title: Signal transducers and activators of transcription 3 (STAT3) directly regulates cytokine-induced fascin expression and is required for breast cancer cell migration.
abstract: The cytokines oncostatin M (OSM) and IL-6 promote breast cancer cell migration and metastasis. Both cytokines activate STAT3, a member of the STAT (signal transducers and activators of transcription) family of transcription factors. Through transcriptional regulation of its target genes, STAT3 controls a wide range of cellular processes, including cellular proliferation, oncogenesis, and cancer metastasis. Fascin is an actin-bundling protein involved in cell migration. Elevated levels of fascin expression are found in many metastatic cancers, and inhibition of fascin function by small chemical compounds leads to a block of tumor metastasis. In this work, we demonstrate that fascin is a direct STAT3 target gene in response to OSM and IL-6 in both mouse and human breast cancer cells. We show that NFκB also binds to the fascin promoter in response to cytokine treatment and this binding is STAT3-dependent. Both STAT3 and NFκB are required for the cytokine-induced expression of fascin in cancer cells. Furthermore, we demonstrate that STAT3, in directly controlling fascin expression, is both necessary and sufficient for breast cancer cell migration.
authors.affiliation: Department of Physiology and Biophysics, Cornell University Weill Medical College, New York, New York 10065, USA.
authors.forename: Marylynn
authors.initials: M
authors.lastname: Snyder
authors.forename: Xin-Yun
authors.initials: XY
authors.lastname: Huang
authors.forename: J Jillian
authors.initials: JJ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D053683:Oncostatin M / Q000378:metabolism* / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D008840:Microfilament Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D053683:Oncostatin M; C020324:fascin