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DNA damage‐induced NF‐kB activation promotes breast cancer metastasis via upregulation of microRNA‐21
Author(s) -
Niu Jixiao,
Tan Guangyun,
Yang Chuan He,
Fan Meiyun,
Pfeffer Lawrence M.,
Wu Zhao-Hui
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.538.1
Subject(s) - cancer research , metastasis , microrna , stat3 , nf κb , dna damage , pten , breast cancer , downregulation and upregulation , stat protein , apoptosis , transcription factor , cancer cell , cancer , chemistry , biology , dna , gene , pi3k/akt/mtor pathway , genetics
OBJECTIVE To investigate the role and mechanism of NF‐κB in cancer metastasis. METHODS DNA damage induced NF‐κB activity was determined by EMSA and microRNA‐21(miR‐21) expression was examined by Quantitative PCR separately. In addition, migration of MDA‐MB‐231 cells was investigated by Transwell invasion and wound healing assay in vitro.RESULTS We found 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 upregulates oncogenic microRNA‐21 expression through eliciting NF‐κB recruitment to miR‐21 promoter region, where it cooperates with signal transducer and activator of transcription 3 (STAT3) to activate miR‐21 transcription. 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. CONCLUSIONS 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. Financial support: This work was supported by NIH grants ‐ CA149251 (to Z.W.) and CA133322 (to L.M.P)