title: Fibulin-4 is a novel Wnt/β-Catenin pathway activator in human osteosarcoma.
abstract: Fibulin-4, an extracellular glycoprotein implicated in connective tissue development and elastic fiber formation, draws increasing focuses in cancer research. However, little is known about the underlying oncogenic roles of Fibulin-4 in human osteosarcoma (OS). In this study, by immunohistochemical analysis, upregulated expression of Fibulin-4 was found in the OS clinical specimens and cell lines compared to their normal counterparts. Fibulin-4 was positively correlated with the T stage of OS patients, and the proliferation index Ki67. Based on informatics analysis and functional verification, microRNA-137 was identified as a potential upstream regulator of Fibulin-4. Knockdown of Fibulin-4 or introduction of microRNA-137 inhibited cell proliferation and promoted cell apoptosis, and adverse effects were observed by overexpression of Fibulin-4. Furthermore, the tumor-suppressive functions of microRNA-137 were markedly abolished by restoration of Fibulin-4 expression in OS cells. Mechanistically, Fibulin-4 activated Wnt/β-Catenin pathway and promoted the expression of its downstream targets, including CCND2, c-Myc and VEGF. Taken together, Fibulin-4 plays critical neoplastic roles in tumor growth of human OS by activating Wnt/β-Catenin signaling and may represent a potential therapeutic target.
authors.affiliation: Department of Othopedics, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe Road, Zhengzhou, 450000 Henan, PR China; Department of Orthopaedics, The No.3 People's Hospital of Anyang City, Anyang 455000, PR China.
authors.forename: Renzeng
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Othopedics, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe Road, Zhengzhou, 450000 Henan, PR China. Electronic address: gu2keo@163.com.
authors.forename: Limin
authors.initials: L
authors.lastname: Wang
mesh_terms: D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology; D060449:Wnt Signaling Pathway
chemical_list: C403672:EFEMP2 protein, human; D016326:Extracellular Matrix Proteins; C545567:MIRN137 microRNA, human; D035683:MicroRNAs
keywords: Fibulin-4; MicroRNA-137; Osteosarcoma; Wnt/β-Catenin