A Sexually Dimorphic Role for STAT3 in Sonic Hedgehog Medulloblastoma

被引:14
作者
White, Christine L. [1 ,2 ]
Jayasekara, W. Samantha N. [1 ,2 ]
Picard, Daniel [3 ,4 ,5 ]
Chen, Jasmine [1 ,2 ]
Watkins, D. Neil [1 ,2 ,6 ,7 ]
Cain, Jason E. [1 ,2 ]
Remke, Marc [3 ,4 ,5 ]
Gough, Daniel J. [1 ,2 ]
机构
[1] Hudson Inst Med Res, Ctr Canc Res, 27-31 Wright St, Clayton, Vic 3168, Australia
[2] Monash Univ, Dept Mol & Translat Sci, Clayton, Vic 3800, Australia
[3] German Canc Res Ctr, Dept Pediat Neurooncogen, D-69120 Heidelberg, Germany
[4] German Canc Consortium DKTK, Partner Site Essen, D-45147 Dusseldorf, Germany
[5] Univ Hosp Dusseldorf, Med Fac, Inst Neuropathol, Dept Pediat Oncol Hematol Clin Immunol, D-40225 Dusseldorf, Germany
[6] Canc Care Manitoba, Res Inst Oncol & Hematol, Winnipeg, MB R3E 0V9, Canada
[7] Univ Manitoba, Rady Fac Hlth Sci, Dept Internal Med, Winnipeg, MB R3T 2N2, Canada
关键词
STAT3; sexual dimorphism; medulloblastoma; sonic hedgehog; CENTRAL-NERVOUS-SYSTEM; MITOCHONDRIAL STAT3; SIGNAL TRANSDUCER; CELLS; ACTIVATION; TRANSCRIPTION-3; CLASSIFICATION; SUBGROUPS; PROMOTES; TUMORS;
D O I
10.3390/cancers11111702
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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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页数:13
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共 43 条
[1]   Medulloblastoma: Molecular Classification-Based Personal Therapeutics [J].
Archer, Tenley C. ;
Mahoney, Elizabeth L. ;
Pomeroy, Scott L. .
NEUROTHERAPEUTICS, 2017, 14 (02) :265-273
[2]   Disruption of the ciliary GTPase Arl13b suppresses Sonic hedgehog overactivation and inhibits medulloblastoma formation [J].
Bay, Sarah N. ;
Long, Alyssa B. ;
Caspary, Tamara .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2018, 115 (07) :1570-1575
[3]   STAT3 tyrosine phosphorylation influences survival in glioblastoma [J].
Birner, Peter ;
Toumangelova-Uzeir, Kalina ;
Natchev, Sevdalin ;
Guentchev, Marin .
JOURNAL OF NEURO-ONCOLOGY, 2010, 100 (03) :339-343
[4]   Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway [J].
Bonni, A ;
Sun, Y ;
NadalVicens, M ;
Bhatt, A ;
Frank, DA ;
Rozovsky, I ;
Stahl, N ;
Yancopoulos, GD ;
Greenberg, ME .
SCIENCE, 1997, 278 (5337) :477-483
[5]   Should I stay or should I go? Becoming a granule cell [J].
Chedotal, Alain .
TRENDS IN NEUROSCIENCES, 2010, 33 (04) :163-172
[6]   Gender Effect in Experimental Models of Human Medulloblastoma: Does the Estrogen Receptor β Signaling Play a Role? [J].
Ciucci, Alessandra ;
Meco, Daniela ;
De Stefano, Ilaria ;
Travaglia, Daniele ;
Zannoni, Gian Franco ;
Scambia, Giovanni ;
Riccardi, Riccardo ;
Saran, Anna ;
Mancuso, Mariateresa ;
Gallo, Daniela .
PLOS ONE, 2014, 9 (07)
[7]   JAK-STAT PATHWAYS AND TRANSCRIPTIONAL ACTIVATION IN RESPONSE TO IFNS AND OTHER EXTRACELLULAR SIGNALING PROTEINS [J].
DARNELL, JE ;
KERR, IM ;
STARK, GR .
SCIENCE, 1994, 264 (5164) :1415-1421
[8]   Involvement of stat3 in mouse brain development and sexual dimorphism: A proteomics approach [J].
Di Domenico, Fabio ;
Casalena, Gabriella ;
Sultana, Rukhsana ;
Cai, Jian ;
Pierce, William M. ;
Perluigi, Marzia ;
Cini, Chiara ;
Baracca, Alessandra ;
Solaini, Giancarlo ;
Lenaz, Giorgio ;
Jia, Jia ;
Dziennis, Suzan ;
Murphy, Stephanie J. ;
Alkayed, Nabil J. ;
Butterfield, D. Allan .
BRAIN RESEARCH, 2010, 1362 :1-12
[9]   Demographics, patterns of care, and survival in pediatric medulloblastoma [J].
Dressler, Emily V. ;
Dolecek, Therese A. ;
Liu, Meng ;
Villano, John L. .
JOURNAL OF NEURO-ONCOLOGY, 2017, 132 (03) :497-506
[10]   Role of signal transducer and activator of transcription-3 in estradiol-mediated neuroprotection [J].
Dziennis, Suzan ;
Jia, Taiping ;
Ronnekleiv, Oline K. ;
Hurn, Patricia D. ;
Alkayed, Nabil J. .
JOURNAL OF NEUROSCIENCE, 2007, 27 (27) :7268-7274