STAT3 pathway regulates lung-derived brain metastasis initiating cell capacity through miR-21 activation
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Mohini Singh1,4, Neha Garg1,6, Chitra Venugopal1,6, Robin Hallett2, Tomas Tokar7, Nicole McFarlane1,6, Sujeivan Mahendram1,6, David Bakhshinyan1,4, Branavan Manoranjan1,3,4, Parvez Vora1,6, Maleeha Qazi1,4, Carolynn C. Arpin10, Brent Page10, Sina Haftchenary10, David A. Rosa10, Ping-Shan Lai10, Rodolfo F. Gómez-Biagi10, Ahmed M. Ali11, Andrew Lewis10, Mulu Geletu10, Naresh K. Murty6, John A. Hassell1,2,4,5, Igor Jurisica7,8,9, Patrick T. Gunning10, Sheila K. Singh1,4,6
1McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada
2McMaster Centre for Functional Genomics, McMaster University, Hamilton, Ontario, Canada
3Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
4Departments of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
5Departments of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
6Departments of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
7Princess Margaret Cancer Centre, University Health Network, IBM Life Sciences Discovery Centre, Toronto Medical Discovery Tower, Toronto, Ontario, Canada
8TECHNA Institute for the Advancement of Technology for Health, UHN and University of Toronto, Toronto, Ontario, Canada
9Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, Ontario, Canada
10Department of Chemistry, University of Toronto, Mississauga, Ontario, Canada
11Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt
Sheila K. Singh, e-mail: [email protected]
Keywords: brain metastases, brain metastasis initiating cell, STAT3, miR-21
Received: February 26, 2015 Accepted: July 13, 2015 Published: July 25, 2015
Brain metastases (BM) represent the most common tumor to affect the adult central nervous system. Despite the increasing incidence of BM, likely due to consistently improving treatment of primary cancers, BM remain severely understudied. In this study, we utilized patient-derived stem cell lines from lung-to-brain metastases to examine the regulatory role of STAT3 in brain metastasis initiating cells (BMICs). Annotation of our previously described BMIC regulatory genes with protein-protein interaction network mapping identified STAT3 as a novel protein interactor. STAT3 knockdown showed a reduction in BMIC self-renewal and migration, and decreased tumor size in vivo. Screening of BMIC lines with a library of STAT3 inhibitors identified one inhibitor to significantly reduce tumor formation. Meta-analysis identified the oncomir microRNA-21 (miR-21) as a target of STAT3 activity. Inhibition of miR-21 displayed similar reductions in BMIC self-renewal and migration as STAT3 knockdown. Knockdown of STAT3 also reduced expression of known downstream targets of miR-21. Our studies have thus identified STAT3 and miR-21 as cooperative regulators of stemness, migration and tumor initiation in lung-derived BM. Therefore, STAT3 represents a potential therapeutic target in the treatment of lung-to-brain metastases.
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