Abstract
BackgroundOsteosarcoma is the most common primary malignancy of bone with poorly characterized molecular pathways important in its pathogenesis. Increasing evidence indicates that elevated lipid biosynthesis is a characteristic feature of cancer. We sought to investigate the role of lysophosphatidic acid acyltransferase β (LPAATβ, aka, AGPAT2) in regulating the proliferation and growth of human osteosarcoma cells. LPAATβ can generate phosphatidic acid, which plays a key role in lipid biosynthesis as well as in cell proliferation and survival. Although elevated expression of LPAATβ has been reported in several types of human tumors, the role of LPAATβ in osteosarcoma progression has yet to be elucidated.Methodology/Principal FindingsEndogenous expression of LPAATβ in osteosarcoma cell lines is analyzed by using semi-quantitative PCR and immunohistochemical staining. Adenovirus-mediated overexpression of LPAATβ and silencing LPAATβ expression is employed to determine the effect of LPAATβ on osteosarcoma cell proliferation and migration in vitro and osteosarcoma tumor growth in vivo. We have found that expression of LPAATβ is readily detected in 8 of the 10 analyzed human osteosarcoma lines. Exogenous expression of LPAATβ promotes osteosarcoma cell proliferation and migration, while silencing LPAATβ expression inhibits these cellular characteristics. We further demonstrate that exogenous expression of LPAATβ effectively promotes tumor growth, while knockdown of LPAATβ expression inhibits tumor growth in an orthotopic xenograft model of human osteosarcoma.Conclusions/SignificanceOur results strongly suggest that LPAATβ expression may be associated with the aggressive phenotypes of human osteosarcoma and that LPAATβ may play an important role in regulating osteosarcoma cell proliferation and tumor growth. Thus, targeting LPAATβ may be exploited as a novel therapeutic strategy for the clinical management of osteosarcoma. This is especially attractive given the availability of selective pharmacological inhibitors.
Highlights
Osteosarcoma (OS) is the most common primary malignancy of bone and accounts for,5% of childhood tumors in the United States with incidence peaking during the second decade of life [1,2,3,4,5]
Lysophosphatidic Acid Acyltransferase b (LPAATb) expression is readily detected in most OS cell lines
Our results strongly suggest that LPAATb expression may be associated with aggressive phenotypes of human OS and that LPAATb may play an important role in regulating OS cell proliferation and tumor growth
Summary
Osteosarcoma (OS) is the most common primary malignancy of bone and accounts for ,5% of childhood tumors in the United States with incidence peaking during the second decade of life [1,2,3,4,5]. The molecular pathogenesis underlying OS development remains to be thoroughly elucidated [4,6]. It remains challenging to identify common genetic alterations that lead to OS development given the diversity and complexity in its pathogenesis [4,17,18,19,20,21]. Osteosarcoma is the most common primary malignancy of bone with poorly characterized molecular pathways important in its pathogenesis. LPAATb can generate phosphatidic acid, which plays a key role in lipid biosynthesis as well as in cell proliferation and survival. Elevated expression of LPAATb has been reported in several types of human tumors, the role of LPAATb in osteosarcoma progression has yet to be elucidated
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