Abstract
Alveolar rhabdomyosarcoma (ARMS) is a muscle-derived childhood tumor characterized by production of oncogenic PAX3/7-FOXO1 chimeric transcription factors. While downstream targets of the PAX3-FOXO1 oncoprotein in ARMS have been defined, the functional relevance of these targets is unclear. Here, we show that upregulation of the cannabinoid receptor 1 (Cnr1/Cb1) by PAX3-FOXO1 in mouse primary myoblasts and ARMS cell lines, contributes to PAX3-FOXO1 phenotypes, both in vivo and in vitro. In primary myoblasts, Cnr1 was dispensable for PAX3-FOXO1 to mediate cell proliferation, differentiation, or transformation; however, Cnr1 function was essential to increase the invasive capacity conferred by PAX3-FOXO1 overexpression in these cells. Genetic or pharmacologic abrogation of Cnr1 inhibited the enhanced basement membrane invasion induced by PAX3-FOXO1. Cnr1 loss by either route also dramatically reduced lung metastasis formation. Taken together, our findings strongly implicate Cnr1 as a novel tractable target to inhibit ARMS invasion and metastasis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Cell Line, Tumor
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Cell Movement*
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Cell Transformation, Neoplastic / drug effects
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Cells, Cultured
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism
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Humans
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / secondary
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Mice
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Mice, Inbred C57BL
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Mice, Inbred NOD
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Mice, Knockout
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Mice, SCID
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Myoblasts / cytology
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Myoblasts / drug effects
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Myoblasts / metabolism
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Neoplasm Invasiveness
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Neoplasm Metastasis
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Neoplasms, Experimental / genetics
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Paired Box Transcription Factors / genetics
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Paired Box Transcription Factors / metabolism*
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Piperidines / pharmacology
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Pyrazoles / pharmacology
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Receptor, Cannabinoid, CB1 / antagonists & inhibitors
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Receptor, Cannabinoid, CB1 / genetics
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Receptor, Cannabinoid, CB1 / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Rhabdomyosarcoma, Alveolar / genetics
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Rhabdomyosarcoma, Alveolar / metabolism
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Rhabdomyosarcoma, Alveolar / pathology
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Tumor Suppressor Protein p14ARF / genetics
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Tumor Suppressor Protein p14ARF / metabolism
Substances
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Cyclin-Dependent Kinase Inhibitor p16
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Oncogene Proteins, Fusion
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PAX3-FOXO1A fusion protein, human
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Paired Box Transcription Factors
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Piperidines
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Pyrazoles
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Receptor, Cannabinoid, CB1
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Tumor Suppressor Protein p14ARF
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AM 251