Abstract
BackgroundFAM83H 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.MethodsThe expression and roles of FAM83H and β-catenin were evaluated in human osteosarcomas from 34 patients and osteosarcoma cells.ResultsThe 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.ConclusionsThis 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.
Highlights
(hazard ratio) (HR) hazard ratio (FAM83H) was initially identified as a protein essential for dental enamel formation
The expression of HR hazard ratio (FAM83H) and β-catenin are associated with progressed clinicopathological factors of osteosarcoma patients When we compared FAM83H protein expression in normal human osteoblast cells and human osteosarcoma cells, U2OS, MG63, and KHOS/NP osteosarcoma cells showed higher expression of FAM83H compared with normal osteoblast cells (Fig. 1a)
The cut-off values for the positivity of cytoplasmic expression of FAM83H (Cy-FAM83H), nuclear expression of FAM83H (Nu-FAM83H), and β-catenin expression were determined with receiver operating character curve analysis to predict the death of osteosarcoma patients
Summary
FAM83H was initially identified as a protein essential for dental enamel formation. Recent reports have shown that FAM83H is involved in the progression of human cancers in conjunction with tumorassociated molecules, such as MYC and β-catenin. The roles of FAM83H in the progression of human cancers involve changes in the proliferation and invasiveness of cancer cells. Higher expression of FAM83H is associated with an increased recurrence rate of prostatic cancer patients and shorter survival of uterine cancer [8], hepatocellular carcinoma [4], and clear cell renal cell carcinoma patients [11]. These findings suggest that FAM83H has a vital role in tumorigenesis and progression of human malignant tumors, and might be involved in the progression of various types of human cancers. There is a possibility that the role of FAM83H might be different according to the type of cells and further study is needed
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