title: RAGE-binding S100A8/A9 promotes the migration and invasion of human breast cancer cells through actin polymerization and epithelial-mesenchymal transition.
abstract: S100A8/A9 proteins are members of EF-hand calcium-binding proteins secreted by neutrophils and activated monocytes. S100A8/A9 has cell growth-promoting activity at low concentrations by binding to the receptor for advanced glycation end products (RAGE). In this study, we report for the first time that S100A8/A9 promoted the invasion of breast cancer cells depending on RAGE. In addition, RAGE binding to S100A8/A9 promoted the phosphorylation of LIN-11, Isl1, and MEC-3 protein domain kinase, as well as cofilin. This phosphorylation is a critical step in cofilin recycling and actin polymerization. Interestingly, RAGE binding to S100A8/A9 enhanced cell mesenchymal properties and induced epithelial-mesenchymal transition. Mechanistically, RAGE binding to S100A8/A9 stabilized Snail through the NF-κB signaling pathway. Based on these observations, RAGE expression in breast cancer cells was associated with lymph node and distant metastases in patients with invasive ductal carcinoma. Moreover, RAGE binding to S100A8/A9 promoted lung metastasis in vivo. In summary, our in vitro and in vivo results indicated that RAGE binding to S100A8/A9 played an important role in breast cancer invasion/metastasis. This study identified both RAGE and S100A8/A9 as potential anti-invasion targets for therapeutic intervention in breast cancer.
authors.affiliation: College of Nursing, Weifang Medical University, Weifang, 261053, China.
authors.forename: Chonggao
authors.initials: C
authors.lastname: Yin
authors.forename: Hongli
authors.initials: H
authors.lastname: Li
authors.forename: Baogang
authors.initials: B
authors.lastname: Zhang
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Liu
authors.forename: Guohua
authors.initials: G
authors.lastname: Lu
authors.forename: Shijun
authors.initials: S
authors.lastname: Lu
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.forename: Yueliang
authors.initials: Y
authors.lastname: Qi
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Li
authors.forename: Weiyi
authors.initials: W
authors.lastname: Chen
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D040501:Calgranulin A / Q000378:metabolism*; D040502:Calgranulin B / Q000378:metabolism*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D058105:Polymerization; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D040501:Calgranulin A; D040502:Calgranulin B; D060850:LIM-Homeodomain Proteins; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1