MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene.
MicroRNA-155 (miR-155) is overexpressed in many human cancers; however, the mechanisms by which miR-155 functions as a putative oncomiR are largely unknown. Here, we report that the tumor suppressor gene suppressor of cytokine signaling 1 (socs1) is an evolutionarily conserved target of miR-155 in breast cancer cells. We found that mir-155 expression is inversely correlated with socs1 expression in breast cancer cell lines as well as in a subset of primary breast tumors. We also identified a 24A-->G mutation in the miR-155 binding site of the SOCS1 3' untranslated region in a breast tumor that reduced miR-155 repression, implicating a mechanism for miRNA targets to avoid repression. Ectopic expression of miR-155 significantly promoted the proliferation of breast cancer cells, the formation of soft agar foci in vitro, and the development of tumors in nude mice. In breast cancer cells, RNA interference silencing of socs1 recapitulates the oncogenic effects of miR-155, whereas restoration of socs1 expression attenuates the protumorigenesis function of miR-155, suggesting that miR-155 exerts its oncogenic role by negatively regulating socs1. Overexpression of miR-155 in breast cancer cells leads to constitutive activation of signal transducer and activator of transcription 3 (STAT3) through the Janus-activated kinase (JAK) pathway, and stimulation of breast cancer cells by the inflammatory cytokines IFN-gamma and interleukin-6 (IL-6), lipopolysaccharide (LPS), and polyriboinosinic:polyribocytidylic acid [poly(I:C)] significantly upregulates mir-155 expression, suggesting that miR-155 may serve as a bridge between inflammation and cancer. Taken together, our study reveals that miR-155 is an oncomiR in breast cancer and that miR-155 may be a potential target in breast cancer therapy.
Jiang
Shuai
S
State Key Laboratory of Molecular Biology, Core Facility for Noncoding RNA, and Center of Cell Signaling, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Zhang
Hong-Wei
HW
Lu
Ming-Hua
MH
He
Xiao-Hong
XH
Li
Yong
Y
Gu
Hua
H
Liu
Mo-Fang
MF
Wang
En-Duo
ED
D001943:Breast Neoplasms / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism / Q000502:physiology*; D009154:Mutation; D009841:Oligonucleotides / Q000737:chemistry; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D015854:Up-Regulation
C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D009841:Oligonucleotides; C108944:SOCS1 protein, human; D050796:STAT3 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D049452:Green Fluorescent Proteins; C507924:JAK2 protein, human; D053614:Janus Kinase 2