Src nuclear localization and its prognostic relevance in human osteosarcoma
Osteosarcoma is the most common malignant bone tumor in children and young adults.
The identification of proteins which exhibit different subcellular localization in low- versus
high-risk osteosarcoma can be instrumental to obtain prognostic information and to
develop innovative therapeutic strategies. Beside the well-characterized membrane and
cytoplasmic localization of Src protein, this study evaluated the prognostic relevance of its
so-far unknown nuclear compartmentalization. We analyzed the subcellular distribution
of total and activated (pY418) Src in a tissue microarray including 60 osteosarcoma
samples. Immunohistochemical analyses revealed a variable pattern of Src expression and
localization, ranging from negative to high-stained nuclei combined with a substantial
cytoplasmic staining for total and activated forms. The analysis of Kaplan–Meier survival
curves in relationship to the diverse permutations of cytoplasmic and nuclear staining
suggesteda correlation between Src subcellular localization and the overall survival (OS)of
osteosarcoma patients. In order to explain this different subcellular localization, normal
osteoblasts and three osteosarcoma cell lines were used to investigate the molecular
mechanism. Once confirmed a variable Src localization also in these cell lines, we
demonstrated a correlation between theN-myristoyltransferase enzymes expression and
activity and the Src nuclear content. In conclusion, these results described a so-far
unknown Src nuclear localization in osteosarcoma cells, suggesting that the combined
detection of nuclear and cytoplasmic Src levels can be used as a prognostic marker for
osteosarcoma patient survival. A correlation between the N-myristoyltransferase
enzymes and the Src subcellular localization was described as well.