低氧诱导因子-1α促进人甲状腺未分化癌FRO细胞侵袭转移的分子机制

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目的探讨低氧诱导因子-1α(hypoxia-inducible factor-1α,HIF-1α)对人甲状腺未分化癌FRO细胞侵袭转移的影响,并探讨其分子机制。方法用5%O2的低氧培养箱培养FRO细胞不同时间(0、2、4、8、12 h),倒置显微镜下观察细胞形态的变化,Western blot法检测细胞中上皮间质转化(epithelial mesenchymal transition,EMT)相关蛋白HIF-1α、Snail、E-cadherin、Vimentin、MMP2的表达;另设FRO细胞常氧组、HIF-1α特异性抑制剂3-(5’-羟甲基-2’-呋喃基)-1-苯甲基吲哚(YC-1)+常氧组、YC-1+低氧组、常氧+HIF-1α激活剂氯化钴(CoCl2)组,采用Western blot法检测各组细胞中HIF-1α和EMT相关蛋白的表达,Transwell侵袭和迁移试验检测各组细胞的侵袭和迁移能力。结果随着低氧培养时间的延长,FRO细胞逐渐发生间质样改变,低氧12 hHIF-1α、Snail、Vimentin、MMP2蛋白的表达量较0 h显著升高(P<0.01),上皮细胞特征性蛋白E-cadherin的表达持续降低(P<0.01)。YC-1+低氧组与低氧组比较,HIF-1α、Snail、Vimentin、MMP2蛋白的表达量显著降低(P<0.01),E-cadherin蛋白的表达量显著升高(P<0.05)。低氧组和常氧+CoCl2组与常氧组比较,HIF-1α蛋白的表达量显著升高(P<0.01);常氧+CoCl2组与常氧组比较,Snail、Vimentin、MMP2蛋白的表达量显著升高(P<0.01),E-cadherin蛋白的表达量显著降低(P<0.01);常氧+CoCl2组与低氧组比较,HIF-1α、Snail、Vimentin蛋白的表达量显著升高(P<0.01),E-cadherin蛋白的表达量显著降低(P<0.01),MMP2蛋白的表达量差异无统计学意义(P>0.05)。低氧组和常氧+CoCl2组的穿膜细胞数和迁移细胞数均较常氧组显著增多(P<0.01)。结论低氧使FRO细胞中HIF-1α高表达,HIF-1α可上调Snail、Vimentin和MMP2的表达,下调E-cadherin的表达,对FRO细胞的侵袭转移具有促进作用。 Objective To investigate the effect of hypoxia-inducible factor-1α (HIF-1α) on the invasion and metastasis of human thyroid carcinoma cells (FRO), and to explore its molecular mechanism. Methods FRO cells were cultured in 5% O2 hypoxia incubator at different times (0, 2, 4, 8 and 12 h). The morphology of the cells was observed under inverted microscope. The expression of epithelial mesenchymal cells The expressions of HIF-1α, Snail, E-cadherin, Vimentin and MMP2 were detected by Western blotting in vitro. (YC-1) + normoxia group, YC-1 + hypoxia group and normoxia + HIF-1α activator cobalt chloride group (CoCl2) The expression of HIF-1alpha and EMT-related proteins in each group of cells, Transwell invasion and migration test to detect the invasion and migration of cells in each group. Results With the prolongation of hypoxia, the interstitial cells gradually changed in FRO cells. The expressions of HIF-1α, Snail, Vimentin and MMP2 in hypoxia group were significantly higher than those in 0h group (P <0.01) The expression of E-cadherin protein decreased continuously (P <0.01). The expression of HIF-1α, Snail, Vimentin and MMP2 in YC-1 + hypoxia group was significantly lower than that in hypoxia group (P <0.01), and the expression of E-cadherin protein was significantly increased (P <0.05). Compared with normoxia group, the expression of HIF-1αprotein was significantly increased in hypoxia group and normoxia + CoCl2 group (P <0.01); Compared with normoxia group, the expression of Snail, Vimentin and MMP2 (P <0.01), and the expression of E-cadherin protein was significantly decreased (P <0.01). Compared with hypoxia group, the expression of HIF-1α, Snail and Vimentin in normoxia + CoCl2 group was significantly increased (P <0.01), the expression of E-cadherin protein was significantly lower (P <0.01), and the expression of MMP2 protein was no significant difference (P> 0.05). The number of transmembrane cells and the number of migrating cells in hypoxia group and normoxia + CoCl2 group were significantly higher than those in normoxia group (P <0.01). Conclusion Hypoxia can up-regulate the expression of HIF-1α in FRO cells. HIF-1α up-regulates the expression of Snail, Vimentin and MMP2, and down-regulates the expression of E-cadherin, which may promote the invasion and metastasis of FRO cells.
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