LOX expression and functional analysis in astrocytomas and impact of IDH1 mutation.
LOX expression and functional analysis in astrocytomas and impact of IDH1 mutation.
复制标题
DOI：
10.1371/journal.pone.0119781
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Oba-Shinjo SM
中科院分区：
文献类型：
--
作者：
da Silva R;Uno M;Marie SK;Oba-Shinjo SM
赖氨酰氧化酶（LOX）参与重要的生物过程，如细胞运动，细胞信号和基因调控。这种蛋白质的失调可能有助于肿瘤的形成和发展。尽管LOX在其他类型肿瘤中参与了侵袭、增殖和肿瘤迁移，但在不同级别星形细胞瘤中的研究很少。我们研究的目的是通过实时PCR来表征LOX、BMP 1和HIF 1A在WHO I级至IV级星形细胞瘤中的表达，并与非肿瘤性脑组织进行比较。通过PCR和测序确定IDH1突变状态。LOX蛋白表达也通过免疫组织化学分析。在两个胶质母细胞瘤细胞系中使用siRNA敲低和特异性抑制剂BAPN进行LOX功能分析。LOX、BMP 1和HIF 1A的表达水平与IDH 1突变状态和胶质母细胞瘤患者的总生存期的临床终点相关并进行分析。结果显示LOX、BMP 1和HIF 1A的表达和活性与星形细胞瘤的恶性程度呈正相关。LOX蛋白的表达也随着恶性程度的增加而增加，定位于细胞质和细胞核，并在内皮细胞中观察到染色。IDH1突变的胶质母细胞瘤在细胞核中表达较低水平的LOX，与野生型IDH1病例相比，IDH1突变病例显示较低的LOX表达水平。BAPN对U87 MG和A172细胞株的LOX基因敲除和抑制作用影响细胞的迁移、侵袭和软琼脂集落形成。总之，这些结果证实了LOX在星形细胞瘤的迁移、侵袭和血管生成中的作用。此外，LOX表达受IDH1突变状态的影响。这项工作为旨在设计靶向治疗以控制星形细胞瘤的研究人员提供了新的见解。
Lysyl oxidase (LOX) is involved in vital biological processes such as cell motility, cell signaling and gene regulation. Deregulation of this protein can contribute to tumor formation and progression. Although it is known that LOX is involved in invasion, proliferation and tumor migration in other types of tumors, studies of LOX in astrocytomas of different grades are scarce. The purpose of our study was to characterize LOX, BMP1 and HIF1A expression by real-time PCR in astrocytomas with WHO grades I to IV compared to non-neoplastic brain tissue. IDH1 mutational status was determined by PCR and sequencing. LOX protein expression was also analyzed by immunohistochemistry. LOX functional analyses were performed using siRNA knockdown and the specific inhibitor BAPN in two glioblastoma cell lines. The expression levels of LOX, BMP1 and HIF1A were correlated and analyzed according to IDH1 mutation status and to the clinical end-point of overall survival of glioblastoma patients. The results demonstrate that increased expression and activity of LOX, BMP1 and HIF1A were positively correlated with the malignant grade of astrocytomas. LOX protein expression also increased according to the degree of malignancy, with localization in the cytoplasm and nucleus and staining observed in endothelial cells. Glioblastoma with a mutation in IDH1 expressed lower levels of LOX in the nucleus, and IDH1-mutated cases showed lower LOX expression levels when compared to wild-type IDH1 cases. LOX knockdown and inhibition by BAPN in U87MG and A172 cell lines affected migration, invasion and soft agar colony formation. Taken together, these results corroborate the role of LOX in the migration, invasion and angiogenesis of astrocytomas. Furthermore, LOX expression is influenced by IDH1 mutational status. This work provides new insights for researchers aiming to design targeted therapies to control astrocytomas.
登录
查看更多内容
影响因子：
3.7
作者：
Bondareva A;Downey CM;Ayres F;Liu W;Boyd SK;Hallgrimsson B;Jirik FR
通讯作者：
Jirik FR
影响因子：
56.9
作者：
Kessler, E;Takahara, K;Greenspan, DS
通讯作者：
Greenspan, DS
影响因子：
6.4
作者：
Albinger-Hegyi, Andrea;Stoeckli, Sandro J.;Hegyi, Ivan
通讯作者：
Hegyi, Ivan
影响因子：
4
作者：
Kagan, HM;Li, WD
通讯作者：
Li, WD
影响因子：
15.9
作者：
Ichimura K;Pearson DM;Kocialkowski S;Bäcklund LM;Chan R;Jones DT;Collins VP
通讯作者：
Collins VP