title: Krüppel-like factor 8 activates the transcription of C-X-C cytokine receptor type 4 to promote breast cancer cell invasion, transendothelial migration and metastasis.
abstract: Krüppel-like factor 8 (KLF8) has been strongly implicated in breast cancer metastasis. However, the underlying mechanisms remain largely unknown. Here we report a novel signaling from KLF8 to C-X-C cytokine receptor type 4 (CXCR4) in breast cancer. Overexpression of KLF8 in MCF-10A cells induced CXCR4 expression at both mRNA and protein levels, as determined by quantitative real-time PCR and immunoblotting. This induction was well correlated with increased Boyden chamber migration, matrigel invasion and transendothelial migration (TEM) of the cells towards the ligand CXCL12. On the other hand, knockdown of KLF8 in MDA-MB-231 cells reduced CXCR4 expression associated with decreased cell migration, invasion and TEM towards CXCL12. Histological and database mining analyses of independent cohorts of patient tissue microarrays revealed a correlation of aberrant co-elevation of KLF8 and CXCR4 with metastatic potential. Promoter analysis indicated that KLF8 directly binds and activates the human CXCR4 gene promoter. Interestingly, a CXCR4-dependent activation of focal adhesion kinase (FAK), a known upregulator of KLF8, was highly induced by CXCL12 treatment in KLF8-overexpressing, but not KLF8 deficient cells. This activation of FAK in turn induced a further increase in KLF8 expression. Xenograft studies showed that overexpression of CXCR4, but not a dominant-negative mutant of it, in the MDA-MB-231 cells prevented the invasive growth of primary tumor and lung metastasis from inhibition by knockdown of KLF8. These results collectively suggest a critical role for a previously unidentified feed-forward signaling wheel made of KLF8, CXCR4 and FAK in promoting breast cancer metastasis and shed new light on potentially more effective anti-cancer strategies.
authors.affiliation: Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL, USA.
authors.forename: Debarati
authors.initials: D
authors.lastname: Mukherjee
authors.affiliation: Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Lu
authors.affiliation: Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Yu
authors.affiliation: School of Basic Medical Sciences, Wuhan University, Wuhan, China.
authors.forename: Chunjiang
authors.initials: C
authors.lastname: He
authors.affiliation: Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL, USA.
authors.forename: Satadru K
authors.initials: SK
authors.lastname: Lahiri
authors.affiliation: Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL, USA.|Current address: Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Tianshu
authors.initials: T
authors.lastname: Li
authors.affiliation: Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL, USA.
authors.forename: Jihe
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000378:metabolism; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D019718:Receptors, CXCR4 / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; C507402:KLF8 protein, human; D051741:Kruppel-Like Transcription Factors; D019718:Receptors, CXCR4; D012097:Repressor Proteins; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human
keywords: CXCR4; KLF8; invasion; metastasis; transendothelial migration