title: The cytokine IL-6 reactivates breast stromal fibroblasts through transcription factor STAT3-dependent up-regulation of the RNA-binding protein AUF1.
abstract: The development and spread of mammary carcinomas require synergetic interplay between tumor cells and their microenvironment through paracrine secretions, which are still not well defined. We have shown here that interleukin-6 (IL-6), either recombinant or secreted from highly invasive breast cancer cells, down-regulates the tumor suppressor proteins p16(INK4A), p21(WAF1), and p53 and activates breast stromal fibroblasts in a paracrine manner. The formation of myofibroblasts requires p16(INK4A) down-regulation and the activation of the JAK2/STAT3 pathway. Indeed, the transcription factor STAT3 positively controls the expression of the three major myofibroblast markers, SDF-1, α-smooth muscle actin (α-SMA), and TGF-β1, and mediates IL-6-related down-regulation of p16(INK4A), p21(WAF1), and p53 as well as the activation of stromal fibroblasts. Importantly, these effects were mediated through STAT3-dependent up-regulation of the mRNA-binding protein AUF1, whose promoter contains three canonical STAT3 binding sites. AUF1 binds the SDF-1, α-SMA, TGF-β1, and IL-6 mRNAs and reduces their turnover. Consequently, specific AUF1 down-regulation inhibits IL-6-dependent activation of breast stromal fibroblasts, whereas AUF1 ectopic expression of p37(AUF1) activated these cells and enhanced their paracrine induction of epithelial-to-mesenchymal transition in breast cancer cells, which shows a non-cell-autonomous oncogenic function of AUF1. Together, these results demonstrate a major role of IL-6 in activating breast stromal fibroblasts through STAT3-dependent AUF1 induction.
authors.affiliation: From the Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, MBC 03, P.O. Box 3354, Riyadh 11211, Saudi Arabia and.
authors.forename: Siti-Fauziah
authors.initials: SF
authors.lastname: Hendrayani
authors.affiliation: From the Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, MBC 03, P.O. Box 3354, Riyadh 11211, Saudi Arabia and the Joint Center for Genomics Research, King Abdulaziz City for Science and Technology, Riyadh 11211, Saudi Arabia.
authors.forename: Huda H
authors.initials: HH
authors.lastname: Al-Khalaf
authors.affiliation: From the Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, MBC 03, P.O. Box 3354, Riyadh 11211, Saudi Arabia and aboussekhra@kfshrc.edu.sa.
authors.forename: Abdelilah
authors.initials: A
authors.lastname: Aboussekhra
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D017077:Culture Media, Conditioned / Q000737:chemistry; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D058628:Myofibroblasts / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D017154:Stromal Cells / Q000166:cytology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C493956:CDKN1A protein, human; D017077:Culture Media, Conditioned; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; C508600:IL6 protein, human; D015850:Interleukin-6; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: AUF1; Breast Cancer; Gene Expression; Interleukin 6 (IL-6); Myofibroblast; RNA-binding Protein; STAT3; Tumor Microenvironment; mRNA Decay