Hypoxia-inducible factor-1α and Wnt/β-catenin signaling pathways promote the invasion of hypoxic gastric cancer cells.
Hypoxia-inducible factor-1α and Wnt/β-catenin signaling pathways promote the invasion of hypoxic gastric cancer cells.
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DOI：
10.3892/mmr.2015.3812
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发表时间：
2015-09
影响因子：
3.4
通讯作者：
Zhang JW
中科院分区：
文献类型：
--
作者：
Liu HL;Liu D;Ding GR;Liao PF;Zhang JW
本研究旨在探讨缺氧环境中缺氧诱导因子（HIF）-1α与Wnt/β-catenin信号通路的关系。本研究还探讨了缺氧胃癌细胞体外和体内侵袭的可能机制。将pcDNA™ 6.2-GW/EmGFP-miR-β-catenin质粒转染进SGC-7901胃癌细胞中，导致细胞具有稳定的β-catenin表达抑制。采用侵袭实验检测对照组、脂质体组、阴性对照组、β-catenin敲低组、缺氧组和缺氧β-catenin敲低组的生物学特性。对照组、阴性对照组和脂质体组的侵袭能力差异无统计学意义。低氧组大鼠的侵袭能力较对照组明显增强（P<0.05）。缺氧β-catenin基因敲低组的细胞穿透能力和侵袭能力明显降低（P<0.05）。缺氧组和双重（化学+物理）缺氧组HIF-1α、β-catenin、尿激酶型纤溶酶原激活物（uPA）和基质金属蛋白酶（MMP-7）蛋白和mRNA表达水平均升高。在低氧β-catenin敲低组和双重低氧β-catenin敲低组中，HIF-1α、β-catenin、uPA和MMP-7蛋白及mRNA表达水平均显著降低。在体内实验中，根据蛋白质印迹和免疫组织化学分析，低氧和对照细胞的异种移植肿瘤的生长速率高，同时HIF-1α、β-连环蛋白、uPA和MMP-7水平增加，而来自低氧β-连环蛋白敲低细胞的肿瘤的生长和蛋白质水平显著较低，并且β-连环蛋白敲低细胞的肿瘤的生长和蛋白质水平最低。总之，这些结果表明HIF-1α的激活能够调节Wnt/β-catenin通路，并且HIF-1α可能受Wnt/β-catenin通路的控制。SGC-7901致瘤性的潜在机制是激活Wnt/β-catenin信号通路，其激活uPA和MMP-7表达并有助于增强低氧癌细胞的侵袭。
The present study aimed to examine the association between hypoxia-inducible factor (HIF)-1α and the Wnt/β-catenin signaling pathway in a hypoxic environment. The study also aimed to explore the possible mechanisms underlying the invasion of hypoxic gastric cancer cells in vitro and in vivo. The pcDNA™ 6.2-GW/EmGFP-miR-β-catenin plasmid was transfected into SGC-7901 gastric cancer cells, resulting in cells with stable suppression of β-catenin expression. The biological characteristics of the control, liposome, negative control, β-catenin knockdown, hypoxia and hypoxia β-catenin knockdown groups were tested using an invasion assay. The differences in the invasive capacity of the control, negative control and liposome groups were not statistically significant. However, the hypoxia group demonstrated a significantly enhanced invasive capacity, as compared with that in the control group (P<0.05). In the hypoxia β-catenin knockdown group, reduced cell penetration and diminished invasive behavior was observed (P<0.05). In the hypoxia and double (chemical + physical) hypoxia groups, HIF-1α, β-catenin, urokinase-type plasminogen activator (uPA) and matrix metalloproteinase (MMP-7) protein and mRNA expression levels were elevated. In response to knockdown of β-catenin expression, HIF-1α, β-catenin, uPA and MMP-7 protein as well as mRNA expression levels were significantly reduced in the hypoxia β-catenin knockdown and the double hypoxia β-catenin knockdown groups. In an in vivo experiment, the growth rate of xenograft tumors of hypoxic and control cells was high alongside increased HIF-1α, β-catenin, uPA and MMP-7 levels according to western blot and immunohistochemical analyses, while growth and protein levels of tumors from hypoxic β-catenin knockdown cells were significantly lower and those of β-catenin knockdown cells were lowest. In conclusion, these results suggested that HIF-1α activation was able to regulate the Wnt/β-catenin pathway, and that HIF-1α may be controlled by the Wnt/β-catenin pathway. A potential mechanism underlying SGC-7901 tumorigenicity is the activation of the Wnt/β-catenin signaling pathway, which activates uPA and MMP-7 expression and contributes to the enhanced invasion of hypoxic cancer cells.