title: DNA damage induces NF-κB-dependent microRNA-21 up-regulation and promotes breast cancer cell invasion.
abstract: NF-κB activation induced by genotoxic treatment in cancer cells has been associated with therapeutic resistance in multiple human malignancies. Therapeutic resistance also correlates with high metastatic potential in human cancers, including breast cancer. Whether genotoxic treatment-activated NF-κB also contributes to cancer metastasis following radiation and chemotherapy is unclear. Here, we show that chemotherapeutic drug-induced NF-κB activation promotes breast cancer cell migration and invasion. The increased metastatic potential is dependent on IL-6 induction mediated by genotoxic NF-κB activation. Moreover, genotoxic treatment also up-regulates oncogenic microRNA-21 (miR-21) expression through eliciting NF-κB recruitment to the miR-21 promoter region, where it cooperates with signal transducer and activator of transcription 3 (STAT3) to activate miR-21 transcription. DNA damage-induced histone H3 phosphorylation via activated MSK1 creates an open chromatin structure for NF-κB/STAT3-driven transactivation of miR-21. NF-κB-dependent IL-6 up-regulation is responsible for STAT3 activation and recruitment to the miR-21 promoter upon genotoxic stress. Induction of miR-21 may enable cancer cells to elude DNA damage-induced apoptosis and enhance the metastatic potential of breast cancer cells through repressing expression of PTEN and PDCD4. Our data support a critical role of DNA damage-induced NF-κB activation in promoting cancer metastasis following genotoxic treatment, and NF-κB-dependent miR-21 induction may contribute to both therapeutic resistance and metastasis in breast cancer.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38103, USA.
authors.forename: Jixiao
authors.initials: J
authors.lastname: Niu
authors.forename: Yuling
authors.initials: Y
authors.lastname: Shi
authors.forename: Guangyun
authors.initials: G
authors.lastname: Tan
authors.forename: Chuan He
authors.initials: CH
authors.lastname: Yang
authors.forename: Meiyun
authors.initials: M
authors.lastname: Fan
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Pfeffer
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Wu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D004249:DNA Damage; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D009153:Mutagens; D016328:NF-kappa B / Q000378:metabolism*; D009362:Neoplasm Metastasis; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D014945:Wound Healing
chemical_list: D015850:Interleukin-6; C524940:MIRN21 microRNA, human; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D009153:Mutagens; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse