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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.

Original publication

DOI

10.18632/oncotarget.4742

Type

Journal article

Journal

Oncotarget

Publication Date

29/09/2015

Volume

6

Pages

27461 - 27477

Keywords

STAT3, brain metastases, brain metastasis initiating cell, miR-21, Animals, Brain Neoplasms, Cell Line, Tumor, Cell Movement, Gene Expression Regulation, Neoplastic, Genes, Regulator, Humans, Inhibitory Concentration 50, Lung Neoplasms, Mice, Mice, Inbred NOD, Mice, SCID, MicroRNAs, Neoplasm Metastasis, Neoplasm Transplantation, Protein Interaction Mapping, Proteomics, RNA, Small Interfering, STAT3 Transcription Factor, Stem Cells