Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois, United States of America.
PLoS One. 2010 Dec 1;5(12):e14182. doi: 10.1371/journal.pone.0014182.
Osteosarcoma 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 FINDINGS: Endogenous 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/SIGNIFICANCE: Our 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.
骨肉瘤是最常见的原发性骨恶性肿瘤，其发病机制中的分子途径特征尚不明确。越来越多的证据表明，升高的脂质生物合成是癌症的一个特征。我们试图研究溶血磷脂酸酰基转移酶β（LPAATβ，又名 AGPAT2）在调节人骨肉瘤细胞增殖和生长中的作用。LPAATβ 可以生成磷脂酸，它在脂质生物合成以及细胞增殖和存活中起着关键作用。尽管已经报道 LPAATβ 在几种类型的人类肿瘤中表达升高，但 LPAATβ 在骨肉瘤进展中的作用尚未阐明。
方法/主要发现：通过半定量 PCR 和免疫组织化学染色分析骨肉瘤细胞系中 LPAATβ 的内源性表达。采用腺病毒介导的 LPAATβ 过表达和沉默 LPAATβ 表达来确定 LPAATβ 对骨肉瘤细胞体外增殖和迁移以及骨肉瘤体内肿瘤生长的影响。我们发现，在分析的 10 个人类骨肉瘤系中，有 8 个系中很容易检测到 LPAATβ 的表达。外源性表达 LPAATβ 促进骨肉瘤细胞增殖和迁移，而沉默 LPAATβ 表达则抑制这些细胞特征。我们进一步证明，外源性表达 LPAATβ 可有效促进肿瘤生长，而敲低 LPAATβ 表达则抑制骨肉瘤的肿瘤生长在人骨肉瘤的原位异种移植模型中。
结论/意义：我们的研究结果强烈表明，LPAATβ 的表达可能与人类骨肉瘤的侵袭表型有关，LPAATβ 可能在调节骨肉瘤细胞增殖和肿瘤生长中发挥重要作用。因此，靶向 LPAATβ 可能被用作骨肉瘤临床治疗的一种新的治疗策略。鉴于存在选择性药理抑制剂，这一点尤其具有吸引力。
