title: FHL2 silencing reduces Wnt signaling and osteosarcoma tumorigenesis in vitro and in vivo.
abstract: BACKGROUND
  The molecular mechanisms that are involved in the growth and invasiveness of osteosarcoma, an aggressive and invasive primary bone tumor, are not fully understood. The transcriptional co-factor FHL2 (four and a half LIM domains protein 2) acts as an oncoprotein or as a tumor suppressor depending on the tissue context. In this study, we investigated the role of FHL2 in tumorigenesis in osteosarcoma model.
  
  
  RESULTS
  Western blot analyses showed that FHL2 is expressed above normal in most human and murine osteosarcoma cells. Tissue microarray analysis revealed that FHL2 protein expression is high in human osteosarcoma and correlates with osteosarcoma aggressiveness. In murine osteosarcoma cells, FHL2 silencing using shRNA decreased canonical Wnt/β-catenin signaling and reduced the expression of Wnt responsive genes as well as of the key Wnt molecules Wnt5a and Wnt10b. This effect resulted in inhibition of osteosarcoma cell proliferation, invasion and migration in vitro. Using xenograft experiments, we showed that FHL2 silencing markedly reduced tumor growth and lung metastasis occurence in mice. The anti-oncogenic effect of FHL2 silencing in vivo was associated with reduced cell proliferation and decreased Wnt signaling in the tumors.
  
  
  CONCLUSIONS
  Our findings demonstrate that FHL2 acts as an oncogene in osteosarcoma cells and contributes to tumorigenesis through Wnt signaling. More importantly, FHL2 depletion greatly reduces tumor cell growth and metastasis, which raises the potential therapeutic interest of targeting FHL2 to efficiently impact primary bone tumors.
authors: INSERM UMR 606, Paris, France.
authors: Julia
authors: J
authors: Brun
authors: François-Xavier
authors: FX
authors: Dieudonné
authors: Caroline
authors: C
authors: Marty
authors: Judith
authors: J
authors: Müller
authors: Roland
authors: R
authors: Schüle
authors: Ana
authors: A
authors: Patiño-García
authors: Fernando
authors: F
authors: Lecanda
authors: Olivia
authors: O
authors: Fromigué
authors: Pierre J
authors: PJ
authors: Marie
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020868:Gene Silencing; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000172:deficiency* / Q000235:genetics*; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D058990:Molecular Targeted Therapy; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics*; D009361:Neoplasm Invasiveness; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C105987:FHL2 protein, human; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin
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