Background: FAM83H was initially identified as a protein essential for dental enamel formation. Recent reports have shown that FAM83H is also involved in the progression of human cancers in conjunction with tumor-associated molecules, such as MYC and β-catenin. However, the role of FAM83H in sarcoma has not yet been investigated.
Methods: The expression and roles of FAM83H and β-catenin were evaluated in human osteosarcomas from 34 patients and osteosarcoma cells.
Results: The expression of nuclear FAM83H, cytoplasmic FAM83H, and β-catenin were significantly associated with each other and significantly associated with shorter survival of osteosarcoma patients by univariate analysis. In multivariate analysis, cytoplasmic expression of FAM83H was an independent indicator of shorter survival of osteosarcoma patients (overall survival; P < 0.001, relapse-free survival; P < 0.001). In U2OS, MG63, and KHOS/NP osteosarcoma cells, the knock-down of FAM83H decreased proliferation and invasion activity and overexpression of FAM83H increased proliferation and invasion activity. In KHOS/NP cells, knock-down of FAM83H significantly inhibited, and overexpression of FAM83H significantly increased in vivo growth of cells. In addition, the knock-down of FAM83H decreased protein expression of β-catenin, active β-catenin, cyclin D1, vimentin, and snail. Overexpression of FAM83H increased protein expression of β-catenin, active β-catenin, cyclin D1, vimentin, and snail. However, the expression of β-catenin mRNA was not significantly altered with knock-down or overexpression of FAM83H. In addition, FAM83H and β-catenin shown to directly interact via immunoprecipitation and nuclear and cytoplasmic localization of β-catenin was decreased with knock-down of FAM83H. Moreover, the ubiquitination and proteasomal degradation of β-catenin was increased with knock-down of FAM83H.
Conclusions: This study suggests that FAM83H is involved in the progression of osteosarcomas via a mechanism involving the stabilization of β-catenin and the promotion of proliferation and invasiveness of osteosarcomas.
Keywords: FAM83H; Osteosarcoma; Prognosis; Ubiquitination; β-Catenin.