TAZ促进胃癌中血管生成及相关机制的研究

TAZ promoting angiogenesis and its mechanism in gastric cancer

    摘要
  • 摘要:
      目的   探究Hippo通路关键效应分子TAZ在胃癌组织中的表达及其在胃癌血管生成中的作用。
      方法   通过免疫组织化学法分析150例胃癌组织标本中TAZ和β-catenin的表达情况；将TAZ过表达质粒及干扰质粒通过慢病毒分别转染至胃癌细胞系MGC803和MKN28中，通过细胞功能实验检测内皮细胞成管、增殖及迁移能力；使用Western blot法检测转染后的胃癌细胞中TAZ及β-catenin的表达情况；采用酶联免疫吸附试验（ELISA）检测TAZ转染后血管内皮生长因子（vascular endothelial growth factor，VEGF）蛋白表达的变化。
      结果   免疫组织化学法结果显示150例胃癌组织中，TAZ阳性表达64例（阳性率43%），主要定位于细胞核，其表达与肿瘤分级、TNM分期、转移及微血管密度（microvessel density，MVD）有关（P < 0.05）。此外，在TAZ阳性组中β-catenin阳性表达率为67.2%，明显高于TAZ阴性组，TAZ的表达与β-catenin呈正相关。在MKN28细胞系中上调TAZ的表达，与HUVEC细胞共培养后增强了内皮细胞增殖及管道形成能力，此外还通过促进β-catenin的表达，增强了内皮细胞的迁移能力；相反，在MGC803细胞系中下调TAZ的表达，与HUVEC共培养后减弱了内皮细胞增殖和管道形成能力，此外还通过降低β-catenin的表达，抑制了内皮细胞的迁移能力。
      结论  胃癌细胞TAZ的高表达可能通过促进β-catenin和VEGF的表达，进而增强胃癌血管生成能力。

     

    Abstract:
      Objective  To determine the expression of TAZ and its role in angiogenesis in gastric carcinoma.
      Methods  Immunohistochemical staining was performed to investigate the expression of TAZ and to determine whether a direct relationship exists between TAZ and β-catenin. Transfection with TAZ overexpression plasmid in MKN28 cells was conducted to induce exogenous expression of TAZ and a TAZ knockdown plasmid was transfected into MGC803 cells to reduce TAZ levels. The effects on endothelial cell formation, proliferation, and migration were determined by Matrigel three-dimensional culture, MTT proliferation assay and Transwell migration assay. In addition, the expression of TAZ and β-catenin in transfected gastric cancer cells was detected by Western blot.
      Results  Immunohistochemistry showed that TAZ protein was expressed in 64 of 150 gastric cancer sample tissues (43%), TAZ was localized in the nucleus, and its expression was associated with tumor grade, TNM stage, metastasis, and microvessel density (MVD) (P < 0.05). In addition, the expression frequency of β-catenin in the TAZ positive group was 67.2%, which was significantly higher than that in the TAZ negative group, and the expression of TAZ was positively correlated with β-catenin. After transfection, TAZ overexpression increased the expression of β-catenin and enhanced HUVECs tube formation, proliferation, and migration. In the MGC803 cells transfected with the knockdown plasmid, β-catenin levels were decreased and HUVECs motility was inhibited.
      Conclusions  TAZ may promote angiogenesis in gastric cancer by promoting β-catenin expression.

     

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