biology eye diseases CARD Signaling Adaptor Proteins Gene Expression Regulation Neoplastic Cytoskeletal Proteins Child Preschool Knockout mouse Cancer research biology.protein Female Carcinogenesis Smoothened Apoptosis Regulatory Proteins Transforming growth factor Signal Transduction |
| Popis: | Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is silenced by promoter methylation in many types of tumors, yet ASC's role in most cancers remains unknown. Here, we show that ASC is highly expressed in a model of medulloblastoma, the most common malignant pediatric brain cancer; ASC is also expressed in human medulloblastomas. Importantly, while ASC deficiency did not affect normal cerebellar development, ASC knockout mice on the Smoothened (ND2:SmoA1) transgenic model of medulloblastoma exhibited a profound reduction in medulloblastoma incidence and a delayed tumor onset. A similar decrease in tumorigenesis with ASC deficiency was also seen in the hGFAP-Cre:SmoM2 mouse model of medulloblastoma. Interestingly, hyperproliferation of the external granule layer (EGL) was comparable at P20 in both wild-type and ASC-deficient SmoA1 mice. However, while the apoptosis and differentiation markers remained unchanged at this age, proliferation makers were decreased, and the EGL was reduced in thickness and area by P60. This reduction in proliferation with ASC deficiency was also seen in isolated SmoA1 cerebellar granule precursor cells in vitro, indicating that the effect of ASC deletion on proliferation was cell autonomous. Interestingly, ASC-deficient SmoA1 cerebella exhibited disrupted expression of genes in the transforming growth factor-β pathway and increased level of nuclear Smad3. Taken together, these results demonstrate an unexpected role for ASC in Sonic hedgehog-driven medulloblastoma tumorigenesis, thus identifying ASC as a promising novel target for antitumor therapy. |
| Databáze: | OpenAIRE |
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