title: High-frequency canonical Wnt activation in multiple sarcoma subtypes drives proliferation through a TCF/β-catenin target gene, CDC25A.
abstract: Wnt canonical signaling is critical for normal development as well as homeostasis of several epithelial tissues, and constitutive activation of this pathway is commonly observed in carcinomas. We show here that 50% of human sarcomas (n = 45) and 65% of sarcoma cell lines (n = 23) of diverse histological subtypes exhibit upregulated autocrine canonical Wnt signaling. Furthermore, in Wnt autocrine cell lines, we identify alterations including overexpression or gene amplification of Wnt ligands and/or LRP5/6 coreceptors and epigenetic silencing of different cell surface Wnt antagonists. Mutations in adenomatous polyposis coli (APC) gene were observed in two nonautocrine Wnt-positive sarcoma cell lines. Finally, downregulation of the activated Wnt pathway inhibited sarcoma cell proliferation both in vitro and in vivo by a mechanism involving the downregulation of CDC25A.
authors.affiliation: Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Sapna
authors.initials: S
authors.lastname: Vijayakumar
authors.forename: Guizhong
authors.initials: G
authors.lastname: Liu
authors.forename: Ioana A
authors.initials: IA
authors.lastname: Rus
authors.forename: Shen
authors.initials: S
authors.lastname: Yao
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Gal
authors.initials: G
authors.lastname: Akiri
authors.forename: Luca
authors.initials: L
authors.lastname: Grumolato
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Aaronson
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D017491:Genes, APC; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases