STAT3 pathway regulates lung-derived brain metastasis initiating cell capacity through miR-21 activation.

// Mohini Singh 1, 4 , Neha Garg 1, 6 , Chitra Venugopal 1, 6 , Robin Hallett 2 , Tomas Tokar 7 , Nicole McFarlane 1, 6 , Sujeivan Mahendram 1, 6 , David Bakhshinyan 1, 4 , Branavan Manoranjan 1, 3, 4 , Parvez Vora 1, 6 , Maleeha Qazi 1, 4 , Carolynn C. Arpin 10 , Brent Page 10 , Sina Haftchenary 10 , David A. Rosa 10 , Ping-Shan Lai 10 , Rodolfo F. Gomez-Biagi 10 , Ahmed M. Ali 11 , Andrew Lewis 10 , Mulu Geletu 10 , Naresh K. Murty 6 , John A. Hassell 1, 2, 4, 5 , Igor Jurisica 7, 8, 9 , Patrick T. Gunning 10 , Sheila K. Singh 1, 4, 6 1 McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada 2 McMaster Centre for Functional Genomics, McMaster University, Hamilton, Ontario, Canada 3 Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada 4 Departments of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada 5 Departments of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada 6 Departments of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada 7 Princess Margaret Cancer Centre, University Health Network, IBM Life Sciences Discovery Centre, Toronto Medical Discovery Tower, Toronto, Ontario, Canada 8 TECHNA Institute for the Advancement of Technology for Health, UHN and University of Toronto, Toronto, Ontario, Canada 9 Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, Ontario, Canada 10 Department of Chemistry, University of Toronto, Mississauga, Ontario, Canada 11 Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt Correspondence to: Sheila K. Singh, e-mail: ssingh@mcmaster.ca Keywords: brain metastases, brain metastasis initiating cell, STAT3, miR-21 Received: February 26, 2015      Accepted: July 13, 2015      Published: July 25, 2015 ABSTRACT 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.