Hypoxic inactivation of glycogen synthase kinase-3 promotes gastric tumor growth and angiogenesis by facilitating hypoxia-inducible factor-1 signaling
Hypoxic inactivation of glycogen synthase kinase-3 promotes gastric tumor growth and angiogenesis by facilitating hypoxia-inducible factor-1 signaling
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DOI：
10.1111/apm.12569
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发表时间：
2016-09-01
期刊：
影响因子：
2.8
通讯作者：
Lee, Byung Lan
中科院分区：
文献类型：
--
作者：
Ko, Young San;Cho, Sung Jin;Lee, Byung Lan
由于癌细胞缺氧适应的分子机制是细胞类型特异性的，因此我们研究了糖原合成酶激酶 3 (GSK-3) 激活是否参与缺氧诱导的胃肿瘤促进。在低氧条件下培养稳定的胃癌细胞系（SNU-638、SNU-484、MKN1 和 MKN45）。生成过表达野生型 GSK-3 (WT-GSK-3) 或 GSK-3 激酶死亡突变体 (KD-GSK-3) 的细胞，并将其用于细胞培养和动物研究。在细胞培养实验中，缺氧降低了胃癌细胞中 GSK-3 的激活。在缺氧条件下，KD-GSK-3转染子的胃癌细胞活力以及HIF-1蛋白和VEGF mRNA的表达高于WT-GSK-3转染子，但在常氧条件下则不然。胃癌异种移植物显示，体内 KD-GSK-3 肿瘤中的肿瘤生长、微血管面积、HIF-1 激活和 VEGF 表达高于 WT-GSK-3 肿瘤。此外，缺氧诱导的HIF-1蛋白的表达在翻译水平上受到GSK-3的调节。我们的数据表明，GSK-3 作为 HIF-1/VEGF 信号通路的抑制性上游调节剂参与胃癌细胞的缺氧适应。
Since the molecular mechanism of hypoxic adaptation in cancer cells is cell-type specific, we investigated whether glycogen synthase kinase-3 (GSK-3) activation is involved in hypoxia-induced gastric tumor promotion. Stable gastric cancer cell lines (SNU-638, SNU-484, MKN1, and MKN45) were cultured under hypoxic conditions. Cells overexpressing wild-type GSK-3 (WT-GSK-3) or kinase-dead mutant of GSK-3 (KD-GSK-3) were generated and used for cell culture and animal studies. In cell culture experiments, hypoxia decreased GSK-3 activation in gastric cancer cells. Cell viability and the expressions of HIF-1 protein and VEGF mRNA in gastric cancer cells were higher in KD-GSK-3 transfectants than in WT-GSK-3 transfectants under hypoxic conditions, but not under normoxic conditions. Gastric cancer xenografts showed that tumor growth, microvessel area, HIF-1 activation, and VEGF expression were higher in KD-GSK-3 tumors than in WT-GSK-3 tumors in vivo. In addition, the expression of hypoxia-induced HIF-1 protein was regulated by GSK-3 at the translational level. Our data suggest that GSK-3 is involved in hypoxic adaptation of gastric cancer cells as an inhibitory upstream regulator of the HIF-1/VEGF signaling pathway.