title: Let-7a suppresses macrophage infiltrations and malignant phenotype of Ewing sarcoma via STAT3/NF-κB positive regulatory circuit.
abstract: The interaction between tumors cells, tumor-derived humoral factors and the bone marrow in the bone niches has been shown to be essential for bone tumor initiation and promotion. Among the tumor stromal cells, tumor-associated macrophages (TAMs) are usually the most abundant immune population. Previously, we reported that let-7a functions as a tumor suppressor in ES. Herein, we found that the suppressive effects are not only limited on the malignant phenotype of tumor cells but also on the regulation of macrophage infiltration. We observed that the let-7a expression is negatively related to macrophage infiltrations in ES. Moreover, overexpression of putative ts-miRNA let-7a significantly suppressed the recruitment of PBMCs in vitro and decreased the macrophage infiltrations in ES-xenografted tumors in vivo. Most importantly, a positive regulatory feedback loop consisting of let-7a, signal transducer and activator of transcription 3 (STAT3), and nuclear factor-kappa B (NF-κB) (let-7a/STAT3/NF-κB) was involved in let-7a-mediated suppressive effects. These data might provide evidence of a novel intracellular signaling network function in ES pathogenesis, and manipulating this novel feedback loop will have therapeutic potential for ES patients.
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Department of Orthopedics, The Yongchuan Affiliated Hospital of Chongqing Medical University, Chongqing 402160, China.
authors.forename: Zhongzu
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Gynecology and Obstetrics, The Yongchuan Affiliated Hospital of Chongqing Medical University, Chongqing 402160, China.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Children Health and Care, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
authors.forename: Qianren
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
authors.forename: Junlong
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Han
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Shu
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
authors.forename: Min
authors.initials: M
authors.lastname: Dai
authors.affiliation: Department of Orthopedics, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China. Electronic address: kaichaw@126.com.
authors.forename: Kai
authors.initials: K
authors.lastname: Cao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014162:Transfection
chemical_list: D035683:MicroRNAs; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C487931:mirnlet7 microRNA, human
keywords: Ewing sarcoma; Let-7a; MicroRNA; Nuclear factor-kappa B (NF-κB); Signal transducer and activator of transcription-3 (STAT3); TAMs