Sonic Hedgehog promotes proliferation of Notch-dependent monociliated choroid plexus tumour cells

Li, Li; Grausam, Katie B.; Wang, Jun; Lun, Melody P.; Ohli, Jasmin; Lidov, Hart G.W.; Calicchio, Monica L.; Zeng, Erliang; Salisbury, Jeffrey L.; Wechsler‐Reya, Robert J.; Lehtinen, Maria K.; Schüller, Ulrich; Zhao, Haotian

doi:10.1038/ncb3327

Cited by 61 publications

(71 citation statements)

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“…Ectopic Notch activation increases Gli2 protein [37]. Hh signaling promotes proliferation of monociliated choroid plexus tumor cells in a Notch-dependent pathway [21]. Inactivating Hh results in decreased expression of the Hh/Notch signaling component [20].…”

Section: Discussionmentioning

confidence: 99%

GANT61, a GLI inhibitor, sensitizes glioma cells to the temozolomide treatment

Cai

Zhao

et al. 2016

J Exp Clin Cancer Res

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BackgroundThe aim of this study was to investigate the effect of downregulating Hedgehog pathway by GANT61 on human glioma cells, examine the consequent changes of temozolomide (TMZ)-induced effects and explore the molecular mechanisms.MethodsThe cytotoxicity of a Gli1/2 inhibitor, GANT61 was examined both alone and in combination with TMZ in human glioma cell lines. The mRNA and protein expression alterations were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot, respectively. CCK-8 assay detected the cell proliferative capability. Apoptotic cell number was measured by flow cytometry. The transwell assay was used to test the cell invasive capability. DNA damage effect was identified by COMET assay and γH2AX expression.ResultsProliferation of tumor cells treated with GANT61 in combination with TMZ was significantly suppressed compared with those treated with either drug used alone. The combination treatment induced a higher rate of apoptosis, DNA damage and reduced the invasive capability of glioma cells. DNA damage repair enzyme MGMT and the Notch1 pathway increased in the cells treated by TMZ treatment. However, GANT61 could abrogated the protein increasing.ConclusionsGANT61 sensitizes glioma cells to TMZ treatment by enhancing DNA damage effect, decreasing MGMT expression and the Notch1 pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0463-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

GANT61, a GLI inhibitor, sensitizes glioma cells to the temozolomide treatment

Cai

Zhao

et al. 2016

J Exp Clin Cancer Res

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“…Immunostaining was carried out as described (21). Primary antibodies used include: anti-β-galactosidase (Promega), anti-GFP (Aves Lab), anti-Ki67 (BD Biosciences), anti-cyclin D1 and anti-CDKN1B (both from Santa Cruz), anti-HA, anti-Cleaved Caspase-3 and anti-Pyruvate kinase M2 (PKM2) (all from Cell Signaling Technology), anti-CD31 (abcam), anti-Atoh1 and anti-Pax6 (both from DSHB), anti-Tubulin β 3 (TUJ1, BioLegend), anti-cre, anti-NeuN and anti-GFAP (all from EMD Millipore).…”

Section: Methodsmentioning

confidence: 99%

“…In situ hybridization, microarray and RNA-seq were performed as described (21). ChIP-seq was performed as described using tumor from mice (22).…”

Section: Methodsmentioning

confidence: 99%

ATOH1 Promotes Leptomeningeal Dissemination and Metastasis of Sonic Hedgehog Subgroup Medulloblastomas

et al. 2017

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Medulloblastoma (MB) arising from the cerebellum is the most common pediatric brain malignancy, with leptomeningeal metastases often present at diagnosis and recurrence associated with poor clinical outcome. In this study, we employed mouse MB models to explore the relationship of tumor pathophysiology and dysregulated expression of the NOTCH pathway transcription factor ATOH1, which is present in aggressive MB subtypes driven by aberrant Sonic Hedgehog/Patched (SHH/PTCH) signaling. In experiments with conditional ATOH1 mouse mutants crossed to Ptch1+/− mice which develop SHH-driven MB, animals with Atoh1 transgene expression developed highly penetrant MB at a young age with extensive leptomeningeal disease and metastasis to the spinal cord and brain, resembling xenografts of human SHH MB. Metastatic tumors retained abnormal SHH signaling like tumor xenografts. Conversely, ATOH1 expression was detected consistently in recurrent and metastatic SHH MB. ChIP-seq and gene expression profiling identified candidate ATOH1 targets in tumor cells involved in development and tumorigenesis. Among these targets specific to metastatic tumors, there was an enrichment in those implicated in extracellular matrix remodeling activity, cytoskeletal network and interaction with microenvironment, indicating a shift in transcriptomic and epigenomic landscapes during metastasis. Treatment with bone morphogenetic protein (BMP) or SHH pathway inhibitors decreased tumor cell proliferation and suppressed metastatic tumor growth, respectively. Our work reveals a dynamic ATOH1-driven molecular cascade underlying MB metastasis that offers possible therapeutic opportunities.

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“…CP tumors are believed to arise from monociliated progenitors of the CP epithelium, which are characterized by robust Notch and Sonic Hedgehog (Shh) signaling . Using animal models, Li et al.…”

Section: Biology and Molecular Findingsmentioning

confidence: 99%

Pediatric choroid plexus carcinoma: Biologically and clinically in need of new perspectives

Zaky

Finlay

2018

Pediatric Blood & Cancer

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Choroid plexus (CP) carcinoma is a rare pediatric brain neoplasm. Recent studies have highlighted the potential of genome-wide methylation and gene expression profiling to provide additional layers of information to improve tumor risk-stratification. There is a lack of data regarding the best therapy, and approaches have been heterogeneous. Despite multidisciplinary treatment approaches, the outcome remains guarded and treatments have been based on case series and expert opinions. In this study, we discuss the recent wealth of data regarding CP carcinoma molecular biology and current management. We also briefly highlight the remaining barriers to formulate the best treatment strategies, and future therapeutic potentials.

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Sonic Hedgehog promotes proliferation of Notch-dependent monociliated choroid plexus tumour cells

Cited by 61 publications

References 69 publications

GANT61, a GLI inhibitor, sensitizes glioma cells to the temozolomide treatment

GANT61, a GLI inhibitor, sensitizes glioma cells to the temozolomide treatment

ATOH1 Promotes Leptomeningeal Dissemination and Metastasis of Sonic Hedgehog Subgroup Medulloblastomas

Pediatric choroid plexus carcinoma: Biologically and clinically in need of new perspectives

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