title: STAT3 pathway regulates lung-derived brain metastasis initiating cell capacity through miR-21 activation.
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.
authors: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.|Departments of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors: Mohini
authors: M
authors: Singh
authors: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.|Departments of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors: Neha
authors: N
authors: Garg
authors: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.|Departments of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors: Chitra
authors: C
authors: Venugopal
authors: McMaster Centre for Functional Genomics, McMaster University, Hamilton, Ontario, Canada.
authors: Robin
authors: R
authors: Hallett
authors: Princess Margaret Cancer Centre, University Health Network, IBM Life Sciences Discovery Centre, Toronto Medical Discovery Tower, Toronto, Ontario, Canada.
authors: Tomas
authors: T
authors: Tokar
authors: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.|Departments of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors: Nicole
authors: N
authors: McFarlane
authors: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.|Departments of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors: Sujeivan
authors: S
authors: Mahendram
authors: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.|Departments of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors: David
authors: D
authors: Bakhshinyan
authors: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.|Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.|Departments of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors: Branavan
authors: B
authors: Manoranjan
authors: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.|Departments of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors: Parvez
authors: P
authors: Vora
authors: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.|Departments of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors: Maleeha
authors: M
authors: Qazi
authors: Department of Chemistry, University of Toronto, Mississauga, Ontario, Canada.
authors: Carolynn C
authors: CC
authors: Arpin
authors: Department of Chemistry, University of Toronto, Mississauga, Ontario, Canada.
authors: Brent
authors: B
authors: Page
authors: Department of Chemistry, University of Toronto, Mississauga, Ontario, Canada.
authors: Sina
authors: S
authors: Haftchenary
authors: Department of Chemistry, University of Toronto, Mississauga, Ontario, Canada.
authors: David A
authors: DA
authors: Rosa
authors: Department of Chemistry, University of Toronto, Mississauga, Ontario, Canada.
authors: Ping-Shan
authors: PS
authors: Lai
authors: Department of Chemistry, University of Toronto, Mississauga, Ontario, Canada.
authors: Rodolfo F
authors: RF
authors: Gómez-Biagi
authors: Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt.
authors: Ahmed M
authors: AM
authors: Ali
authors: Department of Chemistry, University of Toronto, Mississauga, Ontario, Canada.
authors: Andrew
authors: A
authors: Lewis
authors: Department of Chemistry, University of Toronto, Mississauga, Ontario, Canada.
authors: Mulu
authors: M
authors: Geletu
authors: Departments of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors: Naresh K
authors: NK
authors: Murty
authors: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.|McMaster Centre for Functional Genomics, McMaster University, Hamilton, Ontario, Canada.|Departments of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.|Departments of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors: John A
authors: JA
authors: Hassell
authors: Princess Margaret Cancer Centre, University Health Network, IBM Life Sciences Discovery Centre, Toronto Medical Discovery Tower, Toronto, Ontario, Canada.|TECHNA Institute for the Advancement of Technology for Health, UHN and University of Toronto, Toronto, Ontario, Canada.|Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, Ontario, Canada.
authors: Igor
authors: I
authors: Jurisica
authors: Department of Chemistry, University of Toronto, Mississauga, Ontario, Canada.
authors: Patrick T
authors: PT
authors: Gunning
authors: McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.|Departments of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.|Departments of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
authors: Sheila K
authors: SK
authors: Singh
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000556:secondary*; D045744:Cell Line, Tumor; D002465:Cell Movement; D015972:Gene Expression Regulation, Neoplastic; D005809:Genes, Regulator; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D025941:Protein Interaction Mapping; D040901:Proteomics; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology
chemical_list: C524940:MIRN21 microRNA, human; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse
keywords: STAT3; brain metastases; brain metastasis initiating cell; miR-21