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An ABC Transporter Drives Medulloblastoma Pathogenesis by Regulating Sonic Hedgehog Signaling
- Source :
- Cancer Res
- Publication Year :
- 2019
-
Abstract
- Mutations in Sonic hedgehog (SHH) signaling promote aberrant proliferation and tumor growth. SHH-medulloblastoma (MB) is among the most frequent brain tumors in children less than 3 years of age. Although key components of the SHH pathway are well-known, we hypothesized that new disease-modifying targets of SHH-MB might be identified from large-scale bioinformatics and systems biology analyses. Using a data-driven systems biology approach, we built a MB-specific interactome. The ATP-binding cassette transporter ABCC4 was identified as a modulator of SHH-MB. Accordingly, increased ABCC4 expression correlated with poor overall survival in patients with SHH-MB. Knockdown of ABCC4 expression markedly blunted the constitutive activation of the SHH pathway secondary to Ptch1 or Sufu insufficiency. In human tumor cell lines, ABCC4 knockdown and inhibition reduced full-length GLI3 levels. In a clinically relevant murine SHH-MB model, targeted ablation of Abcc4 in primary tumors significantly reduced tumor burden and extended the lifespan of tumor-bearing mice. These studies reveal ABCC4 as a potent SHH pathway regulator and a new candidate to target with the potential to improve SHH-MB therapy. Significance: These findings identify ABCC4 transporter as a new target in SHH-MB, prompting the development of inhibitors or the repurporsing of existing drugs to target ABCC4.
- Subjects :
- 0301 basic medicine
Cancer Research
animal structures
Datasets as Topic
Nerve Tissue Proteins
ABCC4
Kaplan-Meier Estimate
Interactome
Article
03 medical and health sciences
Mice
0302 clinical medicine
Zinc Finger Protein Gli3
Cell Line, Tumor
GLI3
Protein Interaction Mapping
medicine
Animals
Humans
Hedgehog Proteins
Protein Interaction Maps
Sonic hedgehog
Child
Medulloblastoma
Mice, Knockout
Gene knockdown
biology
Brain Neoplasms
Systems Biology
medicine.disease
Xenograft Model Antitumor Assays
Hedgehog signaling pathway
Tumor Burden
Gene Expression Regulation, Neoplastic
Disease Models, Animal
030104 developmental biology
Oncology
PTCH1
030220 oncology & carcinogenesis
Gene Knockdown Techniques
embryonic structures
biology.protein
Cancer research
NIH 3T3 Cells
Multidrug Resistance-Associated Proteins
Follow-Up Studies
Signal Transduction
Subjects
Details
- ISSN :
- 15387445
- Volume :
- 80
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Cancer research
- Accession number :
- edsair.doi.dedup.....2f67ab0a35ee0d23f715c2967db66b4b