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A Sexually Dimorphic Role for STAT3 in Sonic Hedgehog Medulloblastoma

Medulloblastoma is the most common malignant brain tumor in children and represents 20% of all pediatric central nervous system neoplasms. While advances in surgery, radiation and chemotherapy have improved overall survival, the lifelong sequelae of these treatments represent a major health care bur...

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Autores principales: White, Christine L., Jayasekara, W. Samantha N., Picard, Daniel, Chen, Jasmine, Watkins, D. Neil, Cain, Jason E., Remke, Marc, Gough, Daniel J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895805/
https://www.ncbi.nlm.nih.gov/pubmed/31683879
http://dx.doi.org/10.3390/cancers11111702
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author White, Christine L.
Jayasekara, W. Samantha N.
Picard, Daniel
Chen, Jasmine
Watkins, D. Neil
Cain, Jason E.
Remke, Marc
Gough, Daniel J.
author_facet White, Christine L.
Jayasekara, W. Samantha N.
Picard, Daniel
Chen, Jasmine
Watkins, D. Neil
Cain, Jason E.
Remke, Marc
Gough, Daniel J.
author_sort White, Christine L.
collection PubMed
description Medulloblastoma is the most common malignant brain tumor in children and represents 20% of all pediatric central nervous system neoplasms. While advances in surgery, radiation and chemotherapy have improved overall survival, the lifelong sequelae of these treatments represent a major health care burden and have led to ongoing efforts to find effective targeted treatments. There is a well-recognized male bias in medulloblastoma diagnosis, although the mechanism remains unknown. Herein, we identify a sex-specific role for the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) in the Sonic Hedgehog (SHH) medulloblastoma subgroup. Specific deletion of Stat3 from granule cell precursors in a spontaneous mouse model of SHH medulloblastoma completely protects male, but not female mice from tumor initiation. Segregation of SHH medulloblastoma patients into high and low STAT3 expressing cohorts shows that low STAT3 expression correlates with improved overall survival in male patients. We observe sex specific changes in IL-10 and IL-6 expression and show that IL-6 stimulation enhances SHH-mediated gene transcription in a STAT3-dependent manner. Together these data identify STAT3 as a key molecule underpinning the sexual dimorphism in medulloblastoma.
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spelling pubmed-68958052019-12-24 A Sexually Dimorphic Role for STAT3 in Sonic Hedgehog Medulloblastoma White, Christine L. Jayasekara, W. Samantha N. Picard, Daniel Chen, Jasmine Watkins, D. Neil Cain, Jason E. Remke, Marc Gough, Daniel J. Cancers (Basel) Brief Report Medulloblastoma is the most common malignant brain tumor in children and represents 20% of all pediatric central nervous system neoplasms. While advances in surgery, radiation and chemotherapy have improved overall survival, the lifelong sequelae of these treatments represent a major health care burden and have led to ongoing efforts to find effective targeted treatments. There is a well-recognized male bias in medulloblastoma diagnosis, although the mechanism remains unknown. Herein, we identify a sex-specific role for the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) in the Sonic Hedgehog (SHH) medulloblastoma subgroup. Specific deletion of Stat3 from granule cell precursors in a spontaneous mouse model of SHH medulloblastoma completely protects male, but not female mice from tumor initiation. Segregation of SHH medulloblastoma patients into high and low STAT3 expressing cohorts shows that low STAT3 expression correlates with improved overall survival in male patients. We observe sex specific changes in IL-10 and IL-6 expression and show that IL-6 stimulation enhances SHH-mediated gene transcription in a STAT3-dependent manner. Together these data identify STAT3 as a key molecule underpinning the sexual dimorphism in medulloblastoma. MDPI 2019-11-01 /pmc/articles/PMC6895805/ /pubmed/31683879 http://dx.doi.org/10.3390/cancers11111702 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Brief Report
White, Christine L.
Jayasekara, W. Samantha N.
Picard, Daniel
Chen, Jasmine
Watkins, D. Neil
Cain, Jason E.
Remke, Marc
Gough, Daniel J.
A Sexually Dimorphic Role for STAT3 in Sonic Hedgehog Medulloblastoma
title A Sexually Dimorphic Role for STAT3 in Sonic Hedgehog Medulloblastoma
title_full A Sexually Dimorphic Role for STAT3 in Sonic Hedgehog Medulloblastoma
title_fullStr A Sexually Dimorphic Role for STAT3 in Sonic Hedgehog Medulloblastoma
title_full_unstemmed A Sexually Dimorphic Role for STAT3 in Sonic Hedgehog Medulloblastoma
title_short A Sexually Dimorphic Role for STAT3 in Sonic Hedgehog Medulloblastoma
title_sort sexually dimorphic role for stat3 in sonic hedgehog medulloblastoma
topic Brief Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895805/
https://www.ncbi.nlm.nih.gov/pubmed/31683879
http://dx.doi.org/10.3390/cancers11111702
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