Recombinant human bone morphogenetic protein-2 inhibits gastric cancer cell proliferation by inactivating Wnt signaling pathway via c-Myc with aurora kinases.
Recombinant human bone morphogenetic protein-2 inhibits gastric cancer cell proliferation by inactivating Wnt signaling pathway via c-Myc with aurora kinases.
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DOI：
10.18632/oncotarget.11969
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发表时间：
2016-11-08
期刊：
影响因子：
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通讯作者：
Kim SM
中科院分区：
文献类型：
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作者：
Lee KB;Jin H;Ye S;Park BH;Kim SM
重组人骨形态发生蛋白-2（rhBMP-2）用于骨移植替代的详细分子机制和安全性问题仍知之甚少。为了研究rhBMP-2在胃癌细胞中的作用的分子机制，我们使用微阵列来确定与rhBMP-2的作用相关的基因表达模式。基于基因本体分析，在细胞周期和BMP信号通路的调节过程中，几个基因被上调。在网络分析中，发现MYC及其下游靶基因极光激酶（aurora kinases，AURKs）被rhBMP-2显著沿着降低。我们用蛋白质印迹数据进一步证实了这一发现，即rhBMP-2抑制SNU 484和SNU 638细胞中的c-Myc、AURKs和β-连环蛋白。AURK抑制剂显著降低胃癌细胞中c-Myc的表达。与分别用rhBMP-2或AURK抑制剂处理的胃癌细胞相比，用rhBMP-2和AURK抑制剂联合处理导致c-Myc表达显著降低。当我们在胃癌细胞中沉默β-连环蛋白时，观察到c-Myc表达降低的类似效果。这些结果表明，rhBMP-2通过c-Myc和AURKs使β-catenin失活而减弱胃癌细胞的生长。因此，我们的研究结果表明，rhBMP-2可以安全地用于接受胃癌或胃食管癌手术的患者。
The detailed molecular mechanisms and safety issues of recombinant human bone morphogenetic protein-2 (rhBMP-2) usage in bone graft substitution remain poorly understood. To investigate the molecular mechanisms underlying the function of rhBMP-2 in gastric cancer cells, we used microarrays to determine the gene expression patterns related to the effects of rhBMP-2. Based on a gene ontology analysis, several genes were upregulated during the regulation of the cell cycle and BMP signaling pathway. MYC was found to be significantly decreased along with its downstream target genes, the aurora kinases (AURKs), by rhBMP-2 in the network analysis. We further confirmed this finding with western blot data that rhBMP-2 inhibited c-Myc, AURKs, and β-catenin in SNU484 and SNU638 cells. An AURK inhibitor significantly decreased c-Myc expression in gastric cancer cells. Combination treatment with rhBMP-2 and AURK inhibitor resulted in significantly decreased c-Myc expression compared with gastric cancer cells treated with an rhBMP-2 or AURK inhibitor, respectively. Similar effects for decreased c-Myc expression were observed when we silenced β-catenin in gastric cancer cells. These results indicate that rhBMP-2 attenuated the growth of gastric cancer cells via the inactivation of β-catenin via c-Myc and AURKs. Therefore, our findings suggest that rhBMP-2 could be safely used with patients who undergo gastric or gastroesophageal cancer surgery.